Source text

Pfizer Canada Inc. v. Teva Canada Limited
Court (s) Database
Federal Court Decisions
Date
2017-08-22
Neutral citation
2017 FC 777
File numbers
T-1399-15
Decision Content
Date: 20170922
Docket: T-1399-15
Citation: 2017 FC 777
Ottawa, Ontario, September 22, 2017
PRESENT: The Honourable Mr. Justice Brown
BETWEEN:
PFIZER CANADA INC. and WYETH LLC
Applicants
and
TEVA CANADA LIMITED 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 4
II. Procedural Note 5
III. Summary of Conclusions 6
IV. Facts 6
1. Witnesses 6
A. Pfizer 6
B. Teva 8
2. Background 8
3. The Invention Story 11
4. Invention story in more detail: the evidence of Pfizer’s Dr. Shah 15
5. Experimentation with ODV fumarate 18
6. Attempt to form pro-drug of ODV 20
7. Attempt to form an acceptable salt of ODV 21
8. Polymorph and crystal screening 25
9. Solubility 26
10. The Preparation of ODV Succinate 27
11. Permeability and bioavailability testing 29
12. |||||||||||||||||||||| 30
13. Rat perfusion test 30
14. Beagle dog testing 34
15. Human Testing 36
16. Solid state forms: crystallinity, amorphous solids, polymorphs 39
17. Polymorph screening and subcontracting polymorph screening to SSCI 40
18. Dr. Aeri Park at SSCI 42
19. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 49
20. Melting points and differential scanning calorimetry (DSC) 49
21. Further temperature studies and amorphous form 50
22. Hygroscopicity testing (a test relevant to drug stability) 51
23. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 52
24. |||||||||||||| (Crystal Form “C”) 52
25. |||||||||||||||||||||||| (Crystal Form “D”) 53
26. Work on other salt candidates and screens 55
V. Issues 56
VI. Statutory provisions and burden of proof 57
VII. Analysis 58
1. Relevant Dates 58
2. Claims Construction 59
3. Obviousness 64
A. Introductory comments and summary 64
B. The obviousness inquiry 65
C. Federal Court of Appeal Jurisprudence 76
D. Analysis of Obviousness 82
E. Identify the notional “person skilled in the art” 82
F. Identify the relevant common general knowledge of the Skilled Person 83
G. Identify the inventive concept of the claim in question or if that cannot readily be done, construe it 97
i. Claims 8 and 9 98
ii. Claim 33 100
iii. Claim 43 101
iv. Claim 44 102
H. 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 103
i. Claims 8 and 9 103
ii. Claim 33 104
iii. Claim 43 and 44 105
I. 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? 106
i. Apply the definition of obvious before Sanofi 107
ii. Consider the doctrine of obvious to try 111
J. 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? 113
K. 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? 125
L. Is there a motive provided in the prior art to find the solution the patent addresses? 127
M. The 668 Patent is not a selection patent 129
N. What is the course of conduct followed which culminated in making the invention? 131
i. Conclusions on obvious to try regarding Claims 8 and 9 134
ii. Conclusions on obvious to try regarding Claims 33, 43 and 44 134
O. Consideration of guidance of obvious to try analysis set out in Sanofi 135
P. Conclusion on obviousness 135
4. Utility 136
A. First identify the subject-matter of the invention as claimed in the patent, and second, is that subject-matter useful – is it capable of a practical purpose (i.e. an actual result) 141
B. Is Form I ODV succinate, the subject matter of Claims 8 and 9, useful - is it capable of a practical purpose (i.e. an actual result)? 141
C. Are the subject matters of Claims 33, 43 and 44 useful – are they capable of a practical purpose (i.e. an actual result)? 145
VIII. Conclusion 147
IX. Costs 148
X. Confidential Reasons 148
***
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 Teva Canada Ltd., [Teva or Respondent] to Pfizer Canada Inc., previously Wyeth LLC [Pfizer or Wyeth or Applicant], dated July 10, 2015, 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] Teva alleges that Claims 8, 9, 33, 43 and 44 of the 668 Patent fail for obviousness and lack of utility. Teva also alleges that the 668 Patent is an invalid selection patent. While Teva raised non-infringement and anticipation in its NOA, it withdrew those allegations.
[3] Teva also withdrew, on the 3rd day of this 5 day NOC, its allegation that Pfizer obtained the 668 patent as a result of having made wilfully misleading statements in its patent application, i.e., conduct tantamount to fraud, contrary to s 53 of the Patent Act, RSC 1985, c P-4.
II. Procedural Note
[4] As a procedural note, this case was argued before I heard argument in Pfizer Canada Inc and Wyeth LLC v Apotex Inc and The Minister of Health, in respect of which I will deliver reasons and judgment later today, 2017 FC 774. These two cases involve different NOAs filed by different second persons (Teva and Apotex), against the same first person (Pfizer) in respect of the same 688 Patent. While the invention story is essentially the same in both, the grounds of 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 resulting in additional repetition.
[5] As guidance for those reading both decisions, I should note that while obviousness and inutility are raised in both proceedings, Teva did not argue non-infringement, anticipation or double patenting as Apotex did in its proceeding. The parties in this Teva proceeding agree on the constructions of Claims 8 and 9, but there was no agreement on claims construction in the Apotex proceeding. Apotex in its proceeding also raised overpromising arising out of subsection 27(3) of the Patent Act as a ground of invalidity, an argument that Teva did not advance in this case.
III. Summary of Conclusions
[6] In the reasons that follow I find on a balance of probabilities that Teva’s allegations of invalidity due to obviousness and inutility are not justified. Therefore, Pfizer will have its Order of prohibition, together with costs on terms the parties have agreed upon.
IV. Facts
1. Witnesses
A. Pfizer
[7] Dr. 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 90s 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. He was offered as a fact witness.
[8] Dr. Allan Myerson is a Professor of the Practice of Chemical Engineering at the Massachusetts Institute of Technology (“MIT”). He is an expert in crystallization and the crystallization of pharmaceutical solids. He was on the SSCI advisory board from 2001 to 2006. He previously provided evidence regarding the corresponding US patent.
[9] Dr. Aeri Park is a former Principal at SSCI, Inc., the research laboratory hired by Wyeth to conduct polymorph and crystal 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. She is one of the named inventors on the 668 Patent. Dr. Park was offered as a fact witness.
[10] Dr. Leonard Chyall is the President of Chyall Pharmaceutical Consulting, LLC. He was formerly a Director at SSCI Inc. and had no direct involvement in the ODV succinate project. He trained under one of the inventors of the 668 Patent. He is an expert in solid state chemistry and has expertise in salt and polymorph screening and in the experimental and analytical techniques used to identify and characterize solid forms.
[11] Dr. 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 is an expert in pharmaceutics, pharmacokinetics and bioavailability.
B. Teva
[12] Dr. Fakhreddin Jamali is a Professor in the Faculty of Pharmacy and Pharmaceutical Sciences at the University of Alberta. He teaches, researches and practices in the field of pharmacy and pharmaceutical sciences. He has expertise in clinical pharmacology, including matters of pharmacokinetics, bioavailability and bioequivalence.
[13] Dr. Eugene F. Fiese is a consultant with Fiese Pharmaceutics Consulting. Dr. Fiese is a pharmaceutical chemist expert in the areas of preformulation, pharmaceutics research and dosage form development.
[14] Dr. Daniel Z. Lieberman is a Professor of Psychiatry and Behavioral Sciences and Clinical Director at George Washington University. He is a clinician who teaches, researches and practices psychiatry and has particular expertise in the treatment of mood disorders including depression.
2. Background
[15] The 668 Patent concerns a drug called o-desmethyl-venlafaxine, henceforth referred to as ODV. ODV is a serotonin and norepinephrine reuptake inhibitor [SNRI] which is indicated 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. 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. Pfizer argues and as will be seen, I have accepted that Form I ODV succinate is the subject of Claims 8 and 9, on which Claims 33, 43 and 44 depend.
[16] ODV is an active metabolite of ODV’s parent drug, venlafaxine. ODV is called a metabolite because when venlafaxine is administered, it is chemically modified in the body to form ODV; it is ODV that is responsible for delivering some or all of the pharmacological effect.
[17] It is common ground that ODV itself and its use as an antidepressant have been known for some time. Venlafaxine had been previously approved to treat depression, and was marketed by Wyeth and now Pfizer, Wyeth’s successor. Wyeth had ODV in hand since at least 1990. Wyeth 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 release version of venlafaxine (which also converts in the body to ODV). ODV is thus the API in both EFFEXOR and EFFEXOR XR.
