2011 FC, 2011 FC 1316

Federal Court Cour fédérale 20111117 Docket: T-154-10 Citation: 2011 FC 1316 Ottawa, Ontario , November 17, 2011 PRESENT: The Honourable Mr. Justice Crampton BETWEEN: ALLERGAN INC., ALLERGAN SALES INC. AND ALLERGAN, INC. Applicants and THE MINISTER OF HEALTH AND SANDOZ CANADA INC.

Respondents REASONS FOR JUDGMENT AND JUDGMENT [ 1 ] The Applicants, (collectively “Allergan”), seek an order pursuant to subsection 6(1) of the Patented Medicines (Notice of Compliance) Regulations , SOR/93-133 to prevent the Minister of Health from issuing a Notice of Compliance (NOC) to Sandoz Canada Inc. until the expiry of two patents that Allergan owns, namely, Canadian Patent No. 2,440,764 (the ‘764 Patent) and Canadian Patent No. 2,225,626 (the ‘626 Patent). [ 2 ] If issued, the NOC that Sandoz has requested would permit it to market in Canada a generic version of a drug which combines two active ingredients, brimonidine tartrate (0.2%) (“brimonidine”) and timolol maleate (0.5%) (“timolol”), used in the treatment of glaucoma.

Allergan currently markets the branded version of that drug under the name “COMBIGAN”. [ 3 ] In support of its NOC, Sandoz filed an abbreviated new drug submission with the Minister in which it compared its drug (the “Generic Drug”) to COMBIGAN. Sandoz then sent a Notice of Allegation (NOA) to Allergan in which it alleged, among other things, that: i. the invention claimed by the ‘764 Patent was obvious as of the priority date of April 19, 2002 (the “Priority Date”), such that the ‘764 Patent is invalid;

ii. the Product Monograph of the Generic Drug will not induce infringement of any of the claims in the ‘626 Patent; iii. the Generic Drug will not infringe any of the claims in the ‘626 Patent; and iv. the ‘626 Patent is invalid for inutility, on the basis that: (

a) the claims therein cover non-useful subject matter; and (

b) the utility of that subject matter could not be soundly predicted as of the Priority Date and the Canadian filing date of the ‘626 Patent. [ 4 ] Allergan submits that Sandoz’s allegations are not justified, as contemplated by subsection 6(2) of the Regulations.

That said, Allergan concedes that Sandoz has put the invalidity issues raised in its NOA “into play”, such that the presumption of validity of the ‘764 Patent and the ‘626 Patent has been rebutted ( Novo Nordisk Canada Inc v Cobalt Pharmaceuticals Inc , 2010 FC 746 , at paras 68-69 [ Novo Nordisk ] ; Pfizer Canada Inc v Novopharm Ltd , 2009 FC 638 , at paras 35-36 [ Pfizer (2009 FC 638)]). [ 5 ] To obtain the order of prohibition that it seeks in this application, Allergan must demonstrate, on the balance of probabilities, that Sandoz’s allegations are not justified, either with respect to: i. the alleged obviousness of the invention claimed by the ‘764 Patent; or ii. all of the above-mentioned allegations that have been made in respect of the ‘626 Patent. [ 6 ] For the reasons that follow, I have concluded that Allergan has met its burden in respect of the alleged obviousness of the invention claimed by the ‘764 Patent.

Therefore, I will issue the requested order of prohibition in respect of the ‘764 Patent. [ 7 ] Given that the ‘764 Patent was issued more recently than the ‘626 Patent, it is not strictly necessary, for the purposes of the present application, to consider the allegations that Sandoz has made in respect of the ‘626 Patent.

In brief, any determinations that may be made in respect of the latter patent cannot affect the period of time during which Sandoz will be unable to market the Generic Drug, due to the conclusion I have reached in respect of the ‘764 Patent. [ 8 ] Nevertheless, in the event that I am found to have erred in my conclusion that the subject matter of the ‘764 Patent was not obvious, I have also assessed the issues that have been raised in respect of the ‘626 Patent.

In this regard, the issue of inducement of infringement is determinative, because the ‘626 Patent is a use patent, which cannot be directly infringed by Sandoz. I have concluded that Allergan has not met its burden on this issue.

In other words, I have determined that Sandoz’s allegation that it will not induce infringement of the ‘626 Patent is justified. [ 9 ] In the event that my conclusion on the inducement issue is overturned, I have proceeded to address the various other allegations that Sandoz has made in support of its position that the Generic Drug will not infringe the ‘626 Patent and that the ‘626 Patent is invalid.

I have concluded that Allergan has demonstrated, on a balance of probabilities, that those allegations are not justified. [ 10 ] In short, for the reasons that follow, I have determined that this application will be allowed with respect to the ‘764 Patent but dismissed with respect to the ‘626 Patent. I. Background A. Glaucoma

[ 11 ] Glaucoma is a chronic disease of the optic nerve that leads to progressive, irreversible loss of vision and can lead to blindness. [ 12 ] The precise cause of damage to the optic nerve is not entirely understood. However, it is often, but not always, associated with increased pressure of the aqueous humor located at the front of the eye. This is usually referred to as increased intraocular pressure (IOP), or ocular hypertension. If left untreated, IOP can lead to the development of glaucoma.

It is for this reason, and the fact that IOP lowering drugs seem to prevent further progression of the disease, that IOP is widely considered to be a major risk factor for glaucoma. [ 13 ] The terms “elevated IOP” and glaucoma were once used synonymously. However, it appears that it is now understood that glaucoma is a complicated disease which may be associated with high IOP, but can also strike people with statistically normal IOP. [ 14 ] Although there is no cure for glaucoma, several different types of drugs have been developed for its treatment.

For more than 100 years, ophthalmologists have been using cholinergic drugs to treat glaucoma and IOP. Drugs in this class mimic and amplify the parasympathetic nervous system, and have the general effect of relaxing muscle tissue. However, they have been associated with significant side effects. [ 15 ] A second class of drugs that have been used since at least the 1920s to treat glaucoma are andrenergic agents, such as epinephrine.

With the advent of modern anti-glaucoma drugs beginning in the 1970s, the use of epinephrine has become progressively less popular, mainly due to its significant side effects. [ 16 ] A third class of drugs that are used to lower IOP and treat glaucoma are best known as beta andrenergic antagonists, or beta (ß) blockers. Beta andrenergic antagonists block natural epinephrine from having activity at the ß-receptors, and are thereby thought to allow the same IOP lowering effects as epinephrine, but with fewer side effects. In addition, beta blockers reduce IOP by decreasing aqueous humor production.

Beta blockers are one of the most commonly used classes of drugs for treating glaucoma, and include drugs such as timolol, which was first made available commercially by Merck Frosst Canada Ltd. in approximately 1978, under the brand name TIMOPTIC. Since that time, timolol has become one of the mainstays in the treatment of glaucoma and IOP. [ 17 ] A fourth class of IOP lowering drugs is comprised of drugs generally known as alpha-2 agonists. Alpha-2 agonists act by stimulating the alpha andrenergic receptors, thereby lowering IOP. Drugs in this class first became commercially available in the 1980s.

