ALLERGAN INC., ALLERGAN SALES INC. v. ALLERGAN, INC., 2012 FC 767

Date: 201206 18 Docket: T-1560-10 Citation: 2012 FC 767 Toronto , Ontario , June 18 , 2012 PRESENT: The Honourable Mr. Justice Hughes BETWEEN: ALLERGAN INC., ALLERGAN SALES INC. and ALLERGAN, INC. Applicants and THE MINISTER OF HEALTH and APOTEX INC.

Respondents REASONS FOR JUDGMENT AND JUDGMENT [ 1 ] This is an application made under the provisions of the Patented Medicines (Notice of Compliance) Regulations SOR/93- 133, as amended ( NOC Regulations ) to prohibit the Minister of Health from issuing a Notice of Compliance to Apotex Inc. for a topical ophthalmic product to be known as APO-BRIMONIDINE-TIMOP, which Apotex has compared to Allergan Inc.’s product known as COMBIGAN, until the expiry of Canadian Letters Patent No. 2,440,764 (the '764 patent) on April 9, 2023.

For reasons of comity, the Application is allowed. [ 2 ] For convenience, the topics discussed can be found at the following paragraphs: INDEX TOPIC PARAS THE PARTIES 3 to 6 THE MEDICINE 7 to 8 THE '764 PATENT 9 to 28 THE EVIDENCE 29 to 33 PREVIOUS FEDERAL COURT DECISION RESPECTING THE '764 PATENT 34 to 36 PREVIOUS UNITED STATES DECISION 37 to 39 ISSUES 40 to 186

ISSUE #1: Who bears the burden? 42 ISSUE #2: The effect of the earlier Federal Court decision 43 to 82

a) The decision 43 to 65

b) Comity 66 to 68

c) The jurisprudence 69 to 80

d) Conclusion as to effect of the previous Federal Court decision 81 to 82 ISSUE #3: Effect of the United States Decision (Judge Ward) 83 to 100 ISSUE #4: Who is the person skilled in the art? 101 – 108 ISSUE #5: Claim construction 109 to 114 ISSUE #6: Are the claims obvious? 116 to 188 ANTICIPATION AND OBVIOUSNESS 116 to 188

A) Anticipation 119 to 127

B) Obviousness 128 to 188 What is the “Inventive Concept”? 135 to 141 Inventive Concept of Claim 22 142 to 149 Differences between the State of the Art and the Inventive Concept 150 to 154 Were these differences obvious? 155 1) Is it more or less self-evident that what is being tried ought to work? Is there a finite number of identified predictable solutions known to skilled persons? 156 - 168 2) What is the extent, nature an amount of effort required?

Are routine trials carried out or is the experimentation prolonged and arduous, such that the trials would not be considered routine? 169 - 176 3) Is there motive provided in the prior art to find the solution? 177 - 181 4) What was the actual course of conduct that culminated in this invention? 182 -186 5) Commercial Success 187 - 188 CONCLUSIONS AS TO OBVIOUSNESS 189 - 195 THE PARTIES [ 3 ] The Applicant Allergan, Inc (note the comma). is the owner of the '764 patent. The Applicant Allergan Inc. (no comma) is a Canadian pharmaceutical manufacturer which sells the COMBIGAN product in Canada.

Allergan Sales Inc. played no active

part in these proceedings. I will refer to the Applicants collectively as Allergan. [ 4 ] The Respondent Minister of Health is, among other matters, responsible for granting Notices of Compliance to those wishing to distribute medicines such as those at issue here, in Canada. The Minister has notice of these proceedings but has taken no active

part in them. [ 5 ] The Respondent Apotex Inc. is a Canadian corporation which manufactures and distributes generic medicines in Canada. In the present case, it wishes to make and sell an ophthalmic drug called APO-BRIMONIDINE-TIMOP, which is a generic version of Allergan’s COMBIGAN. [ 6 ] In the parlance of the NOC Regulations , Allergan is a “first person”, and Apotex is a “second person”. THE MEDICINE [ 7 ] The COMBIGAN medicine is a topical ophthalmic solution to treat intraocular pressure (IOP) in persons suffering from chronic glaucoma.

In short, it is an eye drop medicine used to treat glaucoma. [ 8 ] In particular, the COMBIGAN medicine is in the form of a liquid solution having two active ingredients; 0.2% by

weight/volume of brimonidine, and 0.5% by weight/volume of timolol, together with other pharmaceutically acceptable ingredients (excipients) including a stabilizer known as BAK. THE '764 PATENT [ 9 ] Canadian Letters Patent No. 2,440,764 (the '764 patent), entitled “ Combination of Brimonidine and Timolol for Topical Ophthalmic Use ”, were issued and granted to the Applicant Allergan, Inc. on October 25, 2005. [ 10 ] The application for the patent was filed under the provisions of the Patent Co-Operation Treaty (PCT); with an effective filing date in Canada of April 9, 2003.

The application and patent are governed by the provisions of the Patent Act , RSC 1985, c. P-4, applicable after October 1, 1989, sometimes called the “new” Patent Act . The term of the '764 patent will expire twenty (20) years from its effective filing date in Canada; that is, on April 9, 2023. [ 11 ] The '764 patent claims a priority date of April 19, 2002, which is the date when a similar application was filed in the United States Patent Office.

This is the date upon which the issues of obviousness and anticipation are to be considered. [ 12 ] The application for the '764 patent was laid open for public inspection, through the Patent Co-Operation Treaty, on October 19, 2003. This is the date to be used for construing the patent. [ 13 ] Before reviewing the patent in detail, there a few terms used in the patent and in evidence that require explanation and upon which the parties are agreed.

It is agreed that the prior art included the administration of drops to the eye in order to reduce the intraocular pressure (IOP) in the eyeball as a means to treat or control glaucoma. The known active ingredients included either timolol or brimonidine. The drops were often self-administered by the patient. Administration twice a day is referred to as BID. Administration three times a day is referred to as TID. The precise derivation of these terms is not clear in the record but apparently the B stands for bis and the T for ter.

On occasion drops of one drug would be administered closely followed (usually in five minutes or so) by drops of the other. This type of administration is sometimes called serial administration or adjuvant administration. On occasion a witness may also refer to this as a combination administration. This is not to be confused with administration of a medicine that includes both drugs in one bottle. This is sometimes referred to by a witness as administration of a combination drug. [ 14 ] The '764 patent begins at page 1 with a statement as to the background of the invention and what the invention does.

It acknowledges that two active ingredients, brimonidine and timolol, are known and have been used to treat glaucoma, including the fact that they have been used in serial application (i.e. one after the other). It is important to note what the patent says the need is; and, having regard to the conclusions on page 16 which will be discussed later, what the patent says the invention delivers; this is (

a) a composition including both brimonidine and timolol that is (

b) effective, (

c) safe, (

d) has increased stability, and (

e) requires a lower effective concentration of preservative as compared to each medicine if taken as a separate dose of each of brimonidine and timolol. It says: BACKGROUND OF THE INVENTION This invention relates to the topical ophthalmic use of brimonidine in combination with timolol when indicated for treatment of glaucoma or ocular hypertension. Such combinations or formulations are available for separate use in the ophthalmic art and have been combined in serial application during the course of treatment of glaucoma.

However, there are concerns and expressed reservations in the ophthalmic community about patient compliance when the patient is required to administer separate medications to treat a single disease or condition such as glaucoma. There is, moreover, a long felt need for an effective and safe topical ophthalmic pharmaceutical composition including brimonidine and timolol which has increased stability and requires a lower effective concentration of preservative as compared to the individual agents taken alone.

Finally, there is a need to increase the efficacy of many topical ophthalmic agents, without increasing the systemic concentration of such topical agents, since it is well known that many of such topically-applied ophthalmic agents cause systemic side effects, e.g. drowsiness, heart effects, etc. Unexpectedly it has been discovered that brimonidine in combination with timolol meets these criteria. Brimonidine is disclosed in U.S. Patent 3,890,319. The use of brimonidine for providing neuroprotection to the eye is disclosed in U.S. Patents 5,856,329; 6,194,415 and 6,248,741.

Timolol, as an ophthalmic drug, is disclosed in U.S. Patents 4,195,085 and 4,861,760.

[ 15 ] At pages 2 and 3 chemical depictions of brimonidine and timolol are provided, which I will not repeat, and indications as to where they may be purchased. Two paragraphs at page 3 provide for more specific dosages but it is to be noted that while one drop two times a day is recommended, the precise regimen is left to the discretion of the clinician: The compositions of the present invention are administered topically. The dosage is 0.001 to 1.0, e.g. mg/per eye BID; wherein the cited mass figures represent the sum of the two components, brimonidine and timolol.

The compositions of the present invention can be administered as solutions in a suitable ophthalmic vehicle. In forming compositions for topical administration, the mixtures are preferably formulated as 0.01 to 0.5 percent by weight brimonidine and 0.1 to 1.0 percent by weight timolol solution in water at a pH of 4.5 to 8.0, e.g. about 6.9. While the precise regimen is left to the discretion of the clinician, it is recommended that the solution be topically applied by placing one drop in each eye two times a day.

Other ingredients which may be desirable to use in the ophthalmic preparations of the present invention include preservatives, co- solvents and viscosity building agents. [ 16 ] At the bottom of page 3 and over to page 4, the description addresses preservatives used to prevent microbial contamination.

It acknowledges that benzalkonium chloride (referred to as BAK in these proceedings) is one of the known preservatives and describes, in particular, certain levels of concentration of BAK ( from 0.001% to less than 0.01% e.g. from 0.001% to 0.008% preferably about 0.005% by weight) and dosages (twice a day) of the combination medicine that are advantageous, and that adequate lowering intraocular pressure can be achieved with twice-daily administration of the combination drug as compared to serial administration of Alphagan (brimonidine) and Timoptic (timolol) three times a day: Antimicrobial Preservatives Ophthalmic products are typically packaged in multidose form.

Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, thimersol, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, Onamer M, or other agents known to those skilled in the art. In the prior art ophthalmic products, typically such preservatives are employed at a level from 0.004% to 0.02%.

In the compositions of the present application the preservative, preferably benzalkonium chloride, may be employed at a level of from 0.001% to less than 0.01%, e.g. from 0.001% to 0.008%, preferably about 0.005% by weight. It has been found that a concentration of benzalkonium chloride of 0.005% is sufficient to preserve the compositions of the present invention from microbial attack. This concentration may be advantageously compared to the requirement of 0.01% benzalkonium chloride to preserve timolol in the individual, commercially-available ophthalmic products.

Moreover, it has been found that adequate lowering of intraocular pressure has been obtained when administering the compositions of this invention twice a day as compared to the FDA-approved regimen wherein brimonidine ophthalmic solution, i.e. Alphagan® ophthalmic solution is administered three times a day and timolol ophthalmic solution, i.e. Timoptic® ophthalmic solution is administered twice a day. This results in the exposure of the patient to 67% and 50% of benzalkonium chloride, with the compositions of this invention, as compared to the administration of Alphagan® and Timoptic®, respectively.

In FDA-approved adjunctive therapy, wherein Alphagan® and Timoptic® are serially administered, the patient is exposed to almost three times the concentration of benzalkonium chloride as compared to the administration of the compositions of this invention twice a day. (It is noted that it is known that benzalkonium chloride at high concentrations is cytotoxic. Therefore, minimizing the patient’s exposure to benzalkonium chloride, while providing the preservative effects afforded by benzalkonium chloride, is clearly desirable.) [ 17 ] At pages 4 and 5, co-solvents and viscosity agents are discussed.

This discussion is not relevant to the issues in these proceedings. [ 18 ] Example I at pages 5 and 6 provides for a preparation including 0.20% by weight/volume of brimonidine, 0.68% by weight/volume of timolol maleate, which is equivalent to 0.50% by weight/volume of timolol, and 0.005% by weight/volume of BKC, together with other excipients. [ 19 ] Example II, beginning at page 6 and continuing to the end of the descriptive portion of the patent at page 16, provides extensive information as to the clinical testing of the combination of Example I in twice-a-day dosing in comparison with administration of solutions containing just brimonidine three times a day or just timolol twice a day. [ 20 ] The objectives of the experiment described as Example II are stated at page 6:

To compare the safety and efficacy of twice-daily dosed brimonidine tartrate 0.2% timolol 0.5% ophthalmic solution combination (henceforth referred to as Combination) with that of twice-daily dosed timolol ophthalmic solution 0.5% (henceforth referred to as Timolol) and three-times-daily dosed ALPHAGAN® (brimonidine tartrate ophthalmic solution) 0.2% (henceforth referred to as Brimonidine) administered for three months (plus 9-month masked extension) in patients with glaucoma or ocular hypertension. [ 21 ] The intraocular pressure (IOP) of the participating patients taking each of these doses was periodically measured.

At pages 9 to 11, the patent reports the measured values and their statistical significance in respect of efficacy: Efficacy : At baseline, mean values of diurnal IOP ranged from 22.2 mm Hg to 24.9 mm Hg in the Combination group, 22.5mm Hg to 25.0 mmHg in the Brimonodine group, and 22.3 mm Hg to 24.8 mm Hg in the Timolol group. There were no statistically significant differences between treatment groups.

Mean changes from baseline diurnal IOP at week 2, week 6 and month 3 ranged from: -5.2 to -7.9 mm Hg in the Combination group -3.5 to -5.7 mm Hg in the Brimonidine group -4.5 to -6.4 mm Hg in the Timolol group The mean decreases from baseline diurnal IOP were statistically significant within each treatment group at each follow-up timepoint (p<0.001). The mean decrease from baseline diurnal IOP was statistically significantly greater with Combination that with Brimonidine at hours 0, 2 and 7 at all follow-up visits (p<0.001).

In addition, clinically significant differences of more than 1.5 mm Hg in mean change from baseline IOP favoring Combination over Brimonidine were seen at hours 0, 2, and 7 at all follow-up visits. At hour 9, the decreases from baseline diurnal IOP were greater for the Combination group than the Brimonidine group at all follow-up visits, although the differences were not statistically significant (p≥ 0.104). The mean decrease from baseline diurnal IOP was statistically significantly greater with Combination than with Timolol at hours 0, 2, 7 and 9 at all follow-up visits (p≤ 0.041).

In addition, clinically significant differences of more than 1.5 mm Hg in mean change from baseline IOP favoring Combinatin over Timolol were seen at week 2 (hours 0, 2, and 7), week 6 (hours 2 and 7), and month 3 (hours 0 and 2).

Mean values of diurnal IOP at week 2, week 6 and month 3 ranged from: 15.9 to 18.1 mm Hg in the Combinatin group 17.4 to 21.5 mm Hg in the Brimonidine group 17.5 to 18.9 mm Hg in the Timolol group Mean values of diurnal IOP were statistically significantly less with Combination than with Brimonidine at hours 0, 2, and 7 at all follow-up visits (p<0.001) and at hour 9 at week 6 and month 3 (p≤ 0.011). The mean values of IOP at hour 9 at week 2 were lower for the Combination group than the Brimonidine group, although the difference was not statistically significant (p=0.205).

In addition, clinically significant differences of more than 1.5 mm Hg in mean IOP favoring Combination over Brimonidine were seen at hours 0, 2, and 7 at all follow-up visits and at hour 9 at month 3.

Mean values of diurnal IOP were statistically significantly less with Combination than with Timolol at hour 0 at week 2 and month 3; and at hours 2, 7 and 9 at all follow-up visits (p≤ 0.050). The mean values of IOP at hour 0, week 6, were lower for the Combination group than the Timolol group, although the difference was not statistically significant (p=0.102). In addition, clinically significant differences of more than 1.5 mm Hg in mean IOP favoring Combination over Timolol were seen at week 2 (hours 0, 2, and 7), week 6 (hours 2, 7, and 9), and month 3 (hours 2 and 9).

Mean values of diurnal IOP were statistically significantly less with Combination than with Brimonidine at hours 0, 2, and 7 at all follow-up visits (p<0.001) and at hour 9 at week 6 and month 3 (p≤ 0.011). The mean values of IOP at hour 9 at week 2 were lower for the Combination group than the Brimonidine group, although the difference was not statistically significant (p=0.205). In addition, clinically significant differences of more than 1.5 mm Hg in mean IOP favoring Combination over Brimonidine were seen at hours 0, 2, and 7 at all follow-up visits and at hour 9 at month 3.

Mean values of diurnal IOP were statistically significantly less with Combination than with Timolol at hour 0 at week 2 and month 3; and at hours 2, 7 and 9 at all follow-up visits (p≤0.050). The mean values of IOP at hour 0, week 6, were lower for the Combination group than the Timolol group, although the difference was not statistically significant (p=0.102).

In addition, clinically significant differences of more than 1.5 mm Hg in mean IOP favoring Combination over Timolol were seen at week 2 (hours 0, 2, and 7), week 6 (hours 2, 7, and 9), and month 3 (hours 2 and 9). [ 22 ] At pages 12 to 14 the patent provides an analysis of the experiment from the point of view of safety. I repeat what is stated at page 12: Safety: Through month 3 of the study, 53.4% (103/193) of patients in the Combination group, 61.7% (121/196) of the Brimonidine group, and 50.8% (100/197) of the Timolol group experienced one or more adverse events, regardless of causality.

The incidences of oral dryness, eye pruritus, foreign body sensation and conjunctival folliculosis were statistically significantly lower with the Combination than with Brimonidine (p≤ 0.034), while burning and stinging were statistically significantly higher with the Combination than with Brimonidine (p≤ 0.028).

There were no statistically significant differences in adverse events between the Combination and Timolol, except for a statistically significantly higher incidence of eye discharge with the Combination (2.6%, 5/193) compared to Timolol (0%, 0/197; p = 0.029). [ 23 ] Commencing at page 14, over to page 16, the patent reports the analysis of the pharmacokinetics of the experiment. I will not set out this portion out as no party referred to this portion of the patent in argument. [ 24 ] The conclusions are stated at page 16.

They conclude that the combination of brimonidine and timolol administered twice a day (BID) was superior to just timolol administered twice a day (BID) or just brimonidine administered three times a day (TID) in lowering interocular pressure (IOP) and delivered a safety profile comparable to timolol BID and superior to brimonidine TID : Conclusions The Combination treatment (brimonidine tartrate 0.2%/ timolol 0.5%) administered BID for 3 months was superior to Timolol (timolol 0.5%) BID and Brimonidine (brimonidine tartrate 0.2%) TID in lowering the elevated IOP of patients with glaucoma or ocular hypertension.

The Combination administered BID demonstrated a favourable safety profile that was comparable to Timolol BID and better than Brimonidine TID with regard to the incidence of adverse events and discontinuations due to adverse events. The invention has been described herein by reference to certain preferred embodiments. However, as obvious variations thereon will become apparent to those skilled in the art, the invention is not to be considered as limited thereto. [ 25 ] There are 25 claims altogether, set out in three different ways commencing at page 17.

Claims 1 to 6, inclusive, are directed to a composition containing brimonidine and timolol. Claims 7 to 13 are directed to the packaging of a pharmaceutical agent for reducing intraocular pressure, including brimonidine and timolol (a form of claiming sometimes used in countries that do not permit claims to a

medicine per se ). Claims 14 to 25 are directed to use of a composition including brimonidine and timolol. The claims are drafted in “dependent” form. That is, later claims incorporate by reference the terms of earlier claims, often in cumulative fashion. [ 26 ] Allergan is asserting claims 2 to 6 inclusive, and 14 to 25 inclusive, of the '764 patent. They are dependent in one way or another on claim 1; therefore, I recite claim 1, as well: 1.

An ophthalmic topical pharmaceutical composition for the treatment of glaucoma or ocular hypertension comprising an effective amount of brimonidine and an effective amount of timolol in a pharmaceutically acceptable carrier therefore. 2. A compostion according to Claim 1, wherein the amount of brimonidine is 0.01 to 0.5 percent by weight and the amount of timolol is 0.1 to 1.0 percent by weight. 3. A composition according to Claim 1, wherein the amount of brimonidine is 0.2 percent by weight and the amount of the timolol is 0.5 percent by weight. 4.

A composition according to claim 1 further comprising from 0.001% by weight less than 0.01% by weight of benzalkonium chloride. 5. A composition according to claim 2 further comprising from 0.001% by weight to less than 0.01% by weight of benzalkonium chloride. 6. A composition according to claim 3 further comprising from 0.001% by weight to less than 0.01% by weight of benazalkonium chloride. . . . 14. Topical use of a therapeutically effective amount of a composition according to claim 1 in an affected eye for treating glaucoma. 15.

Topical use of a therapeutically effective amount of a composition according to claim 2 in an affected eye for treating glaucoma. 16. Topical use of a therapeutically effective amount of a composition according to claim 3 in an affected eye for treating glaucoma. 17. Topical use of a therapeutically effective amount of a composition according to claim 1 in an affected eye for lowering intraocular pressure. 18. Topical use of a therapeutically effective amount of a composition according to claim 2 in an affected eye for lowering intraocular pressure. 19.

Topical use of a therapeutically effective amount of a composition according to claim 3 in an affected eye for lowering intraocular pressure. 20. Topical use of a therapeutically effective amount of a composition according to claim 4 in an affected eye for treating glaucoma. 21. Topical use of a therapeutically effective amount of a composition according to claim 5 in an affected eye for treating glaucoma.

22. Topical use of a therapeutically effective amount of a composition according to claim 6 in an affected eye for treating glaucoma. 23. Topical use of a therapeutically effective amount of a composition according to claim 4 in an affected eye for lowering intraocular pressure. 24. Topical use of a therapeutically effective amount of a composition according to claim 5 in an affected eye for lowering intraocular pressure. 25.

Topical use of a therapeutically effective amount of a composition according to claim 6 in an affected eye for lowering intraocular pressure. [ 27 ] Allergan, in its written argument at paragraph 19, puts forward claim 22 as important and representative. It depends upon claim 6, which depends upon claim 3, which depends upon claim 1. I recite these claims in descending order. Claim 22 – Topical use of a therapeutically effective amount of a composition according to claim 6 in an affected eye for treating glaucoma.

Claim 6 – A composition according to claim 3 further comprising from 0.001% by weight to less than 0.01% by weight of benzalkonium chloride. Claim 3 – A composition according to Claim 1, wherein the amount of brimonidine is 0.2 percent by weight and the amount of the timolol is 0.5 percent by weight.

Claim 1 – An ophthalmic topical pharmaceutical composition for the treatment of glaucoma or ocular hypertension comprising an effective amount of brimonidine and an effective amount of timolol in a pharmaceutically acceptable carrier therefore. [ 28 ] Taking into account all of the “dependencies” relating to claim 22, that claim can be rewritten as follows: 22.

Topical use of a therapeutically effective amount of an ophthalmic pharmaceutical composition for the treatment of glaucoma or ocular hypertension wherein the amount of brimonidine is 0.2 percent by weight and the amount of timolol is, 0.5 percent by weight, and from 0.001% by weight to less than 0.01% by weight of benzalkonium chloride. THE EVIDENCE [ 29 ] As is usual in these types of applications, the evidence took the form of affidavits and transcripts of cross-examinations. No witness was examined before the Court.

Thus, the Court is unable to make a truly proper assessment as to credibility of any witness, nor to weigh properly the competing opinions of the experts. However, having reviewed the transcripts of the cross-examination of Allegan’s expert witness Dr. Fechtner, I find him to be evasive and less than forthright on many occasions. I will treat his evidence with great caution. [ 30 ] The issues in this proceeding have been much reduced to those respecting invalidity of certain claims of the ‘764 patent.

At a pre-trial conference, I invited the parties to advise the Court as to what evidence on the record no longer needs to be considered and possibly be removed from the record. The parties advised jointly by a letter from Allergan’s Counsel dated May 9, 2012:

We write further to the case conference held on May 8, 2012 in respect of T-1560-10. We write with the consent of Apotex Inc. (“Apotex”). The parties are in agreement that the following evidence need not be reviewed by the Court in advance of the hearing: Applicants’ Record ▪ The affidavits of Dr. Kevin Parkinson dated March 28 and May 31, 2011 ▪ Paras. 5-8 and Exhibits “C” to “F” of the affidavit of Sonia Atwell dated May 31, 2011 Respondent Apotex’ Record ▪ The affidavit of Biserka Horvat dated March 31, 2011 ▪ The cross-examination transcript of Dr.

Kevin Parkinson dated September 19, 2011 ▪ Paras. 81, 83-88, 91-292 and Exhibits 3-30 to the affidavit of Dr. Harry Quigley dated March 31, 2011 The parties are not asking the Court to strike any portions of the record. [ 31 ] At the hearing, Counsel for each of the parties agreed that the above-referenced material could be removed from the record as it was not referred to in argument. These portions were to be removed following the hearing. None of it was referred to in argument. [ 32 ] The Applicants Allergan filed the following evidence which remains for consideration: 1. Affidavit of Gary J.

Beck , one of the named inventors in the '764 patent. His evidence is factual . He is the Senior Director, Global Project Management, Analysis, at Allergan, Inc. in California. His evidence reviews the developments that led to the '764 patent, provides revenues generated by the sale of the COMBIGAN product and provides cost figures relating to the development of that product. He was cross-examined and a transcript of that cross-examination has been filed in evidence. 2. Affidavit of Sonia Atwell , a law clerk in the offices of the Applicants’ solicitors.

Her evidence is factual ; it serves to place several documents in the record. She was not cross-examined. 3. Affidavit of Dr. Robert Fechtner , a Professor of Ophthalmology and Director of the Glaucoma Division, Glaucoma Diagnostic Laboratory and Clinical Research Development at the Institute of Ophthalmology and Visual Science at New Jersey Medical School of

the University of New Jersey. His evidence is filed as expert evidence. His expertise lies in the fields of study, research and teaching respecting the treatment of glaucoma and other ocular conditions. He is not a formulator of drugs used for that purpose although he has worked with such formulators. During his cross-examination he expressly stated that he was not an expert in formulation (e.g. Q’s 24- 26). He testified in respect of the issues of anticipation and obviousness of the '764 patent. He rebuts some of the evidence given by Apotex’s experts.

He was cross-examined and a transcript of that cross-examination has been filed in evidence. I have already stated my reservations as to his evidence. 4. Affidavit of Jim Tierney , the Business Unit Director, Eye Care for Allergan Inc. His evidence is factual . He testified as to prescription data for bimatoprost and travoprost in Canada. He was not cross-examined. [ 33 ] The Respondent Apotex filed the following evidence which remains for consideration: 1. Affidavit of Salman Hoda , a Marketing Forecast Analyst at Apotex. He is a factual witness.

He provided marketing data, derived from a marketing survey data source, as to sales of brimatoprost, timolol, dorzolamine, dorzolamine-timolol and brimonidine-timolol products in Canada. He was cross-examined and a transcript of that cross-examination was filed in evidence. 2. Affidavit of Harry A. Quigley , A. Edward Maumenee Professor of Ophthalmology at the Wilmer Eye Institute at Johns Hopkins University, Baltimore, Maryland. His evidence was filed as expert evidence. His expertise lies in the field of study, research and teaching in respect of glaucoma and other ocular conditions.

He testified as to the issues of obviousness and anticipation of the '764 patent. He was cross-examined, and a transcript of his cross-examination was filed in evidence. 3. Affidavit of Uday B. Kompella , a Professor in the Department of Pharmaceutical Sciences at the University of Colorado Denver. His evidence was filed as expert evidence. His expertise lies in the field of formulation and delivery of ocular drugs. He testified as to obviousness of the '764 patent. He also responded to the Beck affidavit. He was cross-examined and a transcript of his cross-examination was filed in evidence. 4.

Affidavit of Aidan Hollis , a Professor of Economics at the University of Calgary. His evidence was filed as expert evidence. He testified in respect of COMBIGAN sales and sales of other ophthalmic products in Canada. He was cross-examined and a transcript of that cross-examination was filed in evidence. PREVIOUS FEDERAL COURT DECISION RESPECTING THE '764 PATENT [ 34 ] There has been previous litigation in the Federal Court respecting the '764 patent in the context of the NOC Regulations .

In a decision released November 17, 2011, cited as Allergan Inc, et al v Canada (Minister of Health) and Sandoz Canada Inc , 2011 FC 1316 , Justice Crampton (as he then was – I will refer to him as Crampton J in these Reasons.) determined that allegations made by a generic, Sandoz Canada Inc, inter alia , that the '764 patent was invalid for obviousness, were not justified. He wrote at paragraph 127 of that decision:

127 Allergan has met its burden of establishing, on a balance of probabilities, that Sandoz's allegation that the '764 Patent is invalid on the ground of obviousness is not justified. For the reasons summarized in paragraph 117 above, this would remain true even if the inventive concept of the claims of the '764 Patent did not include the uncontested surprising improvement in safety, the elimination of the afternoon reduction of effectiveness and the reduction in daily load of BAK, relative to concomitant treatment of brimonidine and timolol.

These additional aspects of the inventive concept simply serve to further strengthen that the invention claimed by the '764 Patent was not obvious. [ 35 ] He was not asked to deal with the issue of anticipation of the ‘764 patent. [ 36 ] I am advised that this decision is a final decision. I will refer to this decision as Sandoz . PREVIOUS UNITED STATES DECISION [ 37 ] The United States District Court, Eastern District of Texas, Marshall Division, released a decision dated August 22, 2011 in a case between Allergan, Inc v Sandoz Inc , cited as 2011 WL 3809882 (E.D.Tex.).

I am advised that this decision is under appeal with an oral hearing expected in the fall of this year, 2012. [ 38 ] This decision dealt with four United States patents which emerged from the same priority application as that claimed in the '764 patent; namely, a filing in the United States Patent Office on April 19, 2002 as number 10/126,790.

The District Court determined that these patents were not invalid. [ 39 ] This litigation was brought under the provisions of the United States Hatch-Waxman Act , [Public Law 98-417] (formally known as the Drug Price Competition and Patent Term Restoration Act) , of which our NOC Regulations are an imperfect copy.

ISSUES [ 40 ] The basic issue before me is whether Allergan has discharged its burden of demonstrating that Apotex’s allegation of invalidity of the '764 patent are not justified; thus the Court must determine whether an order for prohibition should issue. [ 41 ] In determining this matter, there are several discrete issues: 1. Who bears the burden? 2. Effect of the previous Federal Court decision. 3. Effect of the United States Federal Court decision 4. Who is the person skilled in the art? 5. .Construction of the claims 6. Are the asserted claims of the '764 patent anticipated? 7.

Are the asserted claims of the '764 patent obvious? ISSUE #1: Who bears the burden? [ 42 ] As to the allegations of invalidity, the Patent Act , RSC 1985, P-4, section 43(2) affords a presumption of validity; however, once a second person, here Apotex, puts in some evidence as to invalidity, the Court must determine the matter on the usual civil burden; namely, balance of probabilities. I repeat what I wrote in GlaxoSmithKline Inc v Pharmascience Inc , 2011 FC 239 at paras 43 and 44 : 43 O'Reilly J of this Court has summarized the question of burden of proof where the issue is invalidity in Pfizer Canada Inc. v.

Apotex Inc., 2007 FC 26 , 59 CPR (4th) 183 (aff'd 2007 FCA 195 , leave to appeal refused [2007] SCCA No. 371) at paragraphs 9 and 12:

9 In my view, the burden on a respondent under the Regulations is an "evidential burden" -- a burden merely to adduce evidence of invalidity. Once it has discharged this burden, the presumption of validity dissolves and the Court must then determine whether the applicant has discharged its legal burden of proof. I believe this is what is meant in those cases where the Court has stated that the respondent must put its allegations "into play".

It must present sufficient evidence to give its allegations of invalidity an air of reality. ... 12 To summarize, Pfizer bears the legal burden of proving on a balance of probabilities that Apotex's allegations of invalidity are unjustified. Apotex merely has an evidentiary burden to put its case "into play" by presenting sufficient evidence to give its allegations of invalidity an air of reality. If it meets that burden, then it has rebutted the presumption of validity. I must then determine whether Pfizer has established that Apotex's allegations of invalidity are unjustified.

If Apotex does not meet its evidential burden, then Pfizer can simply rely on the presumption of validity to obtain its prohibition order. 44 In Pfizer Canada Inc. v. Canada (Minister of Health), 2008 FC 11 , 69 C.P.R. (4th) 191 , I said in respect of the same thing at paragraph 32: 32 I do not view the reasoning of the two panels of the Federal Court of Appeal to be in substantial disagreement. Justice Mosley of this Court reconciled these decisions in his Reasons in Pfizer Canada Inc. v. Apotex Inc., [2007] F.C.J. No. 1271 , 2007 FC 971 at paragraphs 44 to 51 .

What is required, when issues of validity of a patent are raised: 1. The second person, in its Notice of Allegation may raise one or more grounds for alleging invalidity; 2. The first person may in its Notice of Application filed with the Court join issue on any one or more of those grounds; 3. The second person may lead evidence in the Court proceeding to support the grounds upon which issue has been joined; 4. The first person may, at its peril, rely simply upon or, more prudently, adduce its own evidence as to the grounds of invalidity put in issue. 5.

The Court will weigh the evidence; if the first person relies only on the presumption, the Court will the presumption of validity afforded by the Patent Act nonetheless weigh the strength of the evidence led by the second person. If that evidence is weak or irrelevant the presumption will prevail. If both parties lead evidence, the Court will weigh all the evidence and determine the matter on the usual civil balance. 6.

If the evidence weighed in step 5 is evenly balanced (a rare event), the Applicant (first person) will have failed to prove that the allegation of invalidity is not justified and will not be entitled to the Order of prohibition that it seeks. ISSUE #2: The effect of the earlier Federal Court decision

a) The decision [ 43 ] The Federal Court in Allergan Inc et al v Canada (Minister of Health) and Sandoz Canada Inc , 2011 FC 1316 , ( Sandoz ) dealt with proceedings under the NOC Regulations involving two patents; one of them was the same '764 patent, which is the one at issue here; the other was Canadian Patent No. 2,225,626 (the '626 patent), which is not at issue in the present proceedings. The generic in that case was Sandoz Canada Inc., a different generic from Apotex Inc., the generic in these proceedings.

Counsel representing the generics is also different in each proceeding. [ 44 ] In the Sandoz proceeding, Allergan led evidence, including that of Mr Gary J. Beck, one of the named inventors, and that of Dr. Robert Fechtner as an expert. Both are witnesses in the present proceeding and I am advised that the affidavits of these two witnesses

are in many respects essentially the same as their affidavits in the present proceedings. These persons were cross-examined in eachproceeding by different Counsel. I have not been provided with the transcripts of the cross-examinations in the earlier proceeding, but Ifully expect that they are different from those in the present proceedings. [45] Sandoz provided expert evidence from different persons than those offered by Apotex in the present proceedings. Sandoz’sexperts were Dr. Henry Jampel and Dr. Ashim Mitra, as set out in Crampton J’s reasons at paragraphs 30 and 31.

I do not have copies oftheir affidavits or transcripts of their cross-examinations. Crampton J., at paragraph 32, expressed serious reservations as to Mitra’scredibility. [46] Crampton J, in Sandoz, set out the issues at paragraph 33 of his Reasons. The only issue respecting the '764 patent was that ofobviousness. At paragraph 35, he sets out the same claims as Allergan relies upon in the present proceedings; and, in particular, Allerganasserted claim 22 as being representative as it does in the present proceeding.

Crampton J stated at paragraph 36 that there was “nodispute between the parties” as to the construction of the language of these claims: 36 There is no dispute between the parties regarding the construction of the language in claims 1, 3, 6 and 22 of the '764 Patent (the"Representative '764 Claims").

The parties are in general agreement that those claims describe a fixed combination of brimonidine(0.2%) and timolol (0.5%) in a pharmaceutically acceptable carrier containing BAK (0.001% to 0.01%) (the "Composition") and the useof the Composition for the topical treatment of glaucoma and ocular hypertension. [47] At paragraph 37, Crampton J set out the test for obviousness in four steps as derived from the decision of the Supreme Courtof Canada in Apotex Inc v Sanofi-Synthelabo Canada Inc 2008 SCC 61 , [2008] 3 SCR 265: 37 The test for assessing obviousness comprises the following four steps: 1.

Identify the person skilled in the art and the relevant common general knowledge; 2. Identify the inventive concept of the claim in question or, if that cannot readily be done, construe it; 3. Identify what, if any, differences exist between the matter cited as forming part of the "state-of-the-art" and the inventive concept; and 4. Without any knowledge of the alleged invention as claimed, assess whether those differences (

i) constitute steps that would have beenobvious to the skilled person, or (ii) required a degree of invention (Apotex Inc v Sanofi-Synthelabo Canada Inc, 2008 SCC 61, [2008] 3SCR 265, at para 67 [Sanofi]).

(1) Step One - The skilled person and the relevant common general knowledge [48] As to step one, Crampton J defined the person skilled in the art (POSITA) at paragraphs 38 to 40, as follows: 38 Dr.

Fechtner opined that the POSITA to whom the '764 Patent is addressed "is a person engaged in developing pharmaceuticalformulations and treatment for methods for the eye, or is a specialist in treating diseases of the eye such as an optometrist or anophthalmologist who also has experience in either developing ophthalmic pharmaceutical formulations or in designing and runningclinical trials on such formulations" (emphasis added). 39 Drs. Mitra and Jampel took a similar position, when they stated that the '764 Patent is addressed to pharmaceutical formulatorsand to ophthalmologists.

However, Sandoz subsequently took the position that the POSITA is a composite of a practicingophthalmologist and a pharmaceutical formulator. During the oral hearing of this application, Sandoz characterized this differencebetween the views expressed by Dr. Fechtner and its own experts as being a "minor" and as having no "real effect." 40 That said, in my view, the POSITA to whom the '764 Patent is addressed is someone who is either a pharmaceutical formulator or

a specialist in treating diseases of the eye, as described by Dr. Fechtner. This would include persons such as Drs. Jampel (who conceded in cross-examination that he has no experience with formulations), Fechtner, and Mitra, as well as Mr. Beck. This is consistent with the position taken by Sandoz in its NOA. [ 49 ] The knowledge that a person skilled in the art would possess as of the relevant date was set out at paragraphs 41 to 45 of his reasons: 41 Dr.

Jampel stated in his affidavit that the common general knowledge of the POSITA as at the Priority Date included the following: i. a detailed knowledge of ocular hypertension and glaucoma; ii. a detailed knowledge of the IOP lowering medications in use at that time, including those described at paragraphs 14 to 18, above; iii. the knowledge that IOP lowering medications were commonly used in combination, either in concomitant use or combined together, in order to obtain adequate IOP lowering, and that the use of two IOP lowering medications resulted in greater IOP reduction in either individual medication alone; iv. the knowledge that both brimonidine and timolol were well-established IOP lowering medications; v. the knowledge that brimonidine and timolol had been used in concomitant therapy and that such therapy resulted in a larger IOP reduction than with brimonidine or timolol alone; vi. the knowledge that commercially available combination products typically included timolol as one of the active ingredients - such products included COSOPT (combination of dorzolamide and timolol that had been available in the U.S. since 1998 and in Canada since 1999), as well as combinations of pilocarpine and timolol and of latanoprost and timolol (Xalacom) that were commercially available outside the United States prior to 2002; and vii. the knowledge that BAK was a commonly used preservative in ophthalmic solutions. 42 At the oral hearing of this application, Allergan stated that while there might be some "subtle differences" between its experts and Dr.

Jampel, its arguments would be based upon Dr. Jampel's above-described position regarding the common general knowledge of the POSITA as at the Priority Date. Accordingly, I am prepared to accept the foregoing

summary provided by Dr. Jampel for the purposes of the present analysis, subject to the following observations. 43 First, I am satisfied that the evidentiary record demonstrates that a POSITA at the time of the Priority Date would also have been familiar with the fact that Allergan's second generation brimonidine product, ALPHAGAN P, contained (i) 0.15% brimonidine, rather than the 0.2% concentration that is used in the Composition, and (ii) Purite, rather than BAK as a preservative.

That person also would have been aware that, when administering brimonidine and timolol concomitantly, the state-of-the-art was to administer those drugs separately, 5 minutes apart, to avoid the "wash-out" effect. 44 Second, the record also demonstrates that the POSITA would have been aware of U.S.

Patent No. 5,502,052, issued March 26, 1996 (the "DeSantis Patent"), which suggested that anti-glaucoma compositions that comprise a combination of one or more beta- blockers (such as timolol) with one or more alpha-2 agonists (brimonidine was not specifically mentioned) achieve a greater reduction in IOP than that which is achievable with the same concentration of either type of active ingredient used alone. 45 Third, I am satisfied that the POSITA also would have been aware that the benefits associated with a fixed composition of two active ingredients for use in the topical treatment of glaucoma, relative to concomitant therapy involving those same active ingredients, likely would include: (

i) less preservative being administered to patents, and (ii) greater patient compliance with the combined administration.

[50] Crampton J then moved to step two, which he defined as the “inventive concept”. He attempted to make a distinctionbetween what is in the claims, properly construed, and the “inventive concept…for the purposes of performing the third step of theobviousness test”.

At paragraphs 46 to 51 of his reasons, he wrote: 46 Sandoz submits that "it is the claims that define the invention" in any patent and that the inventive concept of the '764 Patent mustbe discerned solely from the language in the claims of the patent. 47 It is settled law that the "fences" and "boundaries" of the "field" of monopoly conferred by a patent are established by the claims ofthe patent (Free World Trust, above, at paras 14, 33, 51, 66).

That said, to achieve a "purposive construction," is permissible to haveregard to other parts of the patent "through the eyes of a skilled addressee," to resolve ambiguity and to achieve flexibility and fairnessin differentiating between the essential and the unessential features of the invention (Whirlpool Corp v Camco Inc, 2000 SCC 67, [2000]2 SCR 1067, at para 48 [Whirlpool]).

Given that there is no dispute in the case at bar with respect to the construction of the claims, thereis no need to look beyond the claims of the '764 Patent to ascertain the field of monopoly claimed therein. 48 The same cannot be said with respect to the inventive concept of the claims. 49 Generally speaking, the Representative '764 Claims simply claim the Composition for topical use in an affected eye for treatingglaucoma. Sandoz submits that the inventive concept of those claims must be discerned from this description alone. Dr. Jampel took thesame position. 50 I disagree.

If that were the case, it would not be possible in this and similar cases to fully ascertain the differences between thestate-of-the-art and the inventive concept of the claim, for the purposes of performing the third step of the obviousness test. 51 In cases such as this, where "the inventive concept of the claims is not readily discernible from the claims themselves," it is bothnecessary and permissible to look to the balance of the patent "to determine its inventiveness" (Sanofi, above, at para 77).

In otherwords, "to ascertain the nature of the invention" that is articulated in the claims, and to understand the extent to which the claimedinvention differs from the prior art, the Court may "look to the whole of the disclosure" in the patent (Whirlpool, above, at para 49(g),quoting Consolboard Inc v MacMillan Bloedel (Saskatchewan) Ltd, (SCC), [1981] 1 SCR 504, at 520-21).

That said, itbears underscoring that "it is not permissible to read the specification in order to construe the claims more narrowly or widely than thetext will allow" (Sanofi, above, at para 77). [51] He concluded at paragraph 58 that the “inventive concept” of the '764 patent also includes (

i) improved safety profile (ii) BIDdosing without afternoon reduction in efficiency (iii) reduction in daily load of preservative. He wrote: 58 I am satisfied that the inventive concept of the claims of the '764Patent also includes (

i) the improved safety profile of theComposition, (ii) BID dosing without an afternoon reduction in efficiency, and (iii) the reduction in the daily load of preservativeadministered to patients taking both brimonidine and timolol. Although Allergan submitted that the inventive concept of the claimsfurther includes "[i]ncreased IOP lowering of the combination as compared to monotherapy with individual agents," this was simplybaldly asserted and was not further developed in Allergan's written or oral submissions.

Accordingly, it will not be further addressed inthese reasons. [52] Crampton J moved to step three, the differences between the state of the art and the innovative concept, beginning atparagraph 64, where he set out the differences that he found: 64 The differences between the prior art discussed at paragraphs 41 to 45 above and the innovative concept of the claims in the '764Patent are the following: (

i) the Composition combines brimonidine and timolol into a single, chemically stable, formulation - thatcombination had never previously been made or reported in the prior art, (ii) the Composition has a superior safety profile, relative tobrimonidine TID, (iii) the Composition permits BID dosing without an afternoon reduction in efficiency, relative to brimonidine TIDtreatment, and (iv) patients who are treated with the Composition receive a significantly reduced daily load of BAK, relative toconcomitant treatment of brimonidine and timolol.

[ 53 ] Crampton J noted at paragraph 65 that much of the evidence as to these differences, as given by Beck, one of the named witnesses, was uncontradicted: 65 With respect to BID dosing without a reduction in afternoon efficiency, the '764 Patent disclosed, among other things, that in the clinical trial mentioned immediately above, the decreases from baseline diurnal IOP at hour 9 of the daily testing "were greater for the Combination group than for the Brimonidine group at all follow-up visits, although the differences were not statistically significant (p > 0.104)." Mr.

Beck's uncontradicted evidence was that "[t]he frequency of administration for which a formulation is approved significantly affects its use and value because of the discomfort, difficulty, unpleasantness, and risk of infection associated with installation of eyedrops." For these reasons, Mr. Beck stated that a formulation approved for BID dosing "is, all else being equal, much better than a drug that must be administered three times a day." Once again, this evidence was not contradicted.

With respect to the Composition in particular, it requires only two administrations per day, versus the five separate administrations that continue to be required in the United States for patients being administered brimonidine (TID) and timolol (BID) concomitantly, and the four separate administrations that are required elsewhere for that concomitant therapy. For this reason, Mr. Beck stated in cross-examination that a "combination product that had a dosing regimen of two times a day would be considered more advantageous, from a compliance standpoint, than monotherapies dosed" four or five times a day.

Again, this evidence was not contradicted. [ 54 ] Crampton J rejected Sandoz’s argument that the claims are simply directed to a formula, and the properties of that formula could not form part of the innovative concept. He wrote at paragraphs 68 and 69: 68 In addition, Sandoz submitted that since the alleged invention claimed in the '764 Patent existed once the combination itself was made, the benefits discovered in Allergan's subsequent clinical trials cannot be part of the innovative concept of the patent.

Sandoz added that recognition of the superior safety profile of the Composition would require this Court to hold that the invention did not exist until the clinical trial was conducted and the results analyzed. 69 I disagree. The cases relied upon by Sandoz on this point simply stand for the proposition that the utility of the pharmaceutical patent does not need to be demonstrated by prior human clinical trials (Apotex Inc v Wellcome Foundation Ltd, 2002 SCC 77 , [2002] 4 SCR 153 , at para 77 ; Pfizer ( 2009 FC 638 ), above, at paras 87-88; aff'd 2010 FCA 242 ).

In the case at bar, the safety data in question was disclosed in the '764 Patent and is a legitimate part of the innovative concept of that patent. [ 55 ] Crampton J then moved to step four , which required a determination as to whether the differences between the inventive concept and the prior art were obvious, beginning at paragraph 70.

He sets out four factors at paragraph 71: 70 In Sanofi, above, at paragraphs 69 and 70, Justice Rothstein identified a number of factors that should be taken into consideration in cases where it is appropriate to assess whether the invention was "obvious to try." In the case at bar, Allergan conceded that it is appropriate to engage in this assessment, because the Composition is a pharmaceutical invention that was achieved by experimentation (Sanofi, above, at para 68; Bridgeview Manufacturing Inc v 931409 Alberta Ltd, 2010 FCA 188 , at para 42 ).

I agree. 71 Accordingly, it is appropriate to consider the following factors that were identified by Justice Rothstein: * Is it more or less self-evident that what is being tried ought to work? Is there a finite number of identified predictable solutions known to skilled persons? * What is the extent, nature and amount of effort required? Are routine trials carried out or is the experimentation prolonged and arduous, such that the trials would not be considered routine? * Is there a motive provided in the prior art to find the solution? * What was the actual course of conduct that culminated in the invention?

(

a) Was it more or less self-evident that the Composition would work? Were there a finite number of identified predictable solutions known to skilled persons? [ 56 ] The first of these factors which he considered was the “self evident” factor. He wrote at paragraph 72: 72 Sandoz submitted that to the extent that there was any recognized need for a product with the alleged benefits of the Composition, it was well known that a combination product would offer such benefits.

However, the fact that it may have been known that a combination product such as the Composition would provide particular benefits is not a sufficient basis upon which to conclude that it was more or less self-evident that the Composition would work or that there were any predictable solutions for achieving the Composition known to the POSITA. It is one thing to have an idea that a potential product would or might have certain beneficial properties. It is quite another thing to actually create that product.

It is on the latter that this assessment must focus (Pfizer Canada Inc v Apotex Inc, 2009 FCA 8 , at para 29 [Pfizer (2009 FCA 8)]). [ 57 ] Sandoz relied upon what is described as the DeSantis Patent (US Patent 5,502,052) as identified at paragraph 44 of Crampton J’s Reasons, as well as “a series of articles” appended to Dr. Jampel’s affidavit. Crampton J, at paragraphs 72 through 90 of his Reasons, reviewed the evidence of Allergan’s and Sandoz’s witnesses, particularly with respect to several of the properties of the particular formulations as found in claim 22 of the '764 patent.

He concluded at paragraph 91: 91 In

summary, given all of the foregoing, I find that (

i) it would not have been more or less self-evident to the uninventive POSITA that formulating brimonidine and timolol into a chemically stable fixed combination drug ought to work, and (ii) there was not a finite number of identified predictable solutions known to skilled persons. (

b) What was the extent, nature and amount of effort required? Were routine trials carried out or is the experimentation prolonged and arduous, such that the trials would not be considered routine? [ 58 ] The second factor considered by Crampton J was the extent of the effort required. Sandoz argued that Mr. Beck and his team were engaged in a routine exercise. Crampton J found differently. At paragraphs 103 and 104 he wrote: 103 In

summary, before arriving at the final Composition, Mr. Beck and his team: i. considered other active ingredients; ii. encountered failures with their Brimo X and Synergel formulations; iii. encountered a failure with the preservative that they considered to be superior to BAK and had used in their ALPHAGAN P product (that was approved by the U.S. FDA shortly before the Priority Date); and iv. encountered novel degradations when brimonidine and timolol were combined with BAK. 104 Based on the foregoing, I find that Mr. Beck and his team (

i) engaged in a significant amount of difficult, non-routine work and overcame several unexpected obstacles to develop the Composition, and (ii) did not spend any significant amount of time and effort pursuing possible formulations that would not have been pursued by the POSITA.

[ 59 ] The third factor considered by Crampton J was motivation, beginning at paragraph 114 of his Reasons. He accepted the uncontradicted evidence of Allergan’s expert, Dr. Fechtner, at paragraphs 115 and 116: 115 Dr. Fechtner's uncontradicted evidence on this point, which I accept, is that: (

i) the known difficulty in obtaining U.S. FDA approval for fixed combination drugs for the treatment of glaucoma was a major disincentive against the development of such drugs, and the POSITA would not have been motivated to develop a fixed combination drug containing timolol and brimonidine; (ii) the extent of time, effort and resources required to conduct the clinical trials described in Mr.

Beck's affidavit would have given rise to a disincentive for the POSITA to pursue the development of the Composition; and (iii) the cost of the work required to develop such a drug would have been a further disincentive for the POSITA. 116 Another statement made by Dr. Fechtner that is relevant to this consideration is that the POSITA would have been well aware that combining two drugs into a fixed combination may lead to the over-administration or under-administration of one of the active ingredients, which is apparently what happened with the combination product of pilocarpine and epinephrine. [ 60 ] In

summary , Crampton J wrote at paragraph 117: 117 It follows from the conclusions reached under the headings (

a) to (

c) immediately above that combining brimonidine and timolol into a fixed combination drug is not something that would have been "obvious to try" for the POSITA. In short, (

i) it was not more or less self-evident that the steps that were undertaken to achieve a chemically stable formulation of the Composition ought to work, (ii) the experimentation undertaken to achieve that formulation was not routine, (iii) Allergan did not have a strong motivation to pursue that experimentation, and (iv) the course of conduct undertaken to achieve the Composition does not suggest that the Composition was obvious. [ 61 ] Crampton J also considered the actual conduct of the inventors, which included at least three wild goose chases.

He wrote at paragraph 122: 122 Based on the information discussed paragraphs 96 to 103 above, I find that this factor weighs in favour of a finding that the Composition was not obvious. In short, Mr.

Beck and his team did not develop the Composition "quickly, easily, directly and relatively inexpensively, in light of the prior art and common general knowledge." On the contrary, they pursued at least three "wild goose chases" (Sanofi, above, at para 71) and encountered a number of other obstacles before they finally developed the Composition. [ 62 ] Lastly, Crampton J considered commercial success, which he acknowledged to be a secondary factor.

He wrote at paragraph 125: 125 There is evidence to suggest that the commercial success of COMBIGAN is at least in part attributable to the favourable safety dimension of the inventive concept of the '764 Patent. In short, Dr.

Fechtner's uncontradicted evidence is that "one of the reasons why COMBIGAN has been a successful product commercially (and one of the reasons I prescribed it) is because it has an advantageous side effect profile when compared to its components and other available treatment options." This evidence was not contested by Sandoz's experts. [ 63 ] In conclusion , Crampton J found that Sandoz’s allegation that the '764 patent was invalid for obviousness was not justified. He set out in his conclusion at paragraph 127:

127 Allergan has met its burden of establishing, on a balance of probabilities, that Sandoz's allegation that the '764 Patent is invalidon the ground of obviousness is not justified.

For the reasons summarized in paragraph 117 above, this would remain true even if theinventive concept of the claims of the '764 Patent did not include the uncontested surprising improvement in safety, the elimination of theafternoon reduction of effectiveness and the reduction in daily load of BAK, relative to concomitant treatment of brimonidine and timolol.These additional aspects of the inventive concept simply serve to further strengthen that the invention claimed by the '764 Patent was notobvious. [64] It is to be noted that Sandoz made no allegation of invalidity of the '764 patent on the basis of anticipation.

Accordingly,Crampton J made no finding in respect of anticipation. [65] There are two bases for considering the effect of the judgment of Crampton J. One is comity; the other is the jurisprudencespecific to the NOC Regulations. I will consider comity first.

b) Comity [66] Comity comes into consideration when a Court is faced with a decision of the same Court which deals with the same legalissues or factual circumstances. There is a general view that the subsequent Court should respect the decision of the earlier Court unlessit is manifestly wrong or the jurisprudence has changed.

The earlier decision should be followed unless there is strong reason to thecontrary; and, in considering strong reason to the contrary, the Court does not mean a stronger or more persuasive argument of Counsel,but a showing that some jurisprudence has been clearly overlooked or is now changed. Richard J (as he then was) set out the matter in Glaxo Group Ltd v Canada (Minister of National Health and Welfare), (1995), 64 CPR (3d) 65 at pages 67 (line

h) to 68 (line g): The principle of judicial comity has been expressed as follows: The generally accepted view is that this court is bound to follow a previous decision of the court unless it can be shown that theprevious decision was manifestly wrong, or should no longer be followed: for example, (1) the decision failed to consider legislation orbinding authorities which would have produced a different result, or (2) the decision, if followed, would result in a severe injustice. Thereason generally assigned for this approach is a judicial comity.

While doubtless this is a fundamental reason for the approach, I thinkthat an equally fundamental, if not more compelling, reason is the need for certainty in the law, so far as that can be established.Lawyers would be in an intolerable position in advising clients if a division of the court was free to decide an appeal without regard to aprevious decision or the principle involved in it. (Bell v. Cessna Aircraft Co. (1983), (BC CA), 149 D.L.R. (3d) 509 at p. 511, 36 C.P.R. 115, [1983] 6 W.W.R. 178(B.C.C.A.).) A similar position was taken by Mr.

Justice Jackett, President of the Exchequer Court, in Canada Steamship Lines Ltd. v. M.N.R., (CA EXC), [1966] Ex. C.R. 972 at p. 976, [1966] C.T.C. 255, 66 D.T.C. 5205: I think I am bound to approach the matter in the same way as the similar problem was approached in each of these cases until such time,if any, as a different course is indicated by a higher Court. When I say I am bound, I do not mean that I am bound by any strict rule ofstare decisis but by my own view as to the desirability of having the decisions of this Court follow a consistent course as far as possible. In R. v.

Northern Electric Co. (1955), (ON SC), 24 C.P.R. 1 at p. 19, [1955] 3 D.L.R. 449, [1955] O.R. 431(H.C.), McRuer C.J.H.C. stated: Having regard to all rights of appeal that now exist in Ontario, I think Hogg J. stated the right common law principle to beapplied in his judgment in R. ex rel. McWilliam v. Morris, [1942] O.W.N. 447 where he said: “The doctrine of stare decisis is one long recognized as a principle of our law.

Sir Frederick Pollock says, in his First Book of Jurisprudence, 6th ed., p. 321: “The decisions of anordinary superior court are binding on all courts of inferior rank within the same jurisdiction, and, though not absolutely binding oncourts of co-ordinate authority nor on that court itself, will be followed in the absence of strong reason to the contrary’.” I think that “strong reason to the contrary” does not mean a strong argumentative reason appealing to the particular Judge, but

something that may indicate that the prior decision was given without consideration of a statute or some authority that ought to havebeen followed. I do not think “strong reason to the contrary” is to be construed according to the flexibility of the mind of the particularJudge. [67] Justice Barnes of this Court applied the principle of comity in NOC Proceedings in following an earlier decision wherein thesame claims of the patent at issue had been construed.

He applied the same construction in Pfizer Canada Inc v Canada (Minister of Health), 2007 FC 446, (2007), 59 CPR (4th) 166 (FC) where he wrote at paragraph 31: 31 In a case like this one, the principle of comity does apply because Justice Hughes' decisions in Pharmascience, above, and Cobalt,above, turn solely on his construction of claim 22 of the 493 Patent without any reliance upon or reference to the expert opinions offeredby the parties.

Justice Hughes was able to construe the patent by examining only its language and, in so doing, he has made adetermination on an issue of law which is deserving of deference. In such a context it does not matter if the evidentiary record before meis different from that which was placed before Justice Hughes.

If he was able to construe the patent without resorting to extrinsicevidence then comity dictates that I do the same, absent a finding that Justice Hughes was "manifestly wrong". [68] Under the principle of comity, therefore, I must respect the decision of Crampton J in respect of the various findings that hemakes unless I am persuaded that he was “manifestly wrong” in that he overlooked some relevant statute or authority, or that hemisapplied the relevant statute or authority, or that there have been subsequent statutory changes or new authorities that are relevant.Where he makes factual findings on the evidence before him, I am free to make different findings if the evidence before me is different.It is in this latter respect that the jurisprudence that has developed under the NOC Regulations must be examined.