[18] Both EFFEXOR and EFFEXOR XR contain venlafaxine hydrochloride which is a salt; venlafaxine hydrochloride is henceforth simply referred to as venlafaxine.
[19] ODV and “pharmaceutically acceptable salt forms thereof” were claimed in both US Patent No. 4,535,186 (US 186) Claim 22, issued in 1985, and in Canadian Patent No. 1,248,540 (CA 540), Claim 21, issued in 1989. CA 540 was granted to a predecessor company of the Applicant Wyeth, which predecessor company is also shown as an assignee of US 186.
[20] “Pharmaceutically acceptable salts” as the term is used in US 186 and CA 540, are made by reacting an acid and a base. ODV is a base; therefore, to make a salt an appropriate acid is required for such a reaction. Both US 186 and CA 540 claim ODV succinate as one of 11 “illustrative” pharmaceutically acceptable salts, and therefore include reference to reacting ODV with succinic acid. However, there is no suggestion that ODV succinate had ever been made, nor that a crystalline salt ODV succinate had ever been made, nor that Form I ODV succinate had ever been made it was made by Wyeth.
[21] In addition to disclosure in the Canadian (CA 540) and American (US 186) patents just mentioned, it is also 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. Again there is no suggestion that ODV succinate had ever been made, nor that a crystalline salt ODV succinate had ever been made, nor that Form I ODV succinate had ever been made before it was made by Wyeth.
[22] The prior art disclosed that venlafaxine as EFFEXOR or EFFEXOR XR and their metabolite ODV were useful to treat depression.
[23] Depression is and was also well known to be serious medical condition that can be and is often debilitating to those who suffer from it. 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.
3. The Invention Story
[24] The essence of the inventive story is also 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 in the dispute over utility. In my view it warrants being set out in some detail; I will first summarize it and then set it out in more detail.
[25] The inventive story as I have found it is generally drawn from the affidavit of Dr. Shah who was at Wyeth at the time and who was in charge of commercializing ODV generally and then commercializing ODV succinate. The inventive story is also taken from the affidavit of Dr. Park who was in charge of polymorph screening of ODV succinate at a specialized company that performed polymorph screening for Wyeth, namely, SSCI, Inc. [SSCI].
[26] 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 to which they depose. I appreciate that they are both named inventors on the 668 Patent, but am not persuaded this affected their evidence whether by affidavit or in cross-examination.
[27] Wyeth, now Pfizer, had venlafaxine and also knew that ODV was an active metabolite of venlafaxine. Wyeth through a predecessor company (together referred to as Wyeth) and Pfizer marketed venlafaxine as EFFEXOR and EFFEXOR XR. EFFEXOR delivered venlafaxine immediately, but for many patients 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 patients 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 extended or 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.
[28] 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, and in particular on the liver, to be converted into ODV, venlafaxine’s metabolite, which then acted as the anti-depressant in the body and more particularly in the brain.
[29] The new ODV drug which 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 an oral dose involves permeating the GI tract.
[30] The searched-for new ODV drug had to be a stable, that is, it had to be 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.
[31] The searched-for drug had to be a drug that would dissolve in the gastrointestinal [GI] tract i.e., 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.
[32] 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.
[33] In summary, over some two years - with greatly increased activity towards the end - experimentation and drug development was conducted, initially by Wyeth, and then by Wyeth together with I consider a specialized contract laboratory, SSCI. Employees of both Wyeth and SSCI are named inventors on the 668 Patent.
[34] Wyeth and SSCI eventually identified a solid crystalline form of ODV that appeared to be stable, soluble 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 made or disclosed before it was created by Wyeth.
[35] In this connection it is worth noting that while Teva alleged anticipation in its NOA, it subsequently withdrew that allegation. Therefore, in this proceeding it is not disputed that Form I ODV succinate is a “new” composition of matter per s 2 of the Patent Act’s definition of “invention.”
[36] 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 that it would have been impossible for the Skilled Person to 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 would be in terms of stability, solubility, permeability and bioavailability and adverse effects; none of this would be known without conducting doing empirical research.
[37] 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. 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. The work done by SSCI entailed a different type of screening, known as polymorph or crystal screening. Pfizer and Teva 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).