Brimonidine is a drug in this class that has been available as an ophthalmic solution since approximately 1996, when Allergan launched a product containing 0.2% by weight of brimonidine, under the brand name ALPHAGAN.

Sandoz launched a generic version of ALPHAGAN the following year, after sending an NOA to Allergan which was not challenged. [ 18 ] Two additional classes of IOP lowering drugs are prostaglandin analogs, such as latanoprost, and carbonic anhydrase inhibitors (CAIs), such as dorzolamide and brinzolamide. [ 19 ] While both brimonidine and timolol can be effective in reducing IOP in some patients, monotherapy involving these medications does not help everyone.

For example, these drugs may not be considered to be useful for certain patients because of their undesirable side effects or their medical contraindications, or because they are not effective for a particular individual. In other patients, additional IOP lowering beyond the level that can be achieved with either of these drugs administered separately is required. Accordingly, those two drugs began to be prescribed for concomitant (also known as adjunctive or serial) administration prior to the filing date of the ‘764 Patent. B. The Relevant patents [ 20 ] Pursuant to

section 4 of the Regulations, Allergan listed four patents in the Patent Register in respect of COMBIGAN. However, Allergan has chosen to bring this application only in respect of the allegations that Sandoz has made regarding the ‘764 Patent and the ‘626 Patent. [ 21 ] The ‘764 Patent was filed on April 9, 2003, published on October 19, 2003 and issued on October 25, 2005. It claims priority from a U.S.

Patent filed on April 19, 2002. [ 22 ] The ‘764 Patent makes claims with respect to ophthalmic topical pharmaceutical compositions for the treatment of glaucoma or ocular hypertension including, among other things, a composition comprising brimonidine (0.2%), timolol (0.5%) and the preservative

benzalkonium chloride (BAK) (0.001% to 0.01% ) in a pharmaceutically acceptable carrier. The descriptive

section of that patent concludes by stating that, when administered twice a day (BID) for three months, this combination of brimonidine and timolol was superior to equivalent concentrations of timolol administered BID and brimonidine administered three times a day (TID), in lowering the elevated IOP of patients with glaucoma or ocular hypertension.

It also states that the combination “administered BID demonstrated a favorable safety profile that was comparable to Timolol BID and better than Brimonidine TID with regard to the incidence of adverse events and discontinuation due to adverse events.” [ 23 ] The ‘626 Patent was filed on June 17, 1996, published on January 16, 1997, issued on September 3, 2002 and claims priority from U.S.

Patent filed on June 28, 1995. [ 24 ] The ‘626 Patent describes a “new method of protecting the optic nerve and retina of the mammalian eye from damage by glaucoma and other noxious provocations.” This neuroprotection is stated to be provided by a new use of an effective amount of certain compounds, including brimonidine, “to inhibit or prevent nerve cell injury or death … for protecting the retinal or optic nerve cells in a mammal suffering a noxious action or at risk of experiencing a noxious action on said nerve cells.” Prior to the Priority Date, brimonidine had been known to be effective at lowering IOP and was widely used for that purpose.

C. COMBIGAN [ 25 ] COMBIGAN is the brand name of the composition described in the ‘764 Patent. It is sold in Canada pursuant to NOCs issued to Allergan on December 9, 2003 (for the control of IOP) and August 24, 2007 (for the reduction in long term fluctuation of IOP). As is the case with the Generic Drug, the active ingredients in COMBIGAN are brimonidine (0.2%) and timolol (0.5%), and the preservative is BAK (0.005%). II. The Parties’ Experts [ 26 ] Three individuals adduced expert evidence on behalf of Allergan and two adduced such evidence on behalf of Sandoz. A. Allergan’s experts [ 27 ] Mr. Gary J.

Beck is one of the inventors of COMBIGAN identified in the ‘764 Patent. From 1995 to 1999, he held the title of Scientist at Allergan. In that capacity he had responsibility for, among other things, attempting to develop an ophthalmic formulation that combined brimonidine and timolol. In 1999, he became a Global Project Manager and thus remained closely involved in the development of the combination product. He was also part of the team that prepared and submitted the successful application for approval of COMBIGAN to the U.S. Food and Drug Administration (U.S. FDA). Mr.

Beck provided affidavit evidence and was cross- examined with respect to the development of COMBIGAN, its reduced side effects relative to brimonidine monotherapy and timolol monotherapy, its efficacy, its commercial success and its development costs. [ 28 ] Dr. Robert Fechtner is a Professor of Ophthalmology and Director of the Glaucoma Division at the New Jersey Medical School of the University of Medicine and Dentistry of New Jersey.

He is also an attending physician at University Hospital in Newark , New Jersey and conducts his clinical practice at the New Jersey Medical School, where he has studied and treated patients with glaucoma. In addition being on various boards and committees related to glaucoma, he has served on many editorial boards for publications in the field of ophthalmology. His main research focus during his career has been the treatment of glaucoma. He has authored many articles, books and chapters related to glaucoma and the reduction of IOP. Dr.

Fechtner provided affidavit evidence with respect to the subject matter of the ‘764 Patent, the person of ordinary skill in the art (“POSITA”) to which that patent relates, Sandoz’s NOA and the evidence provided by Sandoz’s experts, particularly in respect of the alleged obviousness of the subject matter of certain of the claims in the patent. [ 29 ] Dr. Kevin Parkinson is a practising ophthalmologist in British-Columbia. He also possesses hospital privileges at the Coquitlam Cataract Centre and at Ridge Meadows Hospital.

He has completed fellowship training in the area of glaucoma, has seen approximately 50,000 patients with this disease and gives lectures on the topic of ophthalmology and glaucoma. He swore two affidavits, dated November 13, 2010 and March 15, 2011, with respect to the subject matter of the ‘626 Patent, the POSITA to which that patent relates, Sandoz’s allegations of non-infringement, and the evidence provided by Sandoz’s experts.

B. Sandoz’s experts [ 30 ] Dr. Henry Jampel is a professor of Ophthalmology at the John Hopkins University School of Medicine. He is also a practicing physician who has treated thousands of patients with glaucoma and related eye diseases. He has been active in research on glaucoma, has held editorial roles with various ophthalmological journals, and is the author of numerous papers and book chapters on glaucoma and IOP.

He provided affidavit evidence with respect to the subject matter of both the ‘764 Patent and the ‘626 Patent, the POSITAs to which those patents relate, the allegations in Sandoz’s NOA and the evidence provided by each of Allergan’s experts. [ 31 ] Dr. Ashim Mitra is the Chairman of the Division of Pharmaceutical Sciences at the University of Missouri . He has conducted extensive research with respect to various drug delivery technologies, including ocular drug delivery. He is the Director for Translational Research at the university’s School of Medicine .

In that capacity, he is involved in selecting new technologies from bench research, particularly in the ophthalmic area, and co-ordinating pre-clinical studies. His research has focused on the synthesis and formulation of chemical compounds, including in ophthalmic drugs and examining their ability to be transported through membranes into the body. He has published extensively in the field of ophthalmic drugs and has made hundreds of presentations on the topic for various audiences.

He provided affidavit evidence with respect to the subject matter of the ‘764 Patent, the persons to whom that patent is directed, certain of the allegations in Sandoz’s NOA and the evidence provided by Mr. Beck. [ 32 ] Allergan raised some serious concerns with respect to the credibility of Dr. Mitra. In short, Allergan referred to a number of U.S. cases in which Dr.

Mitra’s testimony has been found to be not credible (including Allergan, Inc v Barr Laboratories, Inc , 2011 US Dist LEXIS 101778, 09333 SLR, at paras 46-52 (D Del) [ Barr Laboratories ]; Syntex LLC v Apotex, Inc , 2006 WL 1530101, C01-02214 MJJ, at para 78 (ND Cal)), or misleading ( Roche Palo Alto et al v Apotex Inc et al , 526 F Supp 2d 985 , at 994 (ND Cal) ). Included among those cases was a case in which Dr.

Mitra took a position before this Court that was inconsistent, to say the least, with the position he subsequently took before a court in the U.S. (compare Barr Laboratories , above, with Pfizer Canada Inc v Canada (Minister of Health) , 2009 FC 1294 , at para 154 ). Allergan also drew the Court’s attention to inconsistent statements made by Dr. Mitra during cross-examination in the case at bar concerning the fact that, in six of the seven proceedings in which he has recently testified, it was his opinion that the patent was invalid (Applicant’s Record, at 940-943).

Given the foregoing, I have serious reservations regarding Dr. Mitra’s credibility. I have therefore approached his evidence with a considerable degree of caution ( Sanofi-Aventis Canada Inc v Ratiopharm Inc , 2010 FC 230 , at para 17 [ Sanofi ] ) and have generally found the evidence of Allergan’s witnesses to be more credible and reliable in instances where their evidence has conflicted with his evidence. III. Issues [ 33 ] Although many issues were raised in Sandoz’s NOA and in Allergan’s Application, the issues that continue to be pursued by the parties are as follows: 1.

Is the allegation that the ‘764 Patent is invalid on the ground of obviousness justified? 2. Will the product monograph (PM) for the Generic Drug induce infringement of any of the claims in the ‘626 Patent? 3. Are Sandoz’s allegations of non-infringement of the claims in the ‘626 Patent justified? 4. Is Sandoz’s allegation that the ‘626 Patent is invalid for inutility justified on the basis that either: (

a) the claims therein cover non-useful subject matter; or (

b) the utility of that subject matter could not be soundly predicted as of the priority date and the Canadian filing date of the ‘626 Patent? IV. Analysis A. Is the allegation that the ‘764 Patent is invalid on the ground of obviousness justified? [ 34 ] To assess this issue, it is necessary to first construe the claims of the patent and to discern the inventive concept in that patent ( Free World Trust v Électro Santé Inc , 2000 SCC 66 , [2000] 2 SCR 1024 , at para 19 [ Free World Trust ] ).

[ 35 ] Allergan has asserted claims 1-6 and 14-25 of the ‘764 Patent. The representative claim is claim 22, which narrows the fixed combination drug claimed in claim 1 to the specific fixed combination found in COMBIGAN. Claim 22 refers to claim 6, which in turn refers to claim 3, which in turn refers to claim 1, as follows: 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 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 therefor. [ 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 use of the Composition for the topical treatment of glaucoma and ocular hypertension. [ 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 been obvious to the skilled person, or (ii) required a degree of invention ( Apotex Inc v Sanofi-Synthelabo Canada Inc , 2008 SCC 61 , [2008] 3 SCR 265 , at para 67 [ Sanofi ] ).

(1) Step One - The skilled person and the relevant common general knowledge [ 38 ] Dr. Fechtner opined that the POSITA to whom the ‘764 Patent is addressed “is a person engaged in developing pharmaceutical formulations and treatment for methods for the eye, or is a specialist in treating diseases of the eye such as an optometrist or an ophthalmologist who also has experience in either developing ophthalmic pharmaceutical formulations or in designing and running clinical 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 formulators and to ophthalmologists. However, Sandoz subsequently took the position that the POSITA is a composite of a practicing ophthalmologist and a pharmaceutical formulator. During the oral hearing of this application, Sandoz characterized this difference between 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. [ 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.

(2) Step Two - The inventive concept

[46] Sandoz submits that “it is the claims that define the invention” in any patent and that the inventive concept of the ‘764 Patentmust be 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 theclaims of the patent (Free World Trust, above, at paras 14, 33, 51, 66).

That said, to achieve a “purposive construction,” is permissible tohave regard to other parts of the patent “through the eyes of a skilled addressee,” to resolve ambiguity and to achieve flexibility andfairness in 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 theclaims, there is 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 fortreating glaucoma. Sandoz submits that the inventive concept of those claims must be discerned from this description alone. Dr. Jampeltook the same 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 isboth necessary 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). [52] In Sanofi, above, at paras 77-78, the Supreme Court looked beyond the claims in question, which were confined to “[a] barechemical formula,” in ascertaining the inventive concept of those claims. A similar approach was adopted in Laboratoires Servier vApotex Inc, 2009 FCA 222, at paras 58-59.

This was necessarily done after claims construction had been completed, because the exerciseof claim construction is antecedent to the assessment of issues concerning validity and infringement (Free World Trust, above, at para19; Whirlpool, above, at para 43). [53] Contrary to Sandoz’s submissions, I do not read Sanofi as suggesting that, in determining the inventive concept of the claimsin a patent, it is only permissible to look beyond the claims of the patent when the claims are confined to a bare chemical formula or to aselection patent.

Indeed, the Court in that case specifically noted that its discussion of anticipation and obviousness was “applicable topatents generally” (Sanofi, above, at para 29). [54] The view expressed above is consistent with the approach taken in Eli Lilly Canada Inc v Novopharm Ltd, 2010 FCA 197 [EliLilly], at paras 33, 57, where the Federal Court of Appeal discerned the inventive concept of the claims from the disclosure

section of thepatent, after observing: “A selection patent is the same as any other patent. Its validity is vulnerable to attack on any of the grounds setout in the Act.” [55] The view expressed above is also consistent with the approach taken by my colleague Justice Mactavish in Novo Nordisk,above, at para 113. As in the case at bar, that case concerned a drug patent containing use claims.

After concluding that the allegedadvantageous properties of the drug repaglinide were not part of the claims because they were not referred to anywhere in the claims,Justice Mactavish observed: “That said, any advantageous properties possessed by repaglinide would indeed be inherent to thecompounds described in those claims, and thus should be taken into account when examining issues such as anticipation andobviousness.” Justice Mactavish proceeded to have regard to the alleged properties set out elsewhere in the patent in concluding that theinventive concept of the relevant claims of the patent, which were not confined to a bare chemical formula, included “repaglinide and itssurprising pharmacokinetic properties when used to treat diabetes mellitus” (Novo Nordisk, above, at paras 186, 308). [56] In the case at bar, Sandoz and Dr.

Jampel submitted that the inventive concept of the claims of the ‘764 Patent is limited tothe Composition itself, for use in treating glaucoma or ocular hypertension. This is essentially what Justice O’Reilly concluded with

respect to the only other fixed combination product (COSOPT) that has been approved for topical treatment of glaucoma in North America ( Merck & Co v Canada (Minister of Health) , 2010 FC 1042 , at para 38 [ Merck (2010 FC 1042) ]). As discussed, above, the position of Sandoz and Dr. Jampel on this point was rooted in their view, which I do not share, that the inventive concept of the claims of the ‘764 Patent must be discerned from the claims themselves. [ 57 ] Allergan submitted that the chemical stability of the Composition was a distinct aspect of the innovative concept of the ‘764 Patent. In the Background

section at the beginning of the patent, reference was made to the recognized need for a composition comprising brimonidine and timolol which, among other things, has “increased stability.” However, as Dr. Jampel noted and as Dr. Fechtner conceded, no evidence of such increased stability was disclosed in the patent, or by Allergan’s experts. As to whether chemical stability itself is part of the innovative concept of the patent, Mr. Beck conceded that a pharmaceutical product has to have sufficient stability to support its shelf life.

Therefore, I prefer to characterize this aspect of the innovative concept as being the combination of brimonidine (0.2%), timolol (0.5%) and BAK (0.005%) in single stable solution with a pharmaceutically acceptable carrier. [ 58 ] I am satisfied that the inventive concept of the claims of the ‘764 Patent also includes (

i) the improved safety profile of the Composition, (ii) BID dosing without an afternoon reduction in efficiency, and (iii) the reduction in the daily load of preservative administered to patients taking both brimonidine and timolol. Although Allergan submitted that the inventive concept of the claims further includes “[i]ncreased IOP lowering of the combination as compared to monotherapy with individual agents,” this was simply baldly asserted and was not further developed in Allergan’s written or oral submissions. Accordingly, it will not be further addressed in these reasons. [ 59 ] With respect to the improved safety profile, the Background

section at the outset of the ‘764 Patent noted that “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.” The patent then states: “Unexpectedly, it has been discovered that brimonidine in combination with timolol meets these criteria.” [ 60 ] After reporting the results of a substantial study comparing the side effect profiles of brimonidine monotherapy, timolol monotherapy and the fixed combination drug claimed by the patent, the disclosure

section of the patent concludes by stating: T he Combination administered BID demonstrated a favorable 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. [ 61 ] I accept Dr.

Fechtner’s opinion that “[t]he POSITA would have considered the improved safety profile [of the fixed combination drug], including the reduction of incidences of adverse events and discontinuance due to adverse events, to be part of the invention claimed in the ‘764 Patent.” That is to say, I accept his view that improved safety profile is part of the inventive concept of the ‘764 Patent. [ 62 ] With respect to BID dosing without an afternoon reduction in efficiency, Dr. Fechtner reported in his affidavit that the U.S.

FDA only approved ALPHAGAN to be administered TID due to concerns of an afternoon reduction (or “trough”) in the efficiency of brimonidine when administered BID. Among other things, the clinical trial that was described in the ‘764 Patent assessed the IOP lowering of the Composition at times 0, 2, 7 and 9 hours. Dr.

Fechtner explained that the nine hour measurement was significant because it was taken at a time when it would be expected that patients being administered brimonidine TID would display a greater IOP lowering, due to the effect of the second daily dose of brimonidine (taken about an hour prior to the nine hour measurement). Dr. Fechtner proceeded to observe: Despite this, the inventors report [in the disclosure of the ‘764 Patent] that the fixed combination drug did not demonstrate a trough in efficiency in the afternoon when compared with patients receiving ALPHAGAN administered TID.

Surprisingly, the inventors report that mean IOP for patients administered the fixed combination drug (BID) was statistically significantly lower at the 9 hour point and for those patients receiving ALPHAGAN (TID) after 6 weeks and after 3 months … The fact that patients that were administered ALPHAGAN TID did not show lower IOP at the 9 hour time point shows that the inventors had developed a formulation which eliminated the afternoon IOP trough despite BID administration. [ 63 ] With respect to the reduction in the daily load of preservative administered to patients taking both brimonidine and timolol, Mr.

Beck reported in his affidavit that his team at Allergan expected that a reduction in the concentration of BAK might result in a reduction in the efficacy of the Composition. Nevertheless, due to the side effects associated with BAK, his team conducted experiments to investigate whether a lower amount of BAK could be used as a preservative in the Composition. Through their work, the team discovered that a combination of brimonidine and timolol “could be effectively preserved from microbial contamination using only

0.005% BAK; less than half the amount of BAK known to be used by Merck in formulating [COSOPT] and a reduction of 70% from the amount to which the eye is exposed when both drugs are used in monotherapy.” Once again, this discovery was described in the disclosure

section of the ‘764 Patent.

(3) Step Three - The differences between the state-of-the-art and the inventive concept [ 64 ] The differences between the prior art discussed at paragraphs 41 to 45 above and the innovative concept of the claims in the ‘764 Patent are the following: (

i) the Composition combines brimonidine and timolol into a single, chemically stable, formulation - that combination had never previously been made or reported in the prior art, (ii) the Composition has a superior safety profile, relative to brimonidine TID, (iii) the Composition permits BID dosing without an afternoon reduction in efficiency, relative to brimonidine TID treatment, and (iv) patients who are treated with the Composition receive a significantly reduced daily load of BAK, relative to concomitant treatment of brimonidine and timolol. [ 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. [ 66 ] With respect to the superior safety profile of the Composition, the ‘764 Patent disclosed, among other things, that in the clinical trial discussed in Example II of the specification, adverse events leading to the discontinuation of patients occurred in only 3.6% (7/193) of the patients who were administered the Composition, versus in 14.3% (28/196) of the patients who were administered brimonidine alone.

In addition, it was disclosed that serious adverse events were reduced by 50% for the combination product, relative to monotherapy treatment of brimonidine or timolol. Moreover, it was disclosed that the composition had what may be described as a statistically significant (p < 0.034) improved allergy profile, compared with brimonidine monotherapy. [ 67 ] Sandoz submitted that various articles referred to by Dr.

Jampel in his affidavit, and attached thereto, reported that the efficacy of the Composition was not found to be statistically significant from the efficacy of concomitant treatment of brimonidine and timolol. However, those articles were all published a number of years after the Priority Date, and did not address the common general knowledge of the POSITA as at the Priority Date. Moreover, those articles were not attached to Sandoz’s NOA. These important facts distinguish this “post-art” evidence from the cases relied upon by Sandoz.

Sandoz was not able to identify any case in which such articles were admitted or given any weight in a proceeding involving an application under the Regulations. In my view, those articles are not admissible, as they are not “probative of a question at issue; in this case, the state-of-the-art at the relevant time” ( Eli Lilly Canada Inc v Apotex Inc , 2007 FC 455 , at para 339 ). In short, they are not relevant to my determination of the differences between the inventive concept of the ‘764 Patent and the state-of-the-art as understood by the POSITA as at the Priority Date.

As an aside, I would add that even if the Composition is simply as effective as concomitant administration of brimonidine and timolol, it would continue to have other demonstrated advantages over that concomitant therapy, including (

i) requiring the administration of only two drops a day versus five in the U.S. and four elsewhere, and (ii) eliminating an afternoon trough, relative to BID administration of brimonidine in monotherapy or concomitant therapy. [ 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.

(4) Step Four - Were the differences between the inventive concept and the state of the art obvious?

[ 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? [ 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) ]). [ 73 ] A similar response is warranted in respect of Sandoz’s submission that a fixed combination of an Alpha2 agonist (a class of drugs that includes brimonidine) and a beta blocker, such as timolol, had been described in the DeSantis Patent. I accept Dr. Fechtner’s opinion that the POSITA would not have read the DeSantis Patent as disclosing the combination of brimonidine and timolol.

Although that patent stated that “the alpha-2 agonists which can be employed in the compositions of the present invention include all pharmaceutically acceptable compounds which have alpha two agonist activity and are effective in controlling intraocular pressure,” I accept Dr. Fechner’s position that the class of compounds described “is indefinite, undefined and unknowable.” As Dr. Fechtner also pointed out, the DeSantis patent provided no experimental data of any kind to guide the POSITA in understanding what was included in this broad language. I note that Dr.

Jampel acknowledged in cross-examination that (i) “[t]here is an almost unlimited number of ways that this patent of combining an Alpha-2 agonists and a beta blocker could be executed”, and (ii) the DeSantis Patent gave no data with respect to efficacy, side effects or stability. [ 74 ] Sandoz observed that the ‘764 Patent recognized that brimonidine and timolol had been combined in concomitant therapy.

Sandoz noted that this is a binding admission as to what constitutes the state-of-the-art, and submitted that Allergan cannot argue that there is anything inventive in using brimonidine and timolol together to treat glaucoma and ocular hypertension. Rather, Sandoz submitted that the invention (which it denies was achieved by Allergan) is confined to the making of a fixed combination product with brimonidine and timolol in “the same bottle.” [ 75 ] I do not interpret Allergan to be taking the position that there is anything inventive in using both brimonidine and timolol to treat glaucoma or ocular hypertension.

Therefore the focus of the assessment below will be upon whether the differences between the inventive concept and the state- of-the-art discussed at Step Three of this analysis immediately above were obvious. Within the specific context of the “obvious to try” analysis, the focus will be upon whether it was more or less self-evident that the Composition would not only work, but also offer those differences, and whether the solutions for achieving the composition were predictable and known to the POSITA.

[76] In that context, a series of articles appended at Tabs H, I, K and AA to Dr. Jampel’s affidavit are of no assistance to Sandoz,because, as Dr. Jampel acknowledged in cross-examination, those articles (

i) did not test a combination of brimonidine and timolol, (ii)did not explore the potential BAK levels that could be used in a combination product, and (iii) did not address the allergies or the kindsof other local side effects that can lead to a discontinuance of therapy. Indeed, the duration of the first three of those studies was limitedto the administration of a single drop, two days, and three weeks, respectively, which was too short to test for allergies and other adverseeffects that often take much longer to manifest themselves. As noted by Mr.

Beck in his affidavit, “allergic conditions would typicallynot appear to be detectable after a short trial of only a few weeks or less.” This evidence was not contradicted. [77] A fifth study, appended at Tab Z of Dr. Jampel’s affidavit, was similarly unhelpful. Although it addressed safety, it did sosimply by assessing vital signs and spontaneously reported adverse events. Dr. Jampel did not suggest that the study yielded any usefuldata in that regard, and Dr. Fechtner’s position that the

article did not disclose useful safety data was not contested. [78] Sandoz submitted that the clinical trial reported in the ‘764 Patent compared the Composition with the monotherapies ofbrimonidine TID and timolol BID, rather than with the concomitant administration of those active ingredients. In this regard, it noted thatthe uncontradicted evidence was that (

i) the concomitant administration of two glaucoma drugs was a common practice at the time of thePriority Date, and (ii) brimonidine and timolol were among the drugs that were being administered concomitantly at that time.

Allerganreplied that it had no obligation to expand its clinical trials to include a comparison with concomitant administration of those ingredients.Stated alternatively, while Allergan recognized that it bears the burden of demonstrating the alleged inventive concepts of theComposition, relative to the state-of-the-art as at the Priority Date, it submitted that it had no obligation to create data pertaining toconcomitant therapy for the purposes of demonstrating those alleged inventive concepts. Allergan also noted that the uncontradictedevidence of Dr.

Fechtner was that the state-of-the-art suggested that the side effect profile of the only other fixed combination drug tohave been approved by the U.S. FDA prior to the Priority Date (COSOPT) was worse than (

i) the side effect profile for concomitantadministration of the two active ingredients (dorzolamide and timolol), with respect to eyelid pain and discomfort (reported in theStrohmaier study), and (ii) the side effect profile of timolol administered as monotherapy (reported in the Clineschmidt study). [79] On the particular facts of this case, I agree with Allergan’s position on this point. Sandoz was not able to identify anyjurisprudence to support its position.

In my view, in the absence of any prior art which demonstrated a safety profile for concomitanttherapy comparable to that which was reported for the Composition in the ‘764 Patent, it is entirely appropriate to recognize that superiorsafety profile as being one of the differences that distinguish the Composition from the prior art. [80] Sandoz raised a similar argument with respect to Allergan’s failure to compare the Composition with brimonidine dosed BID.In this regard, Sandoz noted that brimonidine is approved for BID dosing in Canada and elsewhere outside of the United States.

In myview, this argument ignores the important fact that part of the innovative concept of the Composition is that it eliminated the afternoonreduction in efficacy of brimonidine administered BID. As discussed at paragraph 62 above, according to Dr. Fechtner, whose testimonyon this point was not contested, this was a significant concern of the U.S. FDA. By overcoming this afternoon reduction in efficiency ofbrimonidine administered BID, the Composition achieved an innovation, even if the principal commercial benefit of that innovationarose in the United States.

In short, this discovery, together with the discovery of a way to formulate brimonidine and timolol together ina chemically stable formula, and the discovery of surprising safety effects, (i) “added to the cumulative wisdom on the subject of” theseactive ingredients, and (ii) provided a method whereby these discoveries can reduce the incidence of blindness in the population throughpractical application (Shell Oil Co v Canada (Commissioner of Patents), (SCC), [1982] 2 SCR 536, at 549; CalgonCarbon Corp v North Bay (City), 2005 FCA 410, at paras 11-13). [81] Sandoz was unable to identify any jurisprudence to support the position, which I do not accept, that an innovation cannot berecognized in assessing obviousness unless it has value in Canada.

Sandoz also provided no support for its inference that the innovationwas of no benefit in Canada, where doctors who are concerned about the reduction in afternoon effectiveness of brimonidine BIDtherapy now have the option of prescribing COMBIGAN. [82] Sandoz suggested that the Composition was obvious from the prior art because (

i) the concentrations of timolol (0.5%) andbrimonidine (0.2%) were the same concentrations of those ingredients that were included in other drugs being sold at that time, (ii) theconcentration of BAK (0.005%) is the same as in Allergan’s ALPHAGAN product, which was launched before the Priority Date, and(iii) the excipients in the Composition are the same as those in Merck’s TIMOPTIC product, which also was launched before the PriorityDate. In this regard, Sandoz noted that Dr.

Fechtner acknowledged in cross-examination that the most prescribed concentration of timololin the United States at the time of the Priority Date was 0.5%. Sandoz added that there is no discussion in the ‘764 Patent with respect toany problems encountered in formulating a combination of brimonidine and timolol.

It proceeded to assert that “[t]he skilled formulatorwould be able to easily manufacture such a combination.” However, Sandoz never offered any explanation whatsoever as to why no oneever did so (Beloit Canada Ltd v Valmet Oy (1986), 8 CPR (3d) 289, at 295; Janssen-Ortho Inc v Novopharm Ltd, 2007 FCA 217, atpara 24 [Janssen-Ortho]).

[ 83 ] Sandoz observed that Mr. Beck admitted in cross-examination that it was “not problematic” to make the combination product. In my view, this seriously mischaracterizes Mr. Beck’s evidence. In the passages of his cross-examination to which Sandoz referred, Mr.

Beck’s response was confined to what he characterized as being “the actual physical combining of the various active and inactives.” He explicitly distinguished between “the simple compounding of the formula in its inaqueous solution,” which he characterized as being “not difficult to do,” and the obstacles that he and his team encountered “from a chemical standpoint.” Those obstacles are discussed at paragraphs 96 to 103 below. [ 84 ] I accept Dr.

Fechtner’s statement that the improved safety profile of the Composition is remarkable and could not have been predicted in advance of creating the Composition and conducting experimentation to ascertain the results. I note that, in cross- examination, Dr. Jampel could not identify any prior art which demonstrated that the concomitant administration of brimonidine in timolol BID reduced side effects.

In addition, he ultimately conceded that the improved side effects disclosed in the ‘764 Patent were “unexpected.” The unexpected nature of the improved safety profile of the Composition is further corroborated by Mr. Beck’s statement that he and his colleagues did not predict the improved allergy profile of the Composition and that they considered the results of the clinical trial with respect to that improved allergy profile to have been surprising. [ 85 ] I also accept Dr. Fechtner’s statements that the POSITA would have known that (

i) potential problems might be encountered when formulating brimonidine and timolol into a fixed combination drug, and (ii) “differences in pharmacokinetics, the additive nature of adverse effects with multiple drugs, and potential drug interactions were difficulties to be overcome in developing a fixed combination drug.” The various unexpected difficulties encountered by Mr. Beck and his team are discussed at paragraphs 96 to 103 below. The significant time and effort that Mr. Beck and his team spent overcoming those difficulties lend credence to Dr.

Fechtner’s statement that it would not have been self-evident or obvious to the POSITA that a chemically stable Composition could be achieved. Dr. Fechtner’s conclusion on this point is further supported by Mr. Beck’s statement, which I find credible, that each time he and his team began with a new potential formulation, they believed that it could fail at any stage of the process. [ 86 ] In addition, the significant adverse side effects that were known to exist with BAK lend credence to Dr.

Fechtner’s opinion, which I accept, that the POSITA would not have initially selected BAK as the preservative for the Composition. [ 87 ] In response to all of the foregoing, Sandoz submitted that the POSITA would have started the testing process with a formulation based on TIMOPTIC, including timolol with a concentration of 0.5% and BAK as the preservative . In the latter regard, Dr. Mitra stated that BAK is the preservative in the majority of all ophthalmic products including IOP lowering products.

He also stated that the POSITA would have had no reason to seek to replace BAK, which is the preservative in TIMOPTIC and in ALPHAGAN, with another preservative. With respect, this fails to address that BAK was known to have adverse cytotoxic effects and was replaced by Purite in Allergan’s second generation ALPHAGAN product, ALPHAGAN P. For that reason, Dr. Jampel conceded that if the POSITA used ALPHAGAN P as his starting point, he would have ended up with a formulation that contains Purite, rather than BAK. Dr. Jampel also acknowledged that, by March 2001, the POSITA would have been aware that (

i) Purite was a preservative in ALPHAGAN P, (ii) Purite had a “gentler side effect profile than BAK,” and (iii) ALPHAGAN P was formulated at 0.15 percent brimonidine, rather than the 0.2% used in ALPHAGAN. [ 88 ] Dr. Mitra also stated that the mechanism of action of Purite would suggest that it would be an inappropriate preservative for a formulation containing timolol. He added that the POSITA would have realized that Purite may oxidize the sulfur of the timolol molecule. I place little weight on this evidence because (

i) as discussed at paragraph 32 above, there have been serious credibility issues raised with Mr. Mitra as a witness, (ii) I accept Dr. Fechtner’s position that the prior art (namely, ALPHAGAN

P) taught away from the use of BAK, based on its known adverse side effect profile and Allergan’s successful formulation of ALPHAGAN P with Purite, and (iii) I find it difficult to accept that Allergan would have undertaken the time and expense associated with attempting to formulate a solution with Purite, if it was self-evident that Purite would not work with timolol. The latter observation also applies to the time and effort that Allergan spent attempting to (

i) formulate a product with other active ingredients, including the Brimo X and Synergel formulations, and (ii) determine the appropriate concentration of BAK to use in the Composition. [ 89 ] Dr. Mitra suggested that the POSITA would have known that a fixed combination of timolol and brimonidine could be formulated with a concentration of 0.005% BAK, because brimonidine may have some anti-bacterial activity, such that the 0.01% concentration of BAK that is used with timolol alone could be reduced by 50%.

However, in cross-examination, it was apparent that he was simply speculating on this point, because he stated that brimonidine, “being an active ingredient, maybe has some antibacterial activity so that you don’t need .02 … 01; half is enough” (emphasis added). He subsequently acknowledged that he had not investigated this matter. [ 90 ] Sandoz further submitted that the POSITA would not have considered using Purite because that substance is patented by Allergan.

