Pfizer Canada Inc. v. Mylan Pharmaceuticals ULC

Pfizer Canada Inc. v. Mylan Pharmaceuticals ULC
Court (s) Database
Federal Court Decisions
Date
2011-05-12
Neutral citation
2011 FC 547
File numbers
T-1118-09
Decision Content
Federal Court
Cour fédérale
Date: 20110512
Docket: T-1118-09
Citation: 2011 FC 547
Ottawa, Ontario, May 12, 2011
PRESENT: The Honourable Mr. Justice Hughes
BETWEEN:
PFIZER CANADA INC.
and EISAI CO., LTD.
Applicants
and
MYLAN PHARMACEUTICALS ULC and
THE MINISTER OF HEALTH
Respondents
REASONS FOR JUDGMENT AND JUDGMENT
[1] This is an application for prohibition brought under the Patented Medicines (Notice of Compliance) Regulations SOR/93-133, as amended (NOC Regulations). The medicine at issue is a new compound known as donepezil, which is said to be useful in treating senile dementia. The Applicant Pfizer Canada Inc. has approval from the Respondent Minister of Health to sell in Canada a drug incorporating donepezil hydrochloride in tablet form for oral administration in 5 mg and 10 mg doses. This drug is approved for a use described as symptomatic treatment of patients with mild, moderate and severe dementia of the Alzheimer’s type.
[2] The Respondents (other than the Minister) which I will refer to as Mylan, have sought approval from the Minister in the form of a Notice of Compliance to sell a generic version of that drug in Canada. The Applicants seek an Order prohibiting the Minister from giving that approval until the expiry of Canadian Patent No. 1,338,808.
[3] For the reasons that follow, I find that the application is allowed and the Minister is prohibited from issuing a Notice of Compliance to Mylan until after the expiry of Canadian Patent No. l,338,808.
INDEXING
[4] For convenience, the matters considered in these Reasons can be found at the following paragraphs:
THE PARTIES Paras 5 to 9
SENILE DEMENTIA – ALZHEIMER’S Paras 10 to 13
DEVELOPMENTS AT EISAI Paras 14 to 17
CANADIAN PATENT NO. 1,338,808 Paras 18 to 34
ISSUES Para 35
EVIDENCE Paras 36 to 40
EVIDENCE OF THE EXPERTS Paras 41 to 42
APPLICANTS’ EXPERTS Paras 43 to 134
MYLAN’S EXPERT Paras 135 to 183
NOC PROCEEDINGS Paras 184 to 187
BURDEN OF PROOF Para 188
PERSON SKILLED IN THE ART Paras 189
CLAIMS 6 AND 18 – CONSTRUCTION Paras 190 to 193
THE '808 PATENT – ACCURACY OF DISCLOSURE Paras 194 to 198
UTILITY – PROMISE OF THE PATENT – Paras 199 to 231
SOUND PREDICTION
1) Utility
a) Requirement for Utility paras 201 to 202
b) What is “Useful” paras 203 to 211
c) Useful for What – Promise of the Patent paras 212 to 217
d) Care in Using Expert Evidence in
Matters of Construction paras 218 to 224
e) Achieved Utility or Predicted Utility paras 225 to 228
f) Relevant Date paras 229 to 231
CONSTRUCTION OF THE PROMISE OR Paras 232 to 237
STATED UTILITY OF THE '808 PATENT
SOUND PREDICTION Paras 238 to 248
CONCLUSION AND COSTS Paras 249 to 251
THE PARTIES
[5] The Applicant Pfizer Inc. is referred to as a “first person” in the NOC Regulations. It has received approval to sell the drug containing donepezil, as previously described, from the Respondent Minister of Health. It sells that drug in Canada under the brand name ARICEPT.
[6] The Applicant Eisai Co., Ltd. is a Japanese corporate organization to whom Canadian Patent No. 1,338,808 was issued and granted on December 24, 1996. As far as the record shows, Eisai remains as the owner of that patent (patentee). Under the provisions of section 6(4) of the NOC Regulations, the patentee must be joined as a party to these proceedings
[7] The Respondents previously described as Genpharm ULC and Mylan Pharmaceuticals ULC have been the subject of a previous motion heard by Prothonotary Aalto (2010 FC 684) with an appeal heard by Justice Heneghan with reasons released March 29, 2011. The effect of the decision, as affirmed on appeal, was to strike out certain portions of the Applicants’ Notice of Application challenging the status of Genpharm LLC as a “second person” under the NOC Regulations. The Prothonotary and the Judge reviewed the recent corporate history of both entities, including an amalgamation and name change to Mylan. Prothonotary Aalto wrote at paragraph 5 of his Reasons:
5 In order to understand the issue better a brief chronology is helpful. The following sets out the chronology giving rise to the corporate issue which Pfizer has put in play:
December 21/07
Genpharm ULC is continued under the Alberta Business Corporations Act ("ABCA");
December 23/08
Genpharm ULC files its ANDS with the Minister;
January 1/09
Genpharm ULC amalgamates with Prempharm ULC under the ABCA and continues under the name Genpharm ULC;
April 24/09
Registered amendment of the name of Genpharm ULC to Mylan;
May 27/09
NOA is sent to Pfizer;
June 18/09
Proof of service of the NOA on Pfizer is sent to the Minister;
June 29/09
Pfizer conducts a corporate search of Genpharm ULC;
July 10/09
The Notice of Application is issued by Pfizer;
July 14/09
Pfizer serves Genpharm;
October 1/09
Genpharm officially adopts the Mylan name;
December/09
Mylan files information with the Minister to effect a name change from Genpharm ULC to Mylan Pharmaceuticals ULC
[8] Prothonotary Aalto, and on appeal, Justice Heneghan, both concluded that the Applicants’ challenge to the status of the resulting entity, Mylan as a “second person” under the NOC Regulations should be struck out. Therefore, I will refer to these parties collectively under the name Mylan. They are a “second person” as referred to in the NOC Regulations. By an Order made on consent the style of cause was amended at the hearing to identify the corporate Respondent simply as Mylan Pharmaceuticals ULC.
[9] The Respondent Minister of Health is responsible for approving drugs such as that at issue for sale in Canada by way of issuing a Notice of Compliance under the NOC Regulations. The Minister had notice of these proceedings but did not actively participate.
SENILE DEMENTIA – ALZHEIMER’S
[10] A clinician named Alois Alzheimer working in a Frankfurt hospital in 1901 recognized and subsequently described a condition suffered by a patient who was experiencing difficulties naming familiar objects, writing complete sentences and remembering words. That condition, which is a particular type of senile dementia, is now known as Alzheimer’s, or Alzheimer, or AD. It particularly affects older persons. Memory loss is an early sign of the onset of the condition, followed by more severe symptoms and, ultimately, the death of the person suffering from that condition.
[11] In the 1980’s, which is the period in question, there appear to have been a number of theories as to the causes of Alzheimer’s. One such theory dealt with the effect of what was described as cholinergic function in the brain. Efforts were made to inhibit that function. I repeat the evidence as set out in paragraphs 38 to 43 of the affidavit of Dr. Becker, a Mylan expert. At the hearing, the Applicants’ Counsel stated that the Applicants accepted this evidence:
38. AD is a degenerative disease to the brain. As stated above, in the 1980s, AD was frequently called senile dementia or senile dementia of the Alzheimer’s type (SDAT). The cause of AD was not known in the 1980s and it is still unknown today.
39. However, in the 1980s, there was evidence that a deficiency of cholinergic function played a major role in the development of the symptoms of AD and of the disease itself.
40. In the 1980s, cholinergic function was thought to be involved in AD as follows:
(a) Cholinergic function relevant to learning and memory depended upon cell bodies (cholinergic neurons) located in the base of the front of the brain (basal forebrain in the Nucleus Basalis of Meynert).
(b) These cholinergic neurons in the basal forebrain undergo profound selective damage and death in AD patients.
(c) These cholinergic neurons have long projections called axons throughout wide areas of the brain.
(d) These projections or axons provide acetylcholine required for proper functioning throughout the brain.
(e) Due to the damage and death of the neurons in the basal forebrain, there is a deficiency of the enzyme acetylcholine transferase (the enzyme that makes acetylcholine). As a result, there is a deficiency of acetylcholine in many areas of the brain.
(f) This deficiency of acetylcholine was thought to account for the problems with learning and memory seen in AD patients.
41. Accordingly, researchers set about to compensate for lost acetylcholine function in the brain to cure or alleviate the symptoms of AD.
42. One approach taken was to modulate the effect of cholinesterases that inactivated acetylcholine in the brain. The approach was to try to inhibit the effect of cholinesterase, such as acetylcholinesterase, using compounds known as “inhibitors”. Inhibitors act by various mechanisms, but in general, they either “block” the cholinesterase enzymes from having access to acetylcholine or they “inactivate” the cholinesterease itself. As a result of either of these actions, because the enzyme acetylcholinesterase can no longer break down acetycholine, there is increased acetylcholine in the synapse, hypothesized to restore neurotransmission function to more normal conditions.
43. Two of the most widely studied drugs in the 1980s were physostigmine and tetrahydrominoacrydine (“THA”). Both physostigmine and THA act by blocking cholinesterase enzymes from having access to acetylcholine. These compounds were of interest because some improvement in learning and memory in AD patients was seen with the administration of these and similar compounds in humans. However, having this basic acetylcholinesterase inhibitory activity did not render physostigmine and THA suitable as therapeutic agents for AD.
[12] There emerged in the mid 1980’s what became known as the “cholinergic hypothesis”, which hypothesized that if acetylcholinesterase (AChE) inhibitors could be introduced into the appropriate area of the brain, the symptoms of Alzheimer’s may be alleviated. To be introduced into the appropriate area, a compound would be required to cross what was described as the Blood Brain Barrier (BBB). By June 1988, two particular compounds were known and being studied for this purpose, physostigmine and tacrine (THA). These compounds appeared to work as AChE inhibitors but had drawbacks. Physostigmine had a short duration of action and certain undesirable side effects. Tacrine exhibited liver toxicity at higher doses.
[13] In November 1986, The New England Journal of Medicine, a respected journal, published a paper by Dr. Summers and others in which there was reported a study conducted on a number of patients who were administered dosages of an AChE inhibitor. There was a dispute between the experts in this case as to how widely respected this paper was, and whether the reported results could be considered valid. In this particular proceeding, not much turns on this dispute. It was an early attempt to report on the effects of an AChE inhibitor. It simply indicates that the theory of AChE inhibitors was being pursued in research at the time.
DEVELOPMENTS AT EISAI
[14] According to the evidence of two of the persons named as inventors in the '808 Patent (Araki and Ogura) and two other persons associated with them in the development of donepezil and related compounds (Sumigama and Yamakawa) work began at Eisai in the 1980’s to develop a drug for the treatment of senile dementia such as Alzheimer’s. Many compounds were made and tested. The testing included tests on mouse and rat brain homologates and on live rats, some of which testing is set out in the '808 Patent. Much other testing was done which was not set out in the patent. As of the date that the Canadian patent application was filed, June 21, 1988, no testing had been conducted on human beings.
[15] A substantial report setting out the development of these compounds and conclusions reached by the researchers was prepared and submitted to Eisai management on about January 28, 1988. It is called, in these proceedings, the Chosa Hokoku Proposal. This report has not been made public and contains details of a number of studies beyond those which are set out in the '808 Patent.
[16] In the opening portion of this report entitled Theme Outline, the following is stated (English translation)with respect to the compound we now call donepezil:
Thereafter, we came to study the possibility of commoditizing it as a drug based on drug efficacy, metabolism, safety, and formulation. As a result, it became clear that the compound in question has a strong action of improving learning impairment based on a clear mechanism of action and that it has utility that is superior to that of physostigmine or THA. In addition, it was also proven that it has a duration of action, safety margin, and bioavailability, etc., that are far superior to those of the control drugs, it completely satisfies the theme profile, and it has nearly ideal characteristics of action. Furthermore, no toxic changes in the liver or kidneys, etc., whatsoever were recognized in the results of the Step 2 Exploratory Toxicity trials, and it was found that it has superior safety in comparison with THA.
Based on the above, it is expected that ENAG could be a drug that is extremely useful clinically as an agent for the improvement of intellectual dysfunction that accompanies senile dementia of Alzheimer type, and so we propose the Chōsa Hōkoku herein.
[17] Today as we know donepezil is approved for sale and marketed by Pfizer in Canada for the treatment of Alzheimer’s.
CANADIAN PATENT NO. 1,338,808
[18] There remains only one patent at issue, Canadian Patent No. 1,338,808 (the '808 Patent). The application for this patent was filed with the Canadian Patent Office on June 21, 1988, which means that the provisions of the “old” Patent Act, R.S.C. 1985, c. P-4 pertain to that application and the resulting '808 Patent, as the application was filed before October 1, 1989.
[19] Among the matters pertinent to the '808 Patent under the “old” Patent Act are that the patent endures for a period of seventeen (17) years from the date of its grant unless held to be invalid in an appropriate action (not an NOC proceeding). The term of the '808 Patent expires December 24, 2013.
[20] The '808 Patent is entitled “Cyclic Amine Compound” and lists thirteen (13) persons as inventors. Among them are Hiroo Ogura and Shin Araki, both of whom gave evidence in these proceedings.
[21] In the present case, the Applicants are relying on only two claims of the '808 Patent, claim 6 and claim 18 to the extent that it incorporates claim 6.