[38] Wyeth not only created the Form I ODV succinate salt, but went further and discovered and created the new crystalline Form I ODV succinate claimed in Claims 8 and 9 of the 668 Patent. Wyeth however did not know that the crystal it created |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| SSCI found another three crystalline and one amorphous forms of ODV succinate in addition to crystalline Form I ODV succinate relied upon by Pfizer in Claims 8 and 9 of the 668 Patent.
[39] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 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.
4. Invention story in more detail: the evidence of Pfizer’s Dr. Shah
[40] 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.
[41] 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. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
[42] Wyeth was also interested in improving patient compliance, that is, improving the chances of patients actually taking the medication as prescribed, and potential to reduce 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.
[43] Wyeth’s invention story had several components in addition to this background knowledge.
[44] Initially, Wyeth worked with ODV fumarate, a known salt form of ODV, but without success.
[45] Wyeth also attempted to make a pro-drug of ODV, again without success.
[46] In addition, and previously, Wyeth had worked with a number of other salt forms of ODV, but without success.
[47] 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. 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 the 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.
[48] 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.
[49] 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. The following outlines these steps in more detail.
5. Experimentation with ODV fumarate
[50] 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; as Teva notes, ODV fumarate was disclosed as Example 26 of US 186 as a crystalline salt.
[51] However, ODV fumarate had problems with bioavailability. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
[52] Teva disputes Pfizer’s assertion that ODV fumarate was unsuitable because |||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
[53] 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. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
[54] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||, 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 from its acid when it ceased to be a salt form in the GI tract, the same dissociation could obtain with other salts. Therefore if the dissociated drug ODV did not do well in terms of bioavailability when orally dosed as ODV fumarate, it was unclear why another salt form of ODV might behave better once dissociated from ODV itself:
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||
Affidavit of Dr. Shah, para 22
[55] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||
6. Attempt to form pro-drug of ODV
[56] Wyeth 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. Depending on the modifications that are made, the pro-drug may have improved solubility, dissolution or absorption over the active molecule.
[57] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
[58] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| That said, I accept as a fact that Wyeth did pursue pro-drug development in relation to ODV.
7. Attempt to form an acceptable salt of ODV
[59] The third option contemplated by Wyeth (after the fumarate salt and pro-drugs) 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.
[60] I also accept that it was known, as indeed was 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.
[61] ODV is a base. To attempt to make a salt with ODV, it was therefore necessary to interact ODV with an acceptable acid.
[62] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 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.
[63] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||

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Pfizer Canada Inc. v. Teva Canada Limited Court (s) Database Federal Court Decisions Date 2017-08-22 Neutral citation 2017 FC 777 File numbers T-1399-15 Decision Content Date: 20170922 Docket: T-1399-15 Citation: 2017 FC 777 Ottawa, Ontario, September 22, 2017 PRESENT: The Honourable Mr. Justice Brown BETWEEN: PFIZER CANADA INC. and WYETH LLC Applicants and TEVA CANADA LIMITED 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 4 II. Procedural Note 5 III. Summary of Conclusions 6 IV. Facts 6 1. Witnesses 6 A. Pfizer 6 B. Teva 8 2. Background 8 3. The Invention Story 11 4. Invention story in more detail: the evidence of Pfizer’s Dr. Shah 15 5. Experimentation with ODV fumarate 18 6. Attempt to form pro-drug of ODV 20 7. Attempt to form an acceptable salt of ODV 21 8. Polymorph and crystal screening 25 9. Solubility 26 10. The Preparation of ODV Succinate 27 11. Permeability and bioavailability testing 29 12. |||||||||||||||||||||| 30 13. Rat perfusion test 30 14. Beagle dog testing 34 15. Human Testing 36 16. Solid state forms: crystallinity, amorphous solids, polymorphs 39 17. Polymorph screening and subcontracting polymorph screening to SSCI 40 18. Dr. Aeri Park at SSCI 42 19. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 49 20. Melting points and differential scanning calorimetry (DSC) 49 21. Further temperature studies and amorphous form 50 22. Hygroscopicity testing (a test relevant to drug stability) 51 23. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 52 24. |||||||||||||| (Crystal Form “C”) 52 25. |||||||||||||||||||||||| (Crystal Form “D”) 53 26. Work on other salt candidates and screens 55 V. Issues 56 VI. Statutory provisions and burden of proof 57 VII. Analysis 58 1. Relevant Dates 58 2. Claims Construction 59 3. Obviousness 64 A. Introductory comments and summary 64 B. The obviousness inquiry 65 C. Federal Court of Appeal Jurisprudence 76 D. Analysis of Obviousness 82 E. Identify the notional “person skilled in the art” 82 F. Identify the relevant common general knowledge of the Skilled Person 83 G. Identify the inventive concept of the claim in question or if that cannot readily be done, construe it 97 i. Claims 8 and 9 98 ii. Claim 33 100 iii. Claim 43 101 iv. Claim 44 102 H. 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 103 i. Claims 8 and 9 103 ii. Claim 33 104 iii. Claim 43 and 44 105 I. 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? 106 i. Apply the definition of obvious before Sanofi 107 ii. Consider the doctrine of obvious to try 111 J. 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? 113 K. 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? 125 L. Is there a motive provided in the prior art to find the solution the patent addresses? 127 M. The 668 Patent is not a selection patent 129 N. What is the course of conduct followed which culminated in making the invention? 131 i. Conclusions on obvious to try regarding Claims 8 and 9 134 ii. Conclusions on obvious to try regarding Claims 33, 43 and 44 134 O. Consideration of guidance of obvious to try analysis set out in Sanofi 135 P. Conclusion on obviousness 135 4. Utility 136 A. First identify the subject-matter of the invention as claimed in the patent, and second, is that subject-matter useful – is it capable of a practical purpose (i.e. an actual result) 141 B. Is Form I ODV succinate, the subject matter of Claims 8 and 9, useful - is it capable of a practical purpose (i.e. an actual result)? 141 C. Are the subject matters of Claims 33, 43 and 44 useful – are they capable of a practical purpose (i.e. an actual result)? 145 VIII. Conclusion 147 IX. Costs 148 X. Confidential Reasons 148 *** 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 Teva Canada Ltd., [Teva or Respondent] to Pfizer Canada Inc., previously Wyeth LLC [Pfizer or Wyeth or Applicant], dated July 10, 2015, 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] Teva alleges that Claims 8, 9, 33, 43 and 44 of the 668 Patent fail for obviousness and lack of utility. Teva also alleges that the 668 Patent is an invalid selection patent. While Teva raised non-infringement and anticipation in its NOA, it withdrew those allegations. [3] Teva also withdrew, on the 3rd day of this 5 day NOC, its allegation that Pfizer obtained the 668 patent as a result of having made wilfully misleading statements in its patent application, i.e., conduct tantamount to fraud, contrary to s 53 of the Patent Act, RSC 1985, c P-4. II. Procedural Note [4] As a procedural note, this case was argued before I heard argument in Pfizer Canada Inc and Wyeth LLC v Apotex Inc and The Minister of Health, in respect of which I will deliver reasons and judgment later today, 2017 FC 774. These two cases involve different NOAs filed by different second persons (Teva and Apotex), against the same first person (Pfizer) in respect of the same 688 Patent. While the invention story is essentially the same in both, the grounds of 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 resulting in additional repetition. [5] As guidance for those reading both decisions, I should note that while obviousness and inutility are raised in both proceedings, Teva did not argue non-infringement, anticipation or double patenting as Apotex did in its proceeding. The parties in this Teva proceeding agree on the constructions of Claims 8 and 9, but there was no agreement on claims construction in the Apotex proceeding. Apotex in its proceeding also raised overpromising arising out of subsection 27(3) of the Patent Act as a ground of invalidity, an argument that Teva did not advance in this case. III. Summary of Conclusions [6] In the reasons that follow I find on a balance of probabilities that Teva’s allegations of invalidity due to obviousness and inutility are not justified. Therefore, Pfizer will have its Order of prohibition, together with costs on terms the parties have agreed upon. IV. Facts 1. Witnesses A. Pfizer [7] Dr. 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 90s 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. He was offered as a fact witness. [8] Dr. Allan Myerson is a Professor of the Practice of Chemical Engineering at the Massachusetts Institute of Technology (“MIT”). He is an expert in crystallization and the crystallization of pharmaceutical solids. He was on the SSCI advisory board from 2001 to 2006. He previously provided evidence regarding the corresponding US patent. [9] Dr. Aeri Park is a former Principal at SSCI, Inc., the research laboratory hired by Wyeth to conduct polymorph and crystal 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. She is one of the named inventors on the 668 Patent. Dr. Park was offered as a fact witness. [10] Dr. Leonard Chyall is the President of Chyall Pharmaceutical Consulting, LLC. He was formerly a Director at SSCI Inc. and had no direct involvement in the ODV succinate project. He trained under one of the inventors of the 668 Patent. He is an expert in solid state chemistry and has expertise in salt and polymorph screening and in the experimental and analytical techniques used to identify and characterize solid forms. [11] Dr. 