Allergan Inc. v. Canada (Health)

Allergan Inc. v. Canada (Health)
Court (s) Database
Federal Court Decisions
Date
2011-11-17
Neutral citation
2011 FC 1316
File numbers
T-154-10
Decision Content
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 Patent must 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 the claims of the patent (Free World Trust, above, at paras 14, 33, 51, 66). That said, to achieve a “purposive construction,” is permissible to have regard to other parts of the patent “through the eyes of a skilled addressee,” to resolve ambiguity and to achieve flexibility and fairness 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 the claims, 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 for treating glaucoma. Sandoz submits that the inventive concept of those claims must be discerned from this description alone. Dr. Jampel took 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 the state-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 both necessary and permissible to look to the balance of the patent “to determine its inventiveness” (Sanofi, above, at para 77). In other words, “to ascertain the nature of the invention” that is articulated in the claims, and to understand the extent to which the claimed invention 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, [1981] 1 SCR 504, at 520-21). That said, it bears underscoring that “it is not permissible to read the specification in order to construe the claims more narrowly or widely than the text 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] bare chemical formula,” in ascertaining the inventive concept of those claims. A similar approach was adopted in Laboratoires Servier v Apotex Inc, 2009 FCA 222, at paras 58-59. This was necessarily done after claims construction had been completed, because the exercise of claim construction is antecedent to the assessment of issues concerning validity and infringement (Free World Trust, above, at para 19; 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 claims in 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 a selection patent. Indeed, the Court in that case specifically noted that its discussion of anticipation and obviousness was “applicable to patents 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 [Eli Lilly], at paras 33, 57, where the Federal Court of Appeal discerned the inventive concept of the claims from the disclosure section of the patent, after observing: “A selection patent is the same as any other patent. Its validity is vulnerable to attack on any of the grounds set out 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 alleged advantageous 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 the compounds described in those claims, and thus should be taken into account when examining issues such as anticipation and obviousness.” Justice Mactavish proceeded to have regard to the alleged properties set out elsewhere in the patent in concluding that the inventive concept of the relevant claims of the patent, which were not confined to a bare chemical formula, included “repaglinide and its surprising 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 to the 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:
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 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 su