However, this fails to recognize that the POSITA is a hypothetical person who is able to take into consideration all prior art, including that which may enjoy patent protection (see , for example, Eli Lilly Canada Inc v Apotex Inc , 2009 FC 320 , at para 50 , and Roger T. Hughes, Hughes and Woodley on Patents , 2ed., loose-leaf (Markham, Ont.: Lexis Nexis Butterworths, 2005), ch 5 at 166.4).

[ 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? [ 92 ] As has been noted, Sandoz submitted that the skilled formulator would have been able to easily manufacture the Composition. [ 93 ] In addition, Sandoz submitted that the time and effort spent by Mr. Beck and his team to develop the Composition were “routine.” In this regard, Sandoz asserted that (

i) the inclusion and exclusion criteria for the clinical trial discussed in the ‘764 Patent were typical of those used in clinical trials for IOP lowering drugs, (ii) the criteria for evaluation were typical, (iii) the safety criteria would be included in most, if not all, clinical trials of drugs to treat glaucoma and ocular hypertension, (iv) the methodology was typical of a clinical trial of ophthalmic drugs prior to the Priority Date, (

v) the study design was typical, and (vi) the type of data collected was typical. Sandoz maintained that “there is no invention in doing what is routine, even if unexpected results occur.” [ 94 ] I disagree with Sandoz’s positions that (

i) a skilled formulator would have been able to easily manufacture the Composition, and (ii) the time and effort spent by Mr. Beck and his team to develop the composition were “routine.” [ 95 ] In my view, Mr. Beck described, in a forthright and credible manner, a significant number of difficulties that he and his team encountered in their development of the Composition. Based on his evidence, and the supporting evidence of Dr. Fechtner discussed in the

section immediately above, I am satisfied that the skilled formulator would not have been able to easily manufacture the Composition, and that the efforts undertaken by Dr. Beck and his team to develop the Composition were not “routine.” [ 96 ] Mr. Beck explained that, at the inception of the development project, his team considered additional or alternative beta blockers to timolol. They also considered different salt forms of the beta blocker as well as a formulation that did not contain an alpha-2 agonist (such as brimonidine). At that point in time, Mr.

Beck stated that he did not know whether or not it would be even possible to formulate a combination product with 0.5% timolol. While he acknowledged that a 0.5% solution of timolol had been sold for many years, he explained that he could not have known in advance whether he could achieve a safe, stable and effective formulation with that concentration in combination with another active ingredient.

I accept his statement that “regardless of the fact that timolol was marketed [before the Priority Date] at 0.5 percent, it had no bearing on what I could do as a formulator formulating a new product.” [ 97 ] After initially considering multiple formulation candidates, Mr. Beck and his team began with a “Brimo X” (ALPHAGAN

P) formulation that contained Purite and perhaps carboxymethyl cellulose (CMC). When they were unable to move forward with that formulation, they switched to a formulation they called Synergel. Among other things, one of the benefits that they hoped to achieve with Synergel was the sustained release of the drug, which was considered to be an optimal objective. It was only after they abandoned Synergel that they attempted to work with a formulation that included timolol. [ 98 ] In working with timolol, Mr.

Beck and his team began by using Purite as a preservative rather than BAK, because BAK was known to be cytotoxic, i.e., it comprises cell membranes. Due to those cytotoxic side effects, Allergan developed and launched ALPHAGAN P with Purite, which was approved by the U.S. FDA in 2001. That said, Mr. Beck and his team recognized that it is much more difficult to maintain the stability of Purite in formulations.

During initial stability studies with timolol, they also considered alternate salt forms, including the free base and a heptahydrate salt form. [ 99 ] Approximately two months after beginning their work with a formulation containing Purite and timolol, it became apparent that the timolol in the formula was degrading faster than the team expected (due to its interaction with Purite) and would not meet the minimum 24 month preservative efficacy requirement.

Therefore, the team began to work with a formulation containing BAK, with a phosphate buffer system that was similar to that in Merck’s TIMOPTIC product. [ 100 ] In attempting to formulate a product with BAK, the team conducted titration studies with concentrations of BAK ranging from 0.01% to 0.002%. Notwithstanding the fact that BAK was used in a 0.005% concentration in ALPHAGAN, the team did not know what minimum concentration would be safe and effective for the Composition.

After discovering that the formulation passed the preservative efficacy test with a BAK concentration of 0.002%, the team balanced their objective of having a margin of safety with their objective of

minimizing the concentration of BAK in the formulation, by settling on a concentration of 0.005% for the Composition. [ 101 ] However, two months into their stability studies with that formulation, they once again discovered degradations. Mr. Beck stated that those degradations were novel and entirely unexpected and that the team did not know whether they would be toxic or unsafe for use in humans. Ultimately, they turned out to be harmless.

However, this was another unexpected “obstacle” that was encountered in the testing process, and that led Allergan to incur additional time and expense in formulating the Composition. [ 102 ] In addition to the foregoing, Mr. Beck explained that brimonidine and timolol have optimal pHs that are significantly different. He stated that the pH of ALPHAGAN (brimonidine) is most stable at a pH of about 6.3, whereas the pH of timolol is most stable at a pH of approximately 6.9.

His uncontradicted evidence, which I accept, was that he and his team could not predict whether or not those two active ingredients would be stable at any pH level. [ 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. [ 105 ] In support of its position that the time and effort spent by Mr. Beck and his team to develop the Composition were “routine,” Sandoz relied upon Novo Nordisk , above, at paragraphs 308 to 319 . However, in my view, that case is distinguishable.

The inventive concept there was the drug repaglinide and its “surprising pharmacokinetic properties” when used to treat diabetes mellitus.

Among other things, there was evidence in that case that “it was more or less self-evident that repaglinide’s pharmacokinetic properties could well be very different from those of [the other enantiomer in the racemate compound].” Moreover, Justice Mactavish determined that “the extent, nature and amount of effort required to make repaglinide in the first place was neither prolonged nor arduous, and the methods used in processes followed to test its pharmacokinetic properties were admittedly routine.” In addition, “both sides agreed that the anti- diabetic field was intensely competitive at the time, and that there was a strong demand for a better anti-diabetic medication that did not have some of the drawbacks of the conventional SFU treatments.” Moreover, it was found that “[a]dditional motivation to separate and test enantiomers was provided by the impending move towards increasingly stringent regulatory requirements.” Justice Mactavish noted that during the relevant period, “there was a strong motivation to find a better antidiabetic medication, given the intense competition field.” She then found that (i) “it was self-evident that a person skilled in the art would test enantiomers for their pharmacokinetic properties,” and (ii) there was evidence that “the testing of enantiomers for their pharmacokinetic properties have become a routine part of industry practice as of the relevant date and was not an inventive step by the [Applicant’s] drug development team.” ( Novo Nordisk , above, at paras 308-322 ). [ 106 ] By contrast, in the case at bar, I have found that it would not have been self-evident to the POSITA that formulating brimonidine and timolol into a chemically stable fixed combination drug ought to work.

While the prior art may well have suggested to the POSITA that such a drug would be “worthwhile” to pursue, that would not be a sufficient basis upon which to conclude that the Composition was obvious ( Pfizer ( 2009 FCA 8 ) , above, at para 45). In addition, there was no evidence that a POSITA would have had any basis whatsoever for believing that the Composition ought to (

i) have a superior safety profile, relative to brimonidine TID, or (ii) permit BID dosing without an afternoon reduction in efficiency, relative to brimonidine TID treatment. These discoveries were made only after the completion of a large clinical trial involving 586 individuals, which began as a three-month study and was then expanded to include a nine-month masked extension. Dr.

Fechtner characterized the data collected during that trial as being “at the high end for a clinical trial.” Moreover, there was no evidence in the case at bar to suggest the existence of any competition, let alone intense competition, to develop a fixed combination drug comprising brimonidine and timolol. There was also no evidence that the type of testing conducted by Mr. Beck and his team to develop the Composition had become a routine part of industry practice prior to the Priority Date.

Furthermore, as discussed below, I have determined that there was not a strong motive provided in the prior art to develop a solution such as the Composition. Finally, I am satisfied that the nature and amount of effort required by Mr. Beck and his team to

develop the Composition, as described above, was prolonged and arduous. I note that a similar conclusion was reached in the U.S. proceedings between the parties involving COMBIGAN ( Allergan, Inc v Sandoz , 2:09-cv-00097 TJW, at para 122 (ED Tex 2011)), although I recognize that there are significant differences in (

i) the applicable law in this area in Canada and the U.S., and (ii) the evidentiary records in that case and the case at bar. [ 107 ] In support of its position that the trials conducted by Mr. Beck and his team were routine, Sandoz noted that Mr. Beck acknowledged in cross-examination that the cost of developing a new chemical entity can be in excess of $100 million. Sandoz submitted that the $26.4 million which Mr.

Beck stated was spent by Allergan developing the Composition was small by comparison, and suggests that the nature and amount of effort required to develop the composition was not prolonged and arduous. [ 108 ] I disagree. In the context of an assessment of obviousness and the particular factual matrix of this case, the fact that it may cost in excess of $100 million to develop an entirely new chemical entity provides little helpful information in determining whether the $26.4 million that was spent by Allergan to develop the Composition is indicative of routine, as opposed to prolonged and arduous, work.

Sandoz was unable to identify any jurisprudence to support the proposition that an amount in the range of $26.4 million is, in itself, indicative of work that is merely routine. [ 109 ] A fundamental shortcoming with this particular $100 million benchmark is that it does not provide a useful measure of what might be considered sufficiently routine to weigh in favour of a conclusion that the invention of the Composition was obvious to try. It simply provides a measure of what may be routinely required to invent an entirely new chemical entity.

Moreover, in the absence of additional information, the utility of any particular monetary benchmark may often be limited.

For example, a level of expenditure that may be indicative of work that is routine in the presence of a high motivation may well be indicative of work that is not routine where such motivation is not present. [ 110 ] In response to my request for jurisprudence that is more helpful in distinguishing between effort that is routine and effort that is prolonged and arduous, as contemplated by Sanofi , above, at paragraph 69 , Sandoz referred to Schering-Plough Canada Inc v Pharmascience Inc , 2009 FC 1128 [ Schering-Plough ] .

There, my colleague Justice Snider concluded that the steps that had been taken by the applicant to develop a new drug were not “overly arduous or complex,” but rather appeared to have been somewhat “routine pre- formulation experiments.” She therefore concluded that “this factor would tend to operate in favour of a finding of obviousness, although not strongly so ” (emphasis added) ( Schering-Plough , above, at para 209 ). [ 111 ] In that case, the inventive concept of the patent in question consisted of avoiding lactose and other acidic excipients as the carrier medium and using a basic salt to stabilize the composition ( Schering-Plough , above, at para 200 ).

In reaching her conclusion regarding the routine nature of the experimentation that had been undertaken by the applicants, Justice Snider concluded that the step of identifying the incompatibility between the active ingredient (descarboethoxyloratadine (DCL)) and lactose “was more or less self- evident” (para 204). With respect to the use of a basic salt, she was skeptical of the respondents’ position that this was “more or less self- evident” (para 206), but then proceeded to reach her conclusion regarding the routine nature of the experimentation in question, after considering certain evidence (para 208).

Among other things, that evidence did not include anything analogous to (

i) the failures that Mr. Beck and his team encountered with their Brimo X and Synergel formulations, or (ii) the failure that they encountered with Purite. Accordingly, Schering-Plough is distinguishable . There was also no evidence to suggest that a trial consisting of over 500 persons was undertaken, let alone the additional two trials that Mr. Beck stated were undertaken. [ 112 ] In the course of its arguments regarding the alleged “routine” nature of the work undertaken by Mr.

Beck and his team, Sandoz suggested that I draw an adverse inference from the fact that Allergan failed to provide more evidence regarding the steps that were taken to develop the Composition. In this regard, Sandoz suggested that Allergan should have provided laboratory notebooks, reports and presentations that were made with respect to the Purite degradation issue, documents dealing with the accelerated stability tests that were undertaken and other documentation relating to the testing that was performed.

Sandoz asserted that these documents were being “hidden” from this Court. [ 113 ] I have some sympathy for Sandoz’s position on this point. Nevertheless, if Sandoz truly thought that anything in that documentation may have supported its allegation of obviousness, it should have availed itself of its opportunity to serve a direction, under Rule 91 of the Federal Courts Rules , SOR/98-106, on Mr. Beck to attend and produce that documentation for inspection. It could also have attempted to simply request Allergan’s counsel to provide that documentation.

Given that it did neither of these things, I declined to draw the requested adverse inference. (

c) Was there a motive provided in the prior art to combine brimonidine and timolol into a fixed combination?

[ 114 ] Sandoz submits that the prior art disclosed a motive to develop the Composition because it was known that patient compliance likely would be better with fewer daily administrations of drops to the eye, and that the daily preservative load delivered to a patient would be less with a fixed combination drug. This position was undermined by the statement in Dr. Jampel’s affidavit that he did not recall having ever heard of the “long felt need for an effective and safe ophthalmic pharmaceutical composition including brimonidine and timolol,” described in the ‘764 Patent.

In cross-examination, Sandoz’s position on this point was virtually negated when Dr. Jampel affirmed that he was not aware of any particular motivation among person skilled in the art to combine brimonidine and timolol, although, he speculated that pharmaceutical companies might have such a motivation. [ 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. (

d) Summary of “obvious to try” assessment [ 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 formu

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