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 is an expert in pharmaceutics, pharmacokinetics and bioavailability. B. Teva [12] Dr. Fakhreddin Jamali is a Professor in the Faculty of Pharmacy and Pharmaceutical Sciences at the University of Alberta. He teaches, researches and practices in the field of pharmacy and pharmaceutical sciences. He has expertise in clinical pharmacology, including matters of pharmacokinetics, bioavailability and bioequivalence. [13] Dr. Eugene F. Fiese is a consultant with Fiese Pharmaceutics Consulting. Dr. Fiese is a pharmaceutical chemist expert in the areas of preformulation, pharmaceutics research and dosage form development. [14] Dr. Daniel Z. Lieberman is a Professor of Psychiatry and Behavioral Sciences and Clinical Director at George Washington University. He is a clinician who teaches, researches and practices psychiatry and has particular expertise in the treatment of mood disorders including depression. 2. Background [15] The 668 Patent concerns a drug called o-desmethyl-venlafaxine, henceforth referred to as ODV. ODV is a serotonin and norepinephrine reuptake inhibitor [SNRI] which is indicated 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. 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. Pfizer argues and as will be seen, I have accepted that Form I ODV succinate is the subject of Claims 8 and 9, on which Claims 33, 43 and 44 depend. [16] ODV is an active metabolite of ODV’s parent drug, venlafaxine. ODV is called a metabolite because when venlafaxine is administered, it is chemically modified in the body to form ODV; it is ODV that is responsible for delivering some or all of the pharmacological effect. [17] It is common ground that ODV itself and its use as an antidepressant have been known for some time. Venlafaxine had been previously approved to treat depression, and was marketed by Wyeth and now Pfizer, Wyeth’s successor. Wyeth had ODV in hand since at least 1990. Wyeth 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 release version of venlafaxine (which also converts in the body to ODV). ODV is thus the API in both EFFEXOR and EFFEXOR XR. [18] Both EFFEXOR and EFFEXOR XR contain venlafaxine hydrochloride which is a salt; venlafaxine hydrochloride is henceforth simply referred to as venlafaxine. [19] ODV and “pharmaceutically acceptable salt forms thereof” were claimed in both US Patent No. 4,535,186 (US 186) Claim 22, issued in 1985, and in Canadian Patent No. 1,248,540 (CA 540), Claim 21, issued in 1989. CA 540 was granted to a predecessor company of the Applicant Wyeth, which predecessor company is also shown as an assignee of US 186. [20] “Pharmaceutically acceptable salts” as the term is used in US 186 and CA 540, are made by reacting an acid and a base. ODV is a base; therefore, to make a salt an appropriate acid is required for such a reaction. Both US 186 and CA 540 claim ODV succinate as one of 11 “illustrative” pharmaceutically acceptable salts, and therefore include reference to reacting ODV with succinic acid. However, there is no suggestion that ODV succinate had ever been made, nor that a crystalline salt ODV succinate had ever been made, nor that Form I ODV succinate had ever been made it was made by Wyeth. [21] In addition to disclosure in the Canadian (CA 540) and American (US 186) patents just mentioned, it is also 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. Again there is no suggestion that ODV succinate had ever been made, nor that a crystalline salt ODV succinate had ever been made, nor that Form I ODV succinate had ever been made before it was made by Wyeth. [22] The prior art disclosed that venlafaxine as EFFEXOR or EFFEXOR XR and their metabolite ODV were useful to treat depression. [23] Depression is and was also well known to be serious medical condition that can be and is often debilitating to those who suffer from it. 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. 3. The Invention Story [24] The essence of the inventive story is also 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 in the dispute over utility. In my view it warrants being set out in some detail; I will first summarize it and then set it out in more detail. [25] The inventive story as I have found it is generally drawn from the affidavit of Dr. Shah who was at Wyeth at the time and who was in charge of commercializing ODV generally and then commercializing ODV succinate. The inventive story is also taken from the affidavit of Dr. Park who was in charge of polymorph screening of ODV succinate at a specialized company that performed polymorph screening for Wyeth, namely, SSCI, Inc. [SSCI]. [26] 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 to which they depose. I appreciate that they are both named inventors on the 668 Patent, but am not persuaded this affected their evidence whether by affidavit or in cross-examination. [27] Wyeth, now Pfizer, had venlafaxine and also knew that ODV was an active metabolite of venlafaxine. Wyeth through a predecessor company (together referred to as Wyeth) and Pfizer marketed venlafaxine as EFFEXOR and EFFEXOR XR. EFFEXOR delivered venlafaxine immediately, but for many patients 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 patients 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 extended or 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. [28] 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, and in particular on the liver, to be converted into ODV, venlafaxine’s metabolite, which then acted as the anti-depressant in the body and more particularly in the brain. [29] The new ODV drug which 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 an oral dose involves permeating the GI tract. [30] The searched-for new ODV drug had to be a stable, that is, it had to be 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. [31] The