[22] Claims 6 and 18 read as follows:
6. The compound 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl] methylpiperidine or a pharmaceutically acceptable acid addition salt thereof.
. . .
18. A therapeutical composition for treating senile dementia, which comprises an acetylchlolinesterase inhibitory effective amount of the compound or salt as defined in any one of claims 1 through 17 and a pharmaceutically acceptable carrier.
[23] The chemical formula set out in claim 6 is referred to by the parties more simply as donepezil. With the incorporation of a hydrochloride salt as the pharmaceutically acceptable acid addition salt the compound is referred to as donepezil hydrochloride. Thus, for simplicity, claims 6 and 18 can be written as:
6. The compound donepezil or donepezil hydrochloride.
. . .
18. A therapeutical composition for treating senile dementia, which comprises donepezil or donepezil hydrochloride and a pharmaceutically acceptable carrier.
[24] The specification of the '808 Patent begins at page 1 with a brief statement as to the field of the invention:
Cyclic Amine Compound
The invention relates to a cyclic amine compound, a therapeutical composition and medical treatment of senile dementia.
[25] Following next is a Statement of Prior Arts, which continues over to page 2:
(Statement of Prior Arts)
With a rapid increase in the population of aged people, the establishment of the therapy for senile dementia, such as Alzheimer senile dementia, is eagerly desired.
Various attempts have been made to treat the senile dementia with a drug. So far, however, there has been no drug which is very useful for the treatment of these diseases.
Studies on the development of therapeutic agents for these diseases have been made from various aspects. Particularly, since Alzheimer senile dementia is accompanied by the lowering in cholinergic hypofunction, the development of the therapeutic agent from the aspect of an acetylcholine precursor and an acetyl-cholinesterase inhibitor was proposed and is in fact attempted. Representative examples of the anticholinesterase inhibitor include physostigmine and tetrahydroaminoacridine. However, these drugs have drawbacks such as an unsatisfactory effect and the occurrence of unfavourable side effects. At the present time, there are no decisive therapeutic agents.
[26] Thus the reader is told that attempts have been made to develop drugs that will treat Alzheimer senile dementia but, so far, they have not been satisfactory or have unfavourable side effects.
[27] Beginning at the first full paragraph of page 2 of the '808 Patent, and over to the end of the second full paragraph of page 3, the specification informs the reader that the inventors have found a certain compound, a piperidine derivative , that is effective in treating diseases, including Alzheimer senile dementia:
In view of the above situation, the present inventors have made extensive and intensive studies on various compounds for many years with a view to developing a drug which has a persistent activity and a high safety.
As a result, the present inventors have found that a piperidine derivative represented by the following general formula (I) can attain the desired object.
Specifically, the compound of the present invention represented by the following general formula (I) has great advantages of having strong and highly selective antiacetylcholinesterase activity, increasing the amount of acetylcholine present in the brain, exhibiting an excellent effect on a model with respect to disturbance of memory, and having a persistent activity and a high safety when compared with physostigmine which is a conventional popular drug in the art, which renders the compound of the present invention very valuable.
The compound of the present invention was found based on the acetylcholinesterase inhibitory action and, therefore, is effective for treatment and prevention of various diseases which are thought to be derived from the deficiency of acetylcholine as a neurotransmitter in vivo.
Examples of such diseases include various kinds of dementia including Alzheimer senile dementia and further include Huntington’s chorea, Pick’s disease, and ataxia.
Therefore, the objects of the present invention are to provide a novel piperidine derivative effective as a pharmaceutical, particularly for treatment and prevention of central nervous system diseases, to provide a process for preparing the same, and to provide a pharmaceutical comprising the same as an effective ingredient.
[28] A Summary of the Invention begins at the bottom of page 3 of the '808 Patent and continues with a lengthy description of the chemical structure of the compound and methods for producing it. I reproduce only the beginning at page 3:
(Summary of the Invention)
The invention provides a cyclic amine compound having the following formula (XXV) and a pharmaceutically acceptable salt thereof:
[29] At page 7 of the specification of the '808 Patent is a discussion of the compound and a pharmacologically acceptable salt:
In addition, the invention provides a therapeutical composition which comprises a pharmacologically effective amount of the cyclic amine compound having the formula (XXV) or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier and then a method for preventing and treating a disease due to the acetylcholinesterase activity by administering to a human patient the cyclic amine compound having the formula (XXV) or a pharmacologically acceptable salt thereof.
[30] I jump to pages 63 and 64 of the '808 Patent, which provide Example 4 and a description of the compound we now know as donepezil. This compound is referred to as compound 4 in the '808 Patent.
Example 4
1-Benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yl]-methylpiperidine hydrochloride
· HCI
0.4 g of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2- ylidenyl]methylpiperidine was dissolved in 16 mℓ of THF followed by addition of 0.04 g of 10% palladium-carbon. The mixture was hydrogenated at room temperature under atmospheric pressure for 6 hr. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by making use of a silica gel column (methylene chloride : methanol = 50 : 1). The eluate was concentrated in vacuo, and the residue was dissolved in methylene chloride. A 10% solution of hydrochloric acid in ethyl acetate was added to the resulting solution, followed by concentration in vacuo to obtain a crystal, which was recrystallized from methanol/IPE to obtain 0.36 g (yield: 82%) of the title compound having the following properties:
· m.p. (ºC): 211-212°C (dec.)
· elementary analysis: C24 H 29NO 3· HC1
C H N
calculated (%): 69.30 7.27 3.37
found (%) : 69.33 7.15 3.22
[31] I return to page 47 of the '808 Patent where there begins a discussion as to the utility of the compound in treating various kinds of senile dementia. This discussion continues through to page 53 where, based on the experiments disclosed, the conclusion is made that the compound has potent acetylcholinesterase inhibitory action (compound 4 is donepezil):
The compounds thus prepared and acid addition salts thereof represented by the general formula (I) are useful for treatment of various kinds of senile dementia, in particular senile dementia of the Alzheimer type.
The invention will be described in view of its therapeutical usefulness together with pharmacologically experimental data.
Experimental Example 1
In vitro acetylcholinesterase inhibitory action
A mouse brain homogenate was used as an acetylcholinesterase source and the esterase activity thereof was determined according to the method of Ellman et al.
Ellman G.L.. Courtney, K.D., Andres,
V., and Featherstone, R.M., (1961) Biochem.
Pharmacol., 7, 88-95.
Acetylthiocholine as a substrate, a sample to detect and DTNB were added to the mouse brain homogenate, followed by incubation. The amount of a yellow substance formed by the reaction between the thiocholine and DTNB was determined in the absorbance at 412 nm in terms of the acetylcholinesterase activity.
The acetylcholinesterase inhibitory activity
of the sample was expressed in terms of inhibitory
concentration 50% (IC50).
The results are shown in Table 1.
Table 1
Compound
AChE inhibitory activity IC50 (μM)
Compound
AChE inhibitory activity IC50 (μM)
1
0.23
31
0.025
4
0.0053
33
0.030
5
0.10
45
0.36
6
0.017
48
0.019
8
0.013
52
0.80
9
0.051
54
1.0
10
0.009
56
0.017
11
0.068
62
0.0075
12
0.040
65
0.0016
13
0.026
67
0.10
14
0.038
70
0.28
15
0.094
72
0.020
17
0.052
89
0.018
18
0.68
90
0.035
19
0.064
95
0.085
20
0.54
101
0.11
21
50
120
0.19
23
0.072
124
2.8
24
1.1
176
0.004
26
24
27
0.41
29
0.15
Experimental Example 2
Ex vivo acetylcholinesterase inhibitory action
A sample to detect was orally administered to rats. After one hour of the administration, the cerebral hemispheres were dissected and homogenized, followed by the determination of the acetylcholinesterase activity. The group of rats treated with physiological saline was used as the control. Inhibition of AChE by samples ex vivo was expressed in terms of inhibition percent of the control value. Results are shown in Table 2.
Experimental Example 3
Action on passive avoidance learning impairment induced by scopolamine
See Z. Bokolanecky & Jarvik:Int. J.Neuropharmacol,
6, 217—222 (1967).
Male Wister rats were used as the test animal and a step-through light and dark box was used as an apparatus. A sample to detect was orally administered one hour before the training and the rats were treated with 0.5 mg/kg (i.p.) of scopolamine 30 min. before the training. In a training experiment, the animal was placed into a light room and, just after the animal had entered into a dark room, a guillotine door was closed, followed by delivery of an electric shock from the gid of the floor. After six hours, the animal was again placed into a light room for a retention experiment, and the time taken for the animal to enter the dark room was measured for evaluation of the effect of the sample.
The difference in the response time between the physiological saline administration group and the scopolamine administration group was taken as 100%, and the effect of the sample was expressed in terms of the percentage antagonism by the sample (Reverse %).
The results are shown in Table 3.
Table 2
Compd.
No.
Dose
(mg/kg)
AChE inhibitory action (%)
Saline
0
4
1
3
10
30
5 *
17 **
36 **
47 **
15
10
30
100
5
14 **
18 **
Table 3
Compd.
No.
Dose
(mg/kg)
Reverse%
4
0.125
0.25
55
36
13
0.25
0.5
39
27
15
1.0
2.0
51
30
19
0.5
1.0
37
39
69
0.5
1.0
22
38
The number of animals per dose was 10 to 17.
NE: non-effective
The above-described pharmacological experiments revealed that the compound of the present invention had a potent acetycholinesterase inhibitory action.
[32] It is to be noted that the tests were conducted using mouse brains (Example 1) and rats (Examples 2 and 3). No testing on humans is disclosed in the '808 Patent.
[33] Beginning at the bottom of page 53 of the '808 Patent and continuing to page 55, the Patent states that the compound provides an effective treatment for a number of conditions, including senile dementia. It is to be noted that the first full paragraph of page 54 discloses that compound 4, (donepezil) among others, was the subject of toxicity tests on rats. No serious toxicity was exhibited.
Therefore, the objects of the present invention are to provide a novel compound effective for various kinds of dementia and the sequelae of cerebrovascular diseases, to provide a process for preparing the same, and to provide a novel pharmaceutical comprising the same as an effective ingredient.
Representative compounds of the present invention (Compd. Nos. 4, 13, 15, 19, and 69 in the above Table 3) were applied to toxicity tests on rats. As a result, all the compounds exhibited a toxicity of 100 mg/kg or more, i.e., exhibited no serious toxicity.
The compound of the present invention is effective for treatment, prevention, remission, improvement, etc. of various kinds of senile dementia, particularly senile dementia of the Alzheimer type; cerebrovascular diseases accompanying cerebral apoplexy, e.g. cerebral hemorrhage or cerebral infarcts, cerebral arteriosclerosis, head injury, etc.; and aprosexia, disturbance of speech, hypobulia, emotional1 changes, recent memory disturbance, hallucinatory-paranoid syndrome, behavioral changes, etc. accompanying encephalitis, cerebral palsy, etc.
Further, the compound of the present invention has a strong and highly selective anticholinesterase action, which renders the compound of the present invention useful also as a pharmaceutical based on this kind of action.
Specifically, the compound of the present invention is effective for, for example, Huntington’s chorea, Pick’s disease and delayed ataxia or tardive dyskiaesia other than senile dementia of the Alzheimer type.
[34] After further discussion not relevant here, the '808 Patent concludes with 36 claims. Only two, claims 6 and 18, as discussed earlier, are at issue.
ISSUES
[35] While these proceedings began with two patents, several claims of each and issues of validity and infringement as to each, through the efforts of Counsel and the Case and Trial Management process, the issues have been reduced to one which relates to one validity issue respecting one patent, the '808 Patent, and two claims of that patent, claims 6 and 18. That issue can be expressed as follows:
“Is the '808 Patent, and in particular, claim 6 and claim 18, invalid because it is based upon an unsound prediction of the promised utility?”
EVIDENCE
[36] As discussed above, the issues have been reduced to the single issue. Thus, while the record as originally filed comprised forty volumes, much of that evidence is no longer necessary in considering the issue now before the Court.
[37] By an Order issued on consent April 18, 2011, certain materials not being necessary to these proceedings were removed from the record. Further, by that Order, only some of the materials remaining in the record remain as confidential. I will set out the evidence that remains in the record, and I will indicate whether the evidence, or part of it, remains confidential. I will also indicate whether the evidence was tendered as an expert or factual witness, whether that witness was cross-examined, and whether a translator was used in the cross-examination.
[38] The witnesses whose evidence remain in the record are:
For the Applicants:
1. Dr. Shin Araki, a factual witness. He is one of the persons named as inventor in the '808 Patent. He was cross-examined with the assistance of a Japanese/English language translator.
Dr. Araki’s evidence is confidential (Record Volumes 2 & 3, Tab 6; Volume 4, Tab 7).
2. Dr. Hiroo Ogura, a factual witness. He is one of the persons named as inventor in the '808 Patent. He was cross-examined with the assistance of a Japanese/English language translator.
Dr. Ogura’s evidence is confidential (Record Volumes 5 & 6, Tab 8; Volume 7, tab 9).
3. Suji Sumigama, a factual witness. He was involved at Eisai with certain testing of the compounds disclosed in the '808 Patent. He was cross-examined with the assistance of a Japanese/English language translator.
Sumigama’s evidence is confidential (Record Volumes 8 & 9, Tab 10; Volume 9, Tab 11).
4. Ichiro Yamakawa, a factual witness. He was involved at Eisai with the testing of certain of the compounds disclosed in the '808 Patent. He was cross-examined with the assistance of a Japanese/English language translator. The parties wish to have his evidence remain in the Record although they indicated that they were unlikely to refer to it.
Yamakawa’s evidence is confidential (Record Volume 10, Tab 12 & Tab 13).
5. Dr. Raymond T. Bartus, an expert witness. His evidence was directed to the remaining issue in these proceedings. He was cross-examined.
Dr. Bartus’ evidence is not confidential (Record Volume 11, Tab 14; Volume 12, Tabs 15 & 16; Volume 13, Tab 17).
6. Dr. Kenneth Rockwood, an expert witness. His evidence was directed to the remaining issue in these proceedings. He was cross-examined.
Dr. Rockwood’s evidence is not confidential (Record Volume 14, Tabs 18, 19 & 20).
7. Dr. A.P. Kozikowski, an expert witness. His evidence was largely directed to a question of infringement, which is no longer at issue. Nonetheless, the parties wish his evidence to remain in the record. He was cross-examined.
Dr. Kozikowski’s evidence is confidential (Record Volume 15, Tabs 21 & 22; Volume 16, Tab 23).
8. Dr. Michael McKenna, an expert witness. His evidence was directed to the remaining issue in these proceedings. He was cross-examined.
Dr. McKenna’s evidence is not confidential (Record Volume 17, Tabs 24, 25 & 26).
9. Dr. Jerry Atwood, an expert witness. His evidence was directed to a question of infringement. The parties wish his evidence to remain in the record, though they indicated that they were unlikely to refer to it.
Dr. Atwood’s evidence is confidential (Record Volume 18, Tabs 27, 28, 29 & 30).
10. Mark Kellner, a Japanese/English translator who testified as to the accuracy of his translation of certain Japanese language documents.
His evidence was not challenged and is not confidential (Record Volume 26, Tab 32).
11. Diane Zimmerman, a factual witness. She is a law clerk in the firm of solicitors representing the Applicants. Her affidavit served to put in the record a number of documents. She was not cross-examined.
Her evidence is not confidential (Volumes 27, 28, 29 & 30, Tab 35) except for Exhibits D, E & M (Volumes 28 & 29, Exhibits D & E; Volume 30, Exhibit M).
For the Respondent Mylan:
1. Dr. Robert Becker, an expert witness. His evidence was directed to the remaining issue in these proceedings. He was cross-examined.
His evidence is not confidential (Record Volumes 31 & 32, Tab 36; Volume 33, Tab 37; Volume 34, Tab 38; Volume 35, Tab 39).
2. Professor Thomas T. Tidwell, an expert witness. His evidence was directed to the question of infringement, which is no longer an issue in these proceedings. The parties wish his evidence to remain in the record, although it was indicated that they were unlikely to refer to it. He was cross-examined.
Dr. Tidwell’s evidence is confidential (Record Volume 36, Tabs 40 & 41; Volume 37, Tab 42).
3. A. Louise McLean, a factual witness. She is a law clerk in the firm of Mylan’s previous solicitors. Her affidavit served to put in the record certain documents. She was not cross-examined.
Her evidence is not confidential (Record Volumes 38 & 39, Tab 43).
[39] In a letter to the Court dated March 31, 2011, Counsel for Mylan stated that they did not intend to refer to the affidavits or transcripts of cross-examination of Dr. Tidwell or Dr. Atwood unless in response to any submissions made by the Applicants.
[40] Similarly, in a letter to the Court dated April 1, 2011, Counsel for the Applicants stated that they did not intend to refer to the following evidence:
The applicants do not expect to refer to the following evidence:
(a) affidavits and cross-examination transcript of Dr. Atwood;
(b) affidavit and cross-examination transcript of Mr. Yamakawa;
(c) affidavits of Christine Ingham;
(d) affidavit of Mark Kellner (translator);
(e) cross-examination transcript of David Blais;
(f) affidavits of Dr. Kozikowski sworn February 9, 2010 (we do intend to rely on Dr. Kozikowski’s affidavit sworn September 9, 2010, in particular paragraphs 1-35);
(g) exhibits C-M of the affidavit of Diane Zimmerman
(h) affidavit of Louise MacLean; and
(i) affidavits of Dr. Tidwell and cross-examination transcript of Dr. Tidwell, with the exception of questions 625-645, to which we may refer briefly.
EVIDENCE OF THE EXPERTS
[41] I will consider the evidence of Drs. Bartus, Rockwood, Kozikowski and McKenna for the Applicants and Dr. Becker for Mylan. I will consider the evidence as of June 21, 1988 as it may pertain to the state of the art and specific scientific terms. While their evidence as to construction of the patent specification and claims is in the evidence and I have read and considered it, I will treat it with caution for the reasons as will be discussed later.
[42] I have borne in mind that one must distinguish between what is set out in the '808 Patent and what the Eisai inventors and others actually did, which may not be set out in the patent or is differently set out in the patent.
APPLICANTS’ EXPERTS
[43] Dr. Raymond T. Bartus is the Executive Vice President and Chief Scientific Officer of a biotechnology company, Ceregene Inc. He is also an adjunct professor in the department of pharmacology at Tufts University Medical Center in Boston, Massachusetts as well as an adjunct professor in the department of psychiatry at New York University Medical Center, in New York, New York.
His Mandate was: To determine: (i) what, if any, is the promise of Claim 6 (and Claim 18 as it depends on Claim 6) in the '808 Patent (ii) if the inventors demonstrated the utilities of Claim 6 and 18, and (iii) if demonstrated utility is not present, did the inventors appropriately lead a sound prediction.
[44] Dr. Bartus referred to himself as one of the “key players” that developed the “cholinergic hypothesis”.[1] He stated the skilled person would be a person with “an advanced degree in medicinal chemistry or biology or pharmacology or be a clinician working in the area of dementia”.[2]
[45] At paragraph 23 of his affidavit, Dr. Bartus provided a summary of his opinion which summary will be set out later in these Reasons.
[46] At paragraphs 27 to 36, Dr. Bartus provided a description of the underlying principles of chemical brain function:
Enzymes are protein molecules that facilitate chemical reaction AChE is an enzyme in the brain AChE, a substrate, is a neurotransmitter (a chemical messenger) in the brain AChE acts on ACh, causing it to break down into choline and acetate Enzyme inhibitors bind at the active site of an enzyme, preventing it to act on substrates Enzyme inhibitors can either be irreversible (i.e. bind and chemically alter) or reversible (i.e. bind without any chemical reaction) IC50 is a unit valuation; it represents the lowest concentration of an inhibitor needed to inhibit 50% of a particular enzyme’s activity An inhibitor with a very low IC50 value indicates a potent compound A good inhibitor would be orally bioavailable (able to withstand breakdown in the stomach and kidney) as well as poses the ability to cross the blood brain barrier to bind at the appropriate site of action in the brain
[47] Neurons that release ACh are known as cholinergic neurons.[3] Alzheimer’s disease (AD) is a neurodegenerative disease; as the neurons die, the symptoms of AD progress.
[48] Dr. Bartus stated that prior to June 21, 1988 (the Canadian filing date), one way of explaining the onset of AD symptoms was the cholinergic hypothesis. Although he acknowledged that, at the time, there was “disagreement as to whether it was possible to use animals to model aspects of human memory, especially involving deficits associated with human-specific diseases”[4] he stated:
Recent memory deficits in aged animals and young animals given cholinergic dysfunction (e.g., by the administration of scopolamine) are conceptually and operationally similar to those consistently seen an aged humans. Since it had been established that there was a striking similarity in the nature of the recent memory deficits in animals and those in humans (including those in early-state AD patients), animal models could be used to study cholinergic dysfunction and memory disturbances.[5]
[49] Dr. Bartus praised the tests conducted by Eisai in the development of donepezil:
Studies with rodent models contributed to advances in the elucidation of mechanisms responsible for age-related behavioural deficits. The clearest evidence for the existence of a recent memory deficit similar to that seen in patients with AD (and other forms of senile dementia caused by cholinergic deficit) can be achieved using a single-trial passive avoidance paradigm (similar to the one reported in the '808 Patent).
. . .
Creating artificial brain lesions in animals can be used to evaluate potential pharmacological treatments for some of the symptoms of AD. In other words, while such models do not mimic the cause of the disease (i.e., neuronal death) or even the broad constellation of symptoms associated with AD, lesions in the nucleus basalis can provide animal models that have important neurodegenerative, neurochemical and even behavioural characteristics of AD.[6]
[50] At paragraphs 60 to 80, Dr. Bartus described the general understanding/knowledge prior to June 21, 1988:
It was understood that increasing ACh levels in the brain could be done by the use of AChE inhibitors There were two known AChE inhibitors that had been clinically tested in patients with AD: physostigmine and tacrine (THA) Physostigmine was not a viable compound, since it had a poor half-life Tacrine was reported in a report published by Dr. Summers in 1986 (the Summers Report) where 12 patients were given tacrine and responded positively Tacrine was not a viable compound since it had unrelated drawbacks such as liver toxicity
[51] As between in vitro (testing in test tubes), ex vivo (testing in animals and sacrificing the animals to study the internal effects) and in vivo (test