Source text

Alcon Canada Inc. v. Apotex Inc.
Court (s) Database
Federal Court Decisions
Date
2014-08-08
Neutral citation
2014 FC 699
File numbers
T-1666-12
Decision Content
Date: 20140808
Docket: T-1666-12
Citation: 2014 FC 699
Ottawa, Ontario, August 8, 2014
PRESENT: The Honourable Madam Justice Kane
BETWEEN:
ALCON CANADA INC. and
ALCON RESEARCH, LTD.
Applicants
and
APOTEX INC. and
THE MINISTER OF HEALTH
Respondents
PUBLIC JUDGMENT AND REASONS
(Confidential Judgment and Reasons issued July 15, 2014)
TABLE OF CONTENTS
Page
I. OVERVIEW... 4
II. INTRODUCTION.. 4
III. THE PARTIES. 6
IV. THE ‘287 PATENT GENERALLY.. 7
V. THE EVIDENCE.. 9
A. For the applicant, Alcon: 9
(1) Kingsley Koo: 9
(2) Dr Peter Klimko: 9
(3) Dr Mitchell deLong: 10
B. For the respondent, Apotex: 10
(1) Lisa Ebdon: 10
(2) Dr Manfred Wolff: 11
(3) Dr Thomas Mittag: 11
VI. ISSUES. 11
A. Alcon’s overall position. 12
B. Apotex’s overall position. 14
VII. THE NOTICE OF ALLEGATION.. 15
VIII. BURDEN.. 16
IX. PERSON SKILLED IN THE ART. 18
X. THE ‘287 PATENT IN DETAIL.. 19
XI. CONSTRUCTION OF THE CLAIMS. 33
A. Jurisprudence and Principles Governing the Construction of a Patent and its Claims. 33
B. Claims 12, 27, 35 and 46. 34
XII. THE INVENTION.. 36
A. Is it a selection patent?. 36
B. Jurisprudence and Principles on Selection Patents. 38
C. The ‘287 is not a selection patent 43
XIII. INVENTIVE CONCEPT. 45
A. Alcon’s position. 45
B. Apotex’s position. 46
C. What do the experts say?. 46
D. The inventive concept 48
XIV. UTILITY / SOUND PREDITION.. 49
A. Jurisprudence and Principles on the Promise of the Patent 50
B. Alcon’s position. 53
C. Apotex’s position. 57
D. What do the experts say?. 61
E. The Promised Utility was Soundly Predicted. 66
XV. ANTICIPATION.. 68
A. Jurisprudence and Principles on Anticipation. 69
B. Alcon’s position. 73
C. Apotex’s position. 80
D. What do the Experts Say?. 86
E. The ‘417 anticipates the invention of the ‘287. 92
XVI. OBVIOUSNESS. 98
A. Jurisprudence and Principles on Obviousness. 100
B. Alcon’s position. 102
C. Apotex’s position. 105
D. What do the Experts say?. 113
E. The ‘287 was Obvious. 119
XVII. CONCLUSIONS AND COSTS. 124
I. OVERVIEW [1] This application is brought under the provisions of the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133, as amended [NOC Regulations] by Alcon to prohibit the Minister of Health from issuing a Notice of Compliance to Apotex in respect of its generic product (the Apotex product) until the expiry of Canadian Letters Patent No 2,129,287 (the '287 Patent) on August 3, 2014.
[2] For the reasons that follow, I find that the allegations with respect to the invalidity of the claims at issue for anticipation and obviousness are justified and the allegations with respect to invalidity for lack of utility are not justified.
[3] The application is dismissed with costs to the respondent.
II. INTRODUCTION [4] Glaucoma is a disease of the eye resulting in a progressive loss of vision due to increased intraocular pressure [“IOP”], which is the pressure within the aqueous humour of the eye. There is no cure for glaucoma, however, it can be managed by reducing IOP. Such treatment is ongoing or “chronic” and requires the patient to take medication daily, generally for life, to maintain the IOP at a reduced level.
[5] According to the inventors of the ‘287, drugs were available to treat glaucoma and ocular hypertension prior to the invention of the ‘287, but they had undesirable effects.
[6] As the experts, Dr deLong and Dr Wolfe, described, prostaglandins [PGs] are a large class of biologically active chemical compounds with many different roles in the body. PGs, and in particular PGF2α and their derivatives, were known to reduce IOP since at least the mid 1980s (and Dr deLong suggests as early as 1977).
[7] Although naturally occurring prostaglandins were known to reduce IOP, there were side effects, particularly irritation and hyperemia (blood shot eyes). The goal was therefore to develop a compound that reduced IOP without the side effects. Synthetic prostaglandins also led to side effects, however, various methods may be used to reduce or eliminate the side effects.
[8] Fluprostenol is a PG, more specifically, a synthetic analogue of PGF2α, a naturally occurring prostaglandin. Alcon notes that the isopropyl ester of (+)-fluprostenol, known as travoprost, is the active ingredient in Travatan Z marketed by Alcon for the treatment of glaucoma. Apotex seeks to market its own product, Apo-Travoprost, also for the treatment of glaucoma.
[9] Apotex alleges that it does not infringe the claims of the Patent at issue, the ‘287, because the claims are invalid. Apotex alleges that the patent is a selection patent from the genus of European Patent Application, (EP 0 364 417, referred to as the ‘417), and that it has not lived up to its promise of the substantial advantages over the ‘417 and specifically that its utility was not demonstrated or soundly predicted. Apotex alternatively alleges that if the ‘287 is not a selection patent, but a species patent as Alcon asserts, then it is not novel as it does only what the ‘417 promised, it is anticipated by the ‘417, and it is obvious.
[10] Apotex argues that Alcon cannot characterize the ‘287 as a novel compound with unstated advantages, rather than a selection patent, yet rely on its unstated advantages to support its novelty. If it is novel then it will fail for want of utility because it does not meet its promise.
[11] Alcon acknowledges that the ‘417 application discloses a huge genus of compounds, and that travoprost is included generically in this genus, but argues that the ‘417 application describes what Alcon refers to as a “functional carve out” of compounds that are not useful due to their side effects. Fluprostenol (and its esters) was carved out, therefore fluprostenol (travoprost) does not fall within the ‘417 and it is not anticipated or obvious due to the reference in the ‘417. Alcon also argues that the promised utility of the ‘287 was soundly predicted.
[12] The construction of the claims at issue is not in dispute. However, the determination of the allegations of invalidity is dependant upon the promise of the patent and the inventive concept of the claims, which are in dispute.
III. THE PARTIES [13] The applicant, Alcon, is a “first person” as described in the NOC Regulations. It has listed the '287 Patent in accordance with the Regulations. Alcon obtained a Notice of Compliance [NOC] to sell travoprost, which it does under the brand name Travatan Z, from the Minister of Health.
[14] The applicant, Alcon, is the owner of the '287 Patent and this is not contested.
[15] The respondent, Apotex, is a “second person” as described in the NOC Regulations. In order to sell a generic version of travoprost, as Apo-Travoprost, it must receive a NOC from the Minister of Health. In accordance with the NOC Regulations, Apotex served Alcon with a Notice of Allegation [NOA] dated July 25, 2012.
[16] In the NOA, Apotex alleges that claims 12, 27, 35 and 46 of the ‘287 Patent would not be infringed, and that the patent is invalid on the grounds of anticipation, obviousness, and lack of utility (alternative). Apotex also alleges that it does not infringