PFIZER CANADA INC. v. EISAI CO, 2011 FC 547

Federal Court Cour fédérale Date: 2011 0512 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: C 24 H 29 NO 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% (IC 50 ). The results are shown in Table 1. Table 1 Compound AChE inhibitory activity IC 50 (μ

M) Compound AChE inhibitory activity IC 50 (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) IC 50 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 IC 50 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 (testing in animals and observing the effects), Dr. Bartus did not pick one test above all and stated ​all of the tests are important for each provides different types of information.​ [7] [ 52 ] Dr.

Bartus reviewed the '808 Patent and categorized the claims into two types: claims directed to compounds and claims directed to therapeutic uses. To Dr. Bartus, Claim 6 ​promises a compound that can serve as an AChE inhibitor​ and Claim 18 ​promises treatment of senile dementia.​ [8] [ 53 ] Dr. Bartus rejected Genpharm​s (Mylan​

s) list of promises as set out in the Notice of Allegation and characterized any such promise as potential advantages of the '808 Patent: I do not think that a skilled person would fairly read this Patent in that way. Rather, a skilled person would understand that what the

inventors are saying about claim 6 is that it is an AChE inhibitor that can cross the BBB [blood brain barrier]. The other statements in the Patent are either statements of potential advantages (such as low toxicity, bioavailability, good physical properties) which a skilled person would see as a helpful description but not a promise, or indicators of what one might do with an AChE inhibitor. These latter statements include a predicted use for treating senile dementia, which is the promise of claim 18. [9] [ 54 ] At paragraphs 102 to 104, Dr.

Bartus noted that Claim 18 provides an explicit promise for treatment of senile dementia in humans. [ 55 ] Dr. Bartus stated that Pfizer has demonstrated the utility (i.e. a compound with potent AChE inhibitory activity) of Claim 6 of the '808 Patent, through the disclosure. [10] [ 56 ] At paragraphs 109 to 151, Dr. Bartus reviewed the tests disclosed in the '808 Patent as well as the affidavits of Drs. Araki and Ogura. Dr. Bartus noted the tests and methods ​were appropriate and standard in the industry.​ [11] [ 57 ] Dr.

Bartus acknowledged the error in Example 1 on Page 48 of the '808 Patent, namely it discloses rat data for donepezil when describing a mouse assay. To Dr. Bartus, the conclusion does not change ​ donepezil still exhibits potent AChE inhibitory activity. [12] [ 58 ] Dr. Bartus noted that the test results disclosed at Table 2 of the '808 Patent, found on page 51, demonstrate that donepezil was a potent AChE inhibitor compound. Dr. Bartus rejected any allegations that the test results should have (

i) disclosed the number of rats, (ii) had a positive control and (iii) included a frame of reference. To Dr. Bartus, these factors are ​not really relevant​ and do not change the result that donepezil is a potent AChE inhibitor compound ​ i.e. the demonstrated utility. [13] [ 59 ] Dr. Bartus acknowledged that Table 3 of the '808 Patent (page 52) does not disclose any statistics to better understand the scopolamine-induced memory test result. However, to Dr.

Bartus, lack of a detailed description of the procedure does not deny the results disclosed: Also, even though no statistics are provided, a skilled person is still able to come to the conclusion that donepezil was able to reverse scopolamine-induced memory loss by the data presented in Table 3, using a reasonably large number of animals (10-17), coupled with the magnitude of change seen at consecutive doses and none of the values were noted as being non-effective (i.e., NE). [14] [ 60 ] Dr.

Bartus acknowledged that the description of Example 3 of the '808 Patent (page 50 of the patent) contained an error ​ i.e. the test was conducted at a doses of 1.0 mg/kg of scopolamine and donepezil had been administered two hours before training; not 0.5 mg/kg, one hour before training. Dr.

Bartus did not consider the error material: Having seen the data where donepezil had been administered one hour before training in the Ogura Affidavit (i.e., 16% at 0.25 mg/kg and 51% at 0.5 mg/kg) the conclusion that donepezil is able to reverse scopolamine-induced cholinergic deficit both at one hour and two hours supports the conclusion that donepezil is a compound that is capable of reversing the cholinergic deficit caused by scopolamine. [15] [ 61 ] Dr. Bartus further acknowledged that the '808 Patent does not disclose any comparative data showing the effects of donepezil in tissues other than the brain.

He pointed to data at Exhibit C of the Araki Affidavit generated from Eisai as proof that tissues from the heart, serum, small intestine and pectoral muscle were also tested. [16] [ 62 ] At paragraphs 156 to 158, Dr. Bartus explained that donepezil has demonstrated its ability to increase ACh present in the brain. He pointed to Exhibits P and R from the Ogura Affidavit in support. No reference to the '808 Patent was provided.

[ 63 ] Dr. Bartus stated donepezil demonstrated a wide therapeutic index when compared to physostigmine. He highlighted the data produced in the Chosa Hokoku Report as evidence. [17] [ 64 ] Dr. Bartus stated that Pfizer has demonstrated that donepezil: (

i) is strong and highly selective, (ii) increases the amount of ACh present in the brain, (iii) exhibits an excellent effect on a model with respect to disturbance of memory, (iv) has persistent activity when compared with physostigmine, (

v) has a high safety when compared with physostigmine, (vi) has a large width between the main and the side effects, (vii) has a high bioavailability and (viii) has excellent penetration into the brain. [18] [ 65 ] Dr. Bartus further stated that Claim 18 of the '808 Patent can be soundly predicted. He summarized the data in the patent as creating the following factual basis: ​ even considering only the data in the Patent itself, established that donepezil: (

a) is a potent inhibitor of AChE (both in vitro and ex vivo); (

b) reaches the brain (i.e., crosses the BBB); and (

c) is effective in reversing the cholinergic deficit induced by scopolamine [19] [ 66 ] Dr. Bartus stated that there was a sound line of reasoning to predict donepezil as being effective in the treatment of senile dementia in humans: (

a) ACh was known to be an important neurotransmitter, permitting brain cells to ​speak​ to one another, and specifically playing an important role in memory and learning; (

b) ACh deficit was understood to be a major contributor to senile dementia, including senile dementia caused by AD; (

c) It had been shown that ACh deficit similar to that experienced by patients with senile dementia could be induced by blocking cholinergic function with drugs such as scopolamine or lesions to brain cholinergic neurons; (

d) When the ACh deficit was inducted by scopolamine, the test subjects experienced memory loss similar to that which occurs in senile dementia, including the earliest stages of AD; (

e) AChE was known to break down ACh, so skilled persons understood that inhibiting AChE would increase ACh levels; (

f) AChE inhibitors (physostigmine and tacrine) had been shown to reduce the cholinergic deficit both in animals and in humans, and had reduced the severity of the memory impairment in patients with senile dementia, including AD. The most important of these was the Summers paper in the NEJM, which was understood at the time by skilled persons as demonstrating that tacrine was effective in treating AD. [20] [ 67 ] Dr. Bartus stated that Tables 1, 2, 3 and 10 in the '808 Patent further substantiate the general principles described above. To Dr.

Bartus, the '808 Patent adequately discloses enough information to make a sound prediction. He highlighted the in vitro test results (pages 48-49 and 147 of the Patent), the ex vivo test results (pages 50-51 of the Patent) and in vivo test results (pages 50-52 of the Patent). [21]

[ 68 ] Based on the test results disclosed and the cholinergic hypothesis, Dr. Bartus stated a sound prediction could easily have been made on reading the '808 Patent . [ 69 ] Notwithstanding the lack of human data in the Patent and elsewhere, Dr. Bartus stated the animal test results are/were more than adequate to make a prediction that donepezil would be useful in the treatment of human beings: ​ Extrapolations and predictions are commonly made from animal in vitro, ex vivo and/or in vivo data to effects in humans.

It is part of the way the scientific community works and an integral part of the drug development process​ [22] [ 70 ] In his sur-reply affidavit, Dr. Bartus assessed the reply affidavit of Dr. Becker (expert for Mylan). Dr. Bartus rebutted the criticisms levied by Dr. Becker as it pertains to the Summers paper. [23] [ 71 ] Dr. Bartus stated that to diminish the Summers paper​s significance in the scientific community is a mischaracterization. [24] [ 72 ] Dr. Bartus further defended the cholinergic hypothesis as providing a sound basis to predict AChE inhibitors as potential therapies for AD.

At exhibits D and E of his sur-reply affidavit, Dr. Bartus provides articles published in 1986 and 1984 further substantiating the authority of the cholinergic hypothesis. Dr. Bartus also mentioned an

article he wrote (published in 1982, Exhibit E of his original affidavit) and stated it was highly cited according to Google Scholar ​ no evidence is provided to support such a statement. [25] [ 73 ] Dr. Bartus responded to Dr. Becker​s proposition that lethal organophosphates would meet the criteria of the rationale used to develop donepezil. To Dr. Bartus, the comparison with organophosphates, such as sarin, is irrelevant as the '808 Patent and the data included in reports closed the class of compounds to reversible inhibitors. Dr. Bartus draws the distinction that the compounds suggested by Dr.

Becker are irreversible inhibitors and are therefore irrelevant. [26] [ 74 ] Dr. Bartus rebutted the criticism levied by Dr. Becker by stating it was appropriate for the '808 Patent to conclude from animal test results and that it was not necessary to test with human brain tissue. To Dr. Bartus, it is impracticable and further stated that frozen brain tissue was not readily available in the 1980s ​ therefore to meet Dr.

Becker​s criticism, one would have had to test in humans (i.e. administering the compound and waiting for patients to die), which is unnecessary given the overwhelming animal data disclosed. [27] [ 75 ] On cross-examination Dr. Bartus admitted the '808 Patent relies on a person skilled in the art to fill in the details of what was done experimentally: Q: So the patent is relying on a person skilled in the art to fill in the details based on their knowledge of what​s being done - - A; That​s correct, yes.

Q: I was going to finish it by saying what​s being done in the art by other people elsewhere with these animal test? A: Yes, although again, what has been done elsewhere is a whole wide range of things. By the even succinct description they provide, they eliminate a lot of what else has been done elsewhere, so it limits the elements of what else has been done elsewhere is related to what they are doing. That is not a very clear statement I made. [28] [ 76 ] Dr.

Bartus was asked to interpret the following passage at page 54 of the '808 Patent: 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 central apoplexy, e.g. cerebral hemorrhage or cerebral infarcts, cerebral, arteriosclerosis, head injury, etc.; and aprosexia, disturbance of speech, hypobulia, emotional changes, recent memory disturbance, hallucinatory-paranoid syndrome, behavioural changes, etc. accompanying encephalitis, cerebral palsy, etc. [ 77 ] Dr. Bartus stated the passage described ​[h]opes. They are just laying out hopes.​ [29] He clarified his point: A: This paragraph does not represent a promise. Not because they didn​t demonstrate it.

Promise could simply be something you​re predicting, but they​re not even predicating all these things. [30] [ 78 ] When asked what the '808 Patent teaches, Dr. Bartus stated it ​is teaching somebody how to make a brand new class of compounds that have robust cholinesterase inhibitory activity, among other things.​ When asked if the ​other things​ could include being useful in the treatment of AD, he agreed. [31] [ 79 ] Dr. Bartus was asked to re-determine the promise of the '808 Patent if Claim 18 was hypothetically removed. After a lengthy exchange no explicit answer was given. Dr.

Bartus did agree to a promise put to him: Q: When you look at the patent, since you​re looking at the patent, don​t you see a promise there for therapeutic utility in treating Alzheimer​s disease? A: In total, yes. [32] [ 80 ] Dr.

Bartus was shown a document he published (Exhibit 2 of the cross-examination) in which he confirmed the understanding that there were ​frustrating limitations of animal models​ in 1985. [33] He admitted that no animal model was/is universally accepted as valid or predictive of human cognitive disturbances [34] and that by 1988, ​there was still a significant proportion of the clinical community that weren​t yet appreciating the value of animal models.​ [35] [ 81 ] Dr. Bartus was questioned on the accuracy of the Summers paper.

When asked to discuss why the FDA had levied criticisms to the study conducted in the Summers paper, Dr. Bartus stated: A: You do, but for the FDA​s documentation, you need clear records, as I said before, of how you established the blind, how you maintained the blind, how you handled the blind when it was broken, and what impact it may have on the analysis that you do. Apparently Summers was negligent in all that regard because he had no experience with what the FDA would require, and yet once his data was published, he asked the FDA to go forward towards an approval process.

The FDA is reacting to that, explaining publicly why they cannot approve it. [36] [ 82 ] Dr. Bartus was shown a report prepared by the FDA (Exhbit 9 to the cross-examination) in which the FDA strongly attacks the credibility of the Summers paper. The Summers paper had published the use of tacrine in patients with positive results. The authors of the FDA report state ​At best, we consider the evidence to be the equivalent of uncontrolled, anecdotal clinical information.​ [37] Dr. Bartus stated: A: That​s correct.

Based on the standards that the FDA requires for registration, they had no choice but to conclude that. There were so many discrepancies between what Summers did and what the FDA requires for registration, they reject the trial. [38]

[ 83 ] Dr. Bartus maintained that despite some of the test results being omitted in the '808 Patent, the data is sufficient: Q: Having taken you through these additional animal studies which were not in the patent, what you​re really saying that the inventors didn​t need to do any of those in order to be able to predict that this would work in treating humans? A: I don​t think they needed to do any of those things in order to have a plausible or reasonable prediction that this may work in humans.

I can say with great certainty the reason these studies were done is because of the millions of dollars that had to be invested and they wanted to have greater certainty, so there is an element of truth to that, but it​s all a matter of degree. [39] [ 84 ] Dr. Bartus acknowledged the priority patent application contained comparative data to physostigmine and tacrine whereas the '808 Patent omits the information. Dr.

Bartus admitted that that information would have been valuable to a person skilled in the art ​for getting an understanding of the relative activity of donepezil as compared to known compounds.​ [40] Dr. Bartus would not admit the data would have been useful to predict the utility of donepezil in the treatment of AD; instead he characterized the data as ​feel good data​ that is of no value. [41] [ 85 ] Dr. Kenneth Rockwood is a professor of Medicine (Geriatric Medicine & Neurology) at Dalhousie University . Dr.

Rockwood practices internal medicine and holds the title of Kathryn Allen Weldon Professor of Alzheimer Disease Research. His Mandate was: (

i) to provide background information on dementia, specifically senile dementia of the Alzheimer type, (ii) to respond to Genpharm​s allegation that the utility of Claim 18 of the '808 Patent could not be soundly predicted and to respond to certain allegations made in the affidavit of Dr. Becker (discussed infra ) [ 86 ] Dr.

Rockwood stated his opinion regarding Claim 18, as follows: It is my opinion that the promise of claim 18 of the '808 Patent (as it depends on claim 6) is that the compound of claim 6 (i.e. donepezil) will be useful in the treatment of the symptoms of senile dementia that arise from a cholinergic deficit. It is my opinion that the utility of claim 18 (i.e., the use of donepezil in the treatment of senile dementia) could have been, and in fact was, soundly predicted as of June 21, 1988. [42] [ 87 ] At paragraphs 22 to 28, Dr.

Rockwood provided general information on AD and the chemical process that occurs in the brain. The following passage succinctly summarizes the process occurring in the brain: In the brain, ACh acts as a ​neurotransmitter​, being a brain chemical that relays ​messages​ from one neuron to another across a gap called a ​synapse​. ACh is released from a ​pre-synaptic​ neuron and crosses the small synaptic gap to a neighbouring ​post-synaptic​ neuron. There it activates the post-synaptic neuron by binding to a site called a receptor.

Once ACh has delivered its message to the neighbouring neuron it dissociates from the receptor and is broken down by an enzyme in the synapse called AChE. This mechanism of release of ACh and then its breakdown by AChE allows brain messages to be turned on and off. [43] [ 88 ] Based on, inter alia , articles from 1974 and 1976, he stated that a conclusion could be reached that ​it was a deficiency of ACh in the brain that was responsible for memory loss.​ [44] As a result, a hypothesis was born that ​increasing levels of ACh would help treat corresponding symptoms​ ​ i.e. the cholinergic hypothesis. [45] Dr.

Rockwood wrote ​[t]here was consensus in the scientific community that it was the most promising approach in the treatment of AD.​ [46] [ 89 ] Dr. Rockwood stated that an AChE inhibitor strategy was the most well-developed strategy in the treatment of AD and noted

that currently three out of the four drugs approved by Health Canada for AD are AChE inhibitors. [47] [ 90 ] Dr. Rockwood highlighted the testing of physostigmine as an example of the scientific community embracing the cholinergic hypothesis. In other words, despite the known limitation of physostigmine, the general usefulness of AChE inhibition was well recognized. [48] [ 91 ] Dr. Rockwood highlighted the Summers paper, published in 1986 in the New England Journal of Medicine. The Summers paper showed the use of tacrine to treat AD. To Dr.

Rockwood, the Summers paper laid the theoretical foundation for scientists studying AD: Once it had been established that physostigmine and tacrine improved cognitive function in patients with AD, it was little wonder that others began to search for other AChE inhibitors that could be used in the treatment of patients with AD. [49] [ 92 ] Dr. Rockwood construed Claim 18 as claiming the use of donepezil or its pharmaceutically acceptable salts for treating senile dementia caused by an ACh deficit, observed in AD ​ this is its promise. [50] [ 93 ] Dr.

Rockwood reviewed the data in the Patent and noted: The inventors note that donepezil appears to have some advantages in terms of duration of action and safety with respect to physostigmine, although a skilled person would understand that this is not a ​promise​. Rather this is an observed advantage of donepezil as compared to the prior art compound physostigmine. [51] [ 94 ] Dr. Rockwood stated the data in the '808 Patent sufficiently discloses the factual basis in order to make a sound prediction.

He highlights the following disclosure: Table 1 of the '808 Patent (page 49) and the results of compound 4 (i.e. donepezil) ​ which teaches donepezil is potent and has inhibitory activity. Table 2 of the '808 Patent (page 51) and the results of compound 4 (i.e. donepezil) ​ which teaches donepezil reaches the brain.

Table 3 of the '808 Patent (page 52) and the results of compound 4 (i.e. donepezil) ​ which teaches donepezil is able to reverse the cholinergic deficit, regardless of the error in data (i.e. the compound was tested after two hours at a 1.0 mg/kg dose, not after one hour at a 0.5 mg/kg dose). [52] [ 95 ] Dr. Rockwood summarized his opinion on the sound line of reasoning as follows: ​ To summarize, as of June 21, 1988, it had been well established that AD, and other forms of senile dementia, was associated with a cholinergic deficit.

Therefore, researchers sought various means of addressing the cholinergic deficit in these diseases, including the use of AChE inhibitors. Researchers had shown that AChE inhibitors reversed cholinergic-induced deficiencies. Indeed, clinical studies in patients with AD had already been conducted on two AChE inhibitors: physostigmine and tacrine. By June 21, 1988, both physostigmine and tacrine had been shown to have clinically detectable, positive effects in patients with senile dementia.

Therefore, the ordinary skilled person​s knowledge of the importance of the cholinergic deficit in the pathogenesis of senile dementia, the successful use of AChE inhibitors in reversing cholinergic deficits, and past experience with clinically used AChE inhibitors such as physostigmine and tacrine, served as a sound line of reasoning that AChE inhibitors could be used in the treatment of senile dementia caused by cholinergic deficit, including, most importantly, AD. [53] [ 96 ] Dr.

Rockwood acknowledged that the affidavits of Araki, Ogura, Sumigama and Yamakawa disclose other tests not included in the '808 Patent. He maintained his position that the disclosure in the '808 Patent was still sufficient. [54] [ 97 ] Dr. Rockwood rejected the assertion by Dr. Becker that for an effective sound prediction to be made, testing in two different species needed to have been disclosed. Dr. Rockwood stated there is no such ​rule​ and that the general knowledge available surrounding physostigmine and tacrine combine to negate any such assertion. [55]

[ 98 ] Dr. Rockwood further rejected the assertion by Dr. Becker that the '808 Patent data does not disclose enough to extrapolate to use in humans. Dr. Rockwood stated that such extrapolations were done routinely in the science community. [56] [ 99 ] In his sur-reply affidavit, Dr. Rockwood assessed the reply affidavit of Dr. Becker (expert for Mylan). Dr. Rockwood stated that the Summers paper did, in fact, impact those working on AChE inhibitors and the cholinergic hypothesis was valid. [ 100 ] Dr.

Rockwood addressed the potential criticisms levied against the Summers paper, and noted that the attacks were from those sceptical of whether tacrine could produce the same results in other patients as it did with Dr. Summers​ patients. Dr. Rockwood noted that this does not attack the soundness of the cholinergic hypothesis ​ the AChE inhibitor strategy was still the predominant strategy. [57] [ 101 ] Dr. Rockwood noted the irony of Dr. Becker citing several papers criticizing the Summers paper. To Dr.

Rockwood, the documents show the AChE inhibitor strategy was clearly on the minds of all those skilled in the art at the time. [58] [ 102 ] On cross-examination Dr. Rockwood admitted that since 1996 he has acted as a consultant to Pfizer but stated he had not been to the yearly advisory board meetings in two to three years. He further admitted he consulted for Parke-Davis (a predecessor of Pfizer) in 1994 and was responsible for providing advice to help prepare a clinical submission for the compound, tacrine. [59] [ 103 ] Dr.

Rockwood admitted he would not consider himself an expert in conducting or interpreting animal studies. [60] [ 104 ] Dr. Rockwood agreed that AChE inhibitor treatment was controversial during the 1980s: Q: You would agree with me that not all acetylcholinesterase inhibitors reduce the severity of cognitive loss in AD patients? A: That is correct. Q: At that time, in 1988, no acetylcholinesterase inhibitors had been approved in Canada for treating AD? A: That is correct. Q: Nor, to your knowledge, by the FDA in the United States ? A: That​s right.

Q: Would you agree with me that in 1988 it was controversial whether THA [i.e. tacrine] was an effective drug in the treatment of AD? A: Yes, there was controversy about how effective THA was as a treatment for AD. [61] [ 105 ] Dr. Rockwell admitted that when running a scopolamine induced passive avoidance rodent model, he would want to rule out whether results were caused by peripheral effects. [62] [ 106 ] Dr. Rockwood admitted that Table 2 of the '808 Patent (page 51) contains asterisks which are not defined in the document. He stated a skilled person would know the statistical meaning. Dr.

Rockwood further stated that statistical significance is a clinically important factor. [63] He admitted Table 3 of the '808 Patent (page 52) contains no asterisks and stated that the lack of statistical significance limits ones ability to draw valid conclusions regarding clinical efficacy ​ ​but does not fatally impair.​ [64]

[ 107 ] There was a lengthy exchange between Dr. Rockwood and Counsel for Mylan regarding Exhibit 6 of the cross-examination, [65] a report published in 1991 discussing the FDA​s findings on the Summers paper, in which the Summers paper is heavily criticized. The exchange centred on when did the FDA change its view of the Summers paper ​ i.e. did the view from positive to negative occur before June 21, 1988?

After much debate, it was agreed that the FDA​s investigation of the Summers paper started ​around 1987​ and confirmed the concerns of some in the scientific community regarding ​the methodology of the Summers study​. [66] [ 108 ] During the cross-examination, Counsel for Mylan attempted to ascertain whether Dr. Rockwell interpreted the promise of the patent as a whole or just by a claim.

Counsel for Pfizer interrupted the questioning: Q: Would you agree with the following statement if we were to read paragraph 16 of your affidavit: ​It is my opinion that the promise of the '808 patent is that the compound donepezil will be useful in the treatment of the symptoms of senile dementia that arise from a cholinergic deficit.​ Would you agree with that? (REF) Mr. Bernstein: Don​t answer the question. There is no such thing as a promise of a patent. There is only promise on a claim by claim basis. Mr. White: That is what I am driving that [sic].

Q: Is that how you were instructed to determine the promise; it was on a claim by claim basis?Mr. Bernstein: That is how he was instructed to deliver to [sic]promise. [67] [ 109 ] Dr. Rockwood admitted that based on what was disclosed in the '808 Patent, there is no information to draw a comparison between donepezil and physostigmine or tacrine. [68] [ 110 ] Dr. Alan Kozikowski is a professor in the Department of Medicinal Chemistry and Pharmacognosy at the University of Illinois . He completed postdoctoral work at Harvard University . Dr.

Kozikowski is primarily an academic but has consulted on matters of medicinal chemistry for medical institutions and companies. His Mandate was: To provide an opinion regarding potential infringement of the '808 Patent and to give a general overview of relevant scientific concepts. He was later asked in a sur-reply to respond to the allegation of inutility. [ 111 ] Dr. Kozikowski construed Claims 6 and 18 as follows: In my opinion, claim 6 of the '808 Patent pertains to the discovery of a new and useful chemical composition of matter ​ in other words, a compound.

Claim 18, as it depends on claim 6, concerns a therapeutical composition containing this new and useful compound in the treatment of senile dementia. [69] [ 112 ] Dr. Kozikowski stated Claim 6 contains no promise; however, if a promise is to be construed, ​that promise would be the acetylcholinesterase inhibitory activity, which is the basic biological activity indicated for this new chemical entity.​ [70] [ 113 ] Dr. Kozikowski categorized Mylan​s alleged promises as simply advantages of the claimed compound. [71] To Dr.

Kozikowski, the '808 Patent at Tables 1, 2 and 3 (pages 49-53) disclose sufficient information to demonstrate ​that donepezil is a potent AChE inhibitor. [72] [ 114 ] On cross-examination Dr. Kozikowski was challenged on his

interpretation of Claim 18: Q: This is what I am driving at. What type of expert do you think claim 18 is directed towards, what area of expertise? A: I would say primarily clinical experts.

Q: Of which you are not one? A: That is correct. Q: In terms of actually construing what claim 18 may or may not cover, you would defer to the clinical expert? A: That is correct, which is consistent with 17 and 18 [of his sur-reply affidavit] Q: When you stated, if I understand you correctly, what claim 18 covers, you merely intended that as a restatement of the actual wordage of claim 18 as opposed to providing any expert context into what those terms might be construed to mean. Is that fair? A: That​s fair.

I hope you got what you wanted. [73] [ 115 ] There was a lengthy exchange between Counsel for Mylan and Dr. Kozikowski regarding what scientific aspects, if any, are outside of his expertise when he attempted to construe Claim 18 of the '808 Patent. [74] At the end of the examination Dr.

Kozikowski eventually admitted that the clinical aspect of Claim 18 (i.e. the use to treat element) was beyond his expertise: Q: The area of claim 18 - - again, I appreciate this is a quick repeat, but just so I​m sure that I understand - - it is the use to treat, it is the clinical aspect of claim 18 that is beyond the chemistry and outside your area of expertise and that​s why you didn​t comment on the promise of claim 18. Is that fair? It​s what I​ve understood your evidence to be. A: Yes, that is fair. [75] [ 116 ] Dr. Michael McKenna is a pharmaceutical and biotechnology consultant.

He holds a PhD in toxicology and has over 35 years experience in toxicology and pharmaceutical drug development. In 1984 Dr. McKenna was employed with Parke-Davis in the pre- clinical management team and in between the years 1986 to 1991, he oversaw the development of tacrine (THA). His Mandate was: To answer the following questions: (

a) does the utility of the '808 Patent include promises relating to donepezil​s toxicity and safety profile? And (

b) Accepting Mylan​s allegation that the utility of the '808 Patent does include promises relating to donepezil​s toxicity and safety profile, had the patentee demonstrated these aspects of utility? [ 117 ] Dr. McKenna characterized any reference to toxicity and safety as ​statements supporting some of the observed advantages of this compound​ as compared to what was previously available at the relevant time.​ To Dr. McKenna the statements are only ​instructive​. [76] [ 118 ] Dr.

McKenna stated Claim 6 contains no particular promise; however, on reading the patent as a whole, he stated the compound is an AChE inhibitor. Dr. McKenna stated that Claim 18 is the use of the compound in the treatment of senile dementia. [77] [ 119 ] On reviewing the data disclosed on page 55 of the '808 Patent, Dr. McKenna classified the disclosure as teachings, but not promises. [78] [ 120 ] Dr. McKenna stated that in his experience it is rare to have anything but a general and preliminary understanding of a compound​s toxicity at the time of filing a patent. [79] To Dr.

McKenna, a skilled person, on reading the '808 Patent would not have expected actual clinical doses to be in the patent but would be for future studies to confirm: However, these disclosures do not amount to the promise of the patent. What I mean by this is that there is nothing in the patent to cause

me to think that the inventors promised that donepezil would be safe at any level. [80] [ 121 ] Dr. McKenna reviewed the Chosa Hokoku Report which included the results of a one and four week test in rats and dogs as described by Dr. Sumigama. To Dr. McKenna it was reasonable for Dr. Sumigama to conclude that 100 mg/kg would have caused serious toxicity, regardless if it is not demonstrated in the report or '808 Patent: [54] With reference to the '808 Patent it is my opinion that it was reasonable for Mr.

Sumigama to conclude, based on his observation at 30 mg/kg in rats (at which point no ​serious​ toxicity had been observed), that serious (i.e., irreversible) toxicity would be observed at 100 mg/kg, which was the next incremental dose that would have been tested. This conclusion is consistent with and supports the statement in the patent that donepezil ​exhibited toxicity of 100 mg/kg or more, i.e., exhibited no serious toxicity.​ This statement means that there are no serious toxicity concerns at doses of less than 100 mg/kg, but at doses of 100 mg/kg or more, donepezil exhibits serious toxicity.

This was the conclusion reached by Mr. Sumigama and it was an entirely reasonable conclusion to make. [81] [ 122 ] Dr. McKenna stated that even if the '808 Patent is construed as promising safety and toxicity properties, the teachings of the Chosa Hokoku Report form the reasoning behind the disclosure in the patent and therefore demonstrates utility. [82] [ 123 ] Dr. McKenna responded to the criticism levied by Dr. Becker. To Dr.