I will do that next.

c) The jurisprudence [69] There is no doubt that the NOC Regulations set out an imperfect procedure for the efficient resolution of innovator/genericpharmaceutical disputes. The United States Hatch-Waxman Act, including its various amendments, in general does a much better job ofdealing with several of the procedural matters that vex our Court. Re-litigation is one of them. [70] Given that this Court is overwhelmed at times with NOC Regulation proceedings, several attempts have been made in anendeavour to reduce or eliminate seemingly redundant litigation.

The Regulations, section 6(5)(b), provide an opportunity for a generic(second person) to move to strike an application as an abuse of process. The Federal Courts Rules make provision for striking anyproceeding on a number of grounds, including abuse. These Rules have rarely been effective in dealing with applications as opposed toactions. The Supreme Court of Canada in Toronto (City) v CUPE Local 79, 2003 SCC 63 , [2003] 3 SCR 77, per Arbour J, atparagraph 35 has stated that judges have an inherent and residual discretion to prevent an abuse of the court’s process.

The application ofsuch discretion appears to be tentative at best. [71] There is a concept of comity in the context of NOC proceedings was considered in the decision of Barnes J of this Court inPfizer Canada Inc v Canada (Minister of Health), 2007 FC 446 , [2008] 1 FCR 672, at paragraph 30: 30 I agree with counsel for Pfizer that the principle of judicial comity may not be readily applicable to prohibition proceedingsbrought under section 6(1) [as am. by SOR/98-166, s. 5] of the NOC Regulations.

That can be so because even in cases which involve acommon generic product and challenges to an identical patent, the allegations set out in the respective NOAs of the generic challengers,or the evidence the parties present, may be sufficiently different that disparate judicial outcomes are possible. This point is recognized inthe recent decision in Sanofi-Aventis Canada Inc. v.

Novopharm Ltd., 2007 FCA 163 , [2008] 1 F.C.R. 174 (F.C.A.), where, in a discussion concerning abuse of process, Justice Edgar Sextonobserved at paragraph 50: [page 687] Multiple NOAs issued by the same generic relating to a particular drug and alleging invalidity of a particular patent will generally notbe permitted, even if different grounds for establishing invalidity are put forward in each.

However, where one generic has made anallegation but has failed to put forward the requisite evidence and argument to illustrate the allegation is justified, it would be unjust topreclude a subsequent generic, who is apprised of better evidence or a more appropriate legal argument, from introducing it. Althoughthis situation may give rise to the possibility of an inconsistent result, this concern is overridden by the potential for unfairness to the

generic that is barred from bringing forward its case simply because another generic's approach was inadequate. The concern expressed above does not, however, apply where the issue for determination is one of patent construction. Inasmuch as this is an issue of law for the Court to decide, there should, in theory at least, be only one correct answer regardless of the expert evidence brought to bear upon it.

This is particularly evident when one considers that the experts are speaking objectively for the notional person skilled in the art. [ 72 ] In dealing specifically with the NOC Regulations , the attempts by the Court to deal with re-litigation begins with the decision of the Federal Court of Appeal in Sanofi-Aventis Canada Inc v Novopharm Inc , 2007 FCA 163 . That Court dealt with an appeal - first from a Prothonotary, then the Federal Court - from a decision arising from a motion to strike under section 6(5) (

b) of the NOC Regulations brought by the second person (generic). The first person (innovator) had brought an application for prohibition against the generic in respect of the same patent which, in earlier NOC Proceedings against another generic, had been held to be invalid. The Prothonotary struck out the application; the trial judge reversed that decision. The Court of Appeal, in a two-to-one decision, reversed the Trial Judge and upheld the Prothonotary in striking out the application.

Sexton JA (with whom Sharlow JA concurred) wrote at paragraph 50: 50 Finally, Sanofi-Aventis and Schering argue that a finding of abuse of process in this case will lead to unfairness. They say that while first persons will not be permitted to defend against allegations by subsequent generics after the same allegation made by an earlier generic has been found to be justified, subsequent generics will be permitted to repeat allegations already made earlier by other generics even if the earlier allegations were found to be unjustified. However, there is no unfairness in this scenario.

All parties are held to the same standard: they must each put forward their entire case, complete with all relevant evidence, at first instance. The innovator is prevented from relitigating an issue already decided in a proceeding to which it was a party with the aid of additional evidence it chose not to adduce in the earlier proceedings. Generics likewise must put forward their full case at the first opportunity.

Multiple NOAs issued by the same generic relating to a particular drug and alleging invalidity of a particular patent will generally not be permitted, even if different grounds for establishing invalidity are put forward in each. However, where one generic has made an allegation but has failed to put forward the requisite evidence and argument to illustrate the allegation is justified, it would be unjust to preclude a subsequent generic, who is apprised of better evidence or a more appropriate legal argument, from introducing it.

Although this situation may give rise to the possibility of an inconsistent result, this concern is overridden by the potential for unfairness to the generic that is barred from bringing forward its case simply because another generic's approach was inadequate. In each situation, it is necessary to balance the effect of a proceeding on the administration of justice against the unfairness to a party from precluding it from bringing forward its case. [ 73 ] Nadon JA dissented. He wrote at paragraph 119: 119 To sum up, I conclude that this is not a case where the doctrine of abuse of process should be applied.

First, the parties to the proceedings herein are not the same as those that were before Mactavish J. in Sanofi Aventis, supra. Second, the issue herein and that before Mactavish J. is primarily one of fact and, as a result, it would be open to the trier of fact in this proceeding to come to a different conclusion.

Third, the appellant, in seeking to prohibit the Minister from issuing a NOC to Novopharm, is simply exercising its rights under the NOC Regulations which, as I have explained, do not expressly or implicitly prevent a patentee from relitigating an issue previously litigated against another generic drug manufacturer. Fourth, there is no "additional element" in the present matter which would make of the appellant's application an abuse of process.

Contrary to the situation in Hoffmann-La Roche, supra, it cannot be said that in litigating a second time the issue which it litigated against Apotex in Aventis Pharma, supra, the appellant's conduct calls for the application of the doctrine of abuse of process. Fifth, it cannot be concluded that the proceedings commenced by the appellant, following service of Novopharm's NOA, are either oppressive or vexatious. [ 74 ] Nadon JA revisited this decision in a later appeal, Janssen-Ortho Inc v Apotex Inc , 2009 FCA 212 . Section 6(5) (

b) was not at issue there. What was at issue was whether the Notice of Allegation (NOA) sent by a second person (generic) to a first person (innovator) before any application to the Court had been filed, could be considered to be an abuse of process. It was alleged that certain of the allegations had already been determined by the Courts. Nadon JA held that the remarks of Sexton JA were in obiter; and, in any event, a generic could not be precluded from making allegations in its NOA. He wrote at paragraphs 42 to 45: 42 In Sanofi-Aventis, supra, the question of abuse of process arose by reason of paragraph 6(5)(

b) of the Regulations, which provides that on a motion by a second person, the Federal Court may dismiss an application for prohibition on the ground that it is redundant, scandalous, frivolous or vexatious, or that it is otherwise an abuse of process. 43 In this appeal, however, the question is not whether the first person's application constitutes an abuse of process, but rather

whether the second person's allegations found in its NOA amount to an abuse of process. Paragraph 6(5)(

b) of the Regulations clearly does not apply in the present matter and this Court is not asked to dismiss an application for prohibition on a motion brought by a second person.

There can be no doubt that Sexton J.A.'s comments in Sanofi-Aventis, supra, were made in obiter and, thus, are not binding and, in any event, they do not support the position adopted by the Judge. 44 In my view, a fair reading of paragraph 50 of Sexton J.A.'s Reasons in Sanofi-Aventis, supra, does not lead to the conclusion that a second person can only put forward a NOA on grounds similar to those put forward by a different generic in other proceedings when it has better evidence to offer or better legal arguments to make.

I believe that at paragraph 50 of his Reasons, Sexton J.A. was simply attempting to explain his view that notwithstanding the possibility that different judgments might be rendered with respect to identical or similar NOAs, fairness required that a generic, such as Apotex in the present case, which had not yet litigated the issues which it raised in its NOA, be allowed to have its day in court.

In my view, it cannot be seriously argued that Sexton J.A. was advocating that an assessment of the second generic's evidence and legal arguments had to be made before it could send its NOA and respond to the application for p

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