searched-for drug had to be a drug that would dissolve in the gastrointestinal [GI] tract i.e., 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. [32] 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. [33] In summary, over some two years - with greatly increased activity towards the end - experimentation and drug development was conducted, initially by Wyeth, and then by Wyeth together with I consider a specialized contract laboratory, SSCI. Employees of both Wyeth and SSCI are named inventors on the 668 Patent. [34] Wyeth and SSCI eventually identified a solid crystalline form of ODV that appeared to be stable, soluble 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 made or disclosed before it was created by Wyeth. [35] In this connection it is worth noting that while Teva alleged anticipation in its NOA, it subsequently withdrew that allegation. Therefore, in this proceeding it is not disputed that Form I ODV succinate is a “new” composition of matter per s 2 of the Patent Act’s definition of “invention.” [36] 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 that it would have been impossible for the Skilled Person to 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 would be in terms of stability, solubility, permeability and bioavailability and adverse effects; none of this would be known without conducting doing empirical research. [37] 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. 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. The work done by SSCI entailed a different type of screening, known as polymorph or crystal screening. Pfizer and Teva 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). [38] Wyeth not only created the Form I ODV succinate salt, but went further and discovered and created the new crystalline Form I ODV succinate claimed in Claims 8 and 9 of the 668 Patent. Wyeth however did not know that the crystal it created |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| SSCI found another three crystalline and one amorphous forms of ODV succinate in addition to crystalline Form I ODV succinate relied upon by Pfizer in Claims 8 and 9 of the 668 Patent. [39] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 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. 4. Invention story in more detail: the evidence of Pfizer’s Dr. Shah [40] 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. [41] 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. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| [42] Wyeth was also interested in improving patient compliance, that is, improving the chances of patients actually taking the medication as prescribed, and potential to reduce 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. [43] Wyeth’s invention story had several components in addition to this background knowledge. [44] Initially, Wyeth worked with ODV fumarate, a known salt form of ODV, but without success. [45] Wyeth also attempted to make a pro-drug of ODV, again without success. [46] In addition, and previously, Wyeth had worked with a number of other salt forms of ODV, but without success. [47] 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. 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 the 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. [48] 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. [49] 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. The following outlines these steps in more detail. 5. Experimentation with ODV fumarate [50] 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; as Teva notes, ODV fumarate was disclosed as Example 26 of US 186 as a crystalline salt. [51] However, ODV fumarate had problems with bioavailability. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 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|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| [53] 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. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||| [54] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||, 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 from its acid when it ceased to be a salt form in the GI tract, the same dissociation could obtain with other salts. Therefore if the dissociated drug ODV did not do well in terms of bioavailability when orally dosed as ODV fumarate, it was unclear why another salt form of ODV might behave better once dissociated from ODV itself: |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||| Affidavit of Dr. Shah, para 22 [55] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||| 6. Attempt to form pro-drug of ODV [56] Wyeth 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. Depending on the modifications that are made, the pro-drug may have improved solubility, dissolution or absorption over the active molecule. [57] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| [58] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| That said, I accept as a fact that Wyeth did pursue pro-drug development in relation to ODV. 7. Attempt to form an acceptable salt of ODV [59] The third option contemplated by Wyeth (after the fumarate salt and pro-drugs) 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. [60] I also accept that it was known, as indeed was 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. [61] ODV is a base. To attempt to make a salt with ODV, it was therefore necessary to interact ODV with an acceptable acid. [62] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 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. [63] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||

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