McKenna it is improper to hold the lack of human testing against the '808 Patent; such testing is impractical, unrealistic and is uncommon at the patent filing stage in drug development. [83] He stated: Fundamentally, skilled persons understand that it is regulatory approval, rather than a patent, that reflects a drug​s safety for administration to human patients, and would not see anything in this patent to disturb this ordinary understanding. [84] [ 124 ] In his sur-reply affidavit, Dr. McKenna assessed the reply affidavit of Dr. Becker (expert for Mylan). Dr.

McKenna stated that the Summers paper did, in fact, impact those working on AChE inhibitors, specifically Parke-Davis ​ his employer from 1984-1995. [ 125 ] Dr. McKenna appeared to state that it was because of the Summers paper that Parke-Davis pursued development of tacrine (THA): Indeed, Parke-Davis, a large sophisticated pharmaceutical company, decided to pursue the development of THA on the basis that there was good scientific opinion in support of the cholinergic hypothesis and the strong inference to be drawn from Summers​ work.

The proposal for the development of THA was accepted by management, and clinical trials were initiated, in 1987. In fact, Parke-Davis continued to pursue the development of THA all the way through clinical trials, to its ultimate approval by the FDA. [85] [ 126 ] On cross-examination Dr. McKenna admitted that AChE inhibitory activity in and of itself is not pharmaceutically useful unless it can be used in a way that is not unacceptably toxic. [86] [ 127 ] When asked to distinguish between the threshold of what is a promise and what is an advantage, Dr.

McKenna stated that promises are only statements that are supported with data: Q: Do I understand that the promise of the patent will be the statements that are supported by data in the patent, whereas advantages are statements that are made but not supported by data in the patent? A: I think that​s a reasonable way to approach it. That​s the way I would approach it I believe, allowing for perhaps some translation difficulties here and some language issues. [87] [ 128 ] Dr. McKenna stated that when reading the '808 Patent one can conclude that a comparative study between donepezil and physostigmine was done.

He further stated that upon reading the '808 Patent one can conclude that tests were run to evaluate the side effect dose and minimum effective dose. However, he admitted that the data was not in the '808 Patent and that one ​had to go to the

other documentation to find that.​ [88] [ 129 ] Dr. McKenna admitted his statement at paragraph 48 of his affidavit that no where in the patent is there a promise of safety in humans was incorrect. When confronted with page 55 of the '808 Patent, Dr. McKenna admitted the statements were inconsistent. [89] [ 130 ] Dr. McKenna admitted that his assessment of threshold dose for dogs (i.e. 30 mg/kg at paragraph 51 of his affidavit) was inconsistent with the data disclosed in the reports and that the threshold was actually 10mg/kg. [90] [ 131 ] Dr.

McKenna admitted that the statement at paragraph 54 of his affidavit (excerpted above) and the statement in the '808 Patent (i.e. page 54: ​As a result, all the compounds exhibited a toxicity of 100 mg/kg or more, i.e., exhibited no serious toxicity​) could only apply to rats and that the data could not be extrapolated to humans. He further admitted that the data is inconsistent with the data disclosed when donepezil was tested on dogs. [91] [ 132 ] Dr.

McKenna noted the statements in the '808 Patent regarding safety and efficacy as they relate to humans are based on a prediction not a demonstration: Q: The statements regarding safety and efficacy in the patent, insofar as they relate to humans, is based upon prediction, not demonstration? A: That​s correct. Q: The patent itself does not disclose the toxicity testing upon which that prediction is based? A: That​s correct. Q: The person skilled in the art reading the patent really isn​t in the same position as the inventors, who where Mr.

Sumigama and others, to predict that donepezil would have a high safety when compared to physostigmine? A person skilled in the art just doesn​t have the data to - - A: You would have to rely on the statement in the patent. Q: Right, but the person skilled in the art reading the patent doesn​t have the background information and is not in the same position as the inventors were to make the prediction? A: That​s correct, yes. [92] [ 133 ] Based solely on reading the patent, Dr. McKenna admitted that one could not predict donepezil would have a high safety when compared with physostigmine. [93] [ 134 ] Dr.

McKenna stated that prior to the Summers paper, Parke-Davis did not think to apply the cholinergic hypothesis to clinical trials. [94] MYLAN​S EXPERT [ 135 ] Dr. Robert Becker is a Clinical Consultant (Drug Design and Development Section, Laboratory of Neurosciences) at the National Institute of Aging. Since 1983, Dr. Becker​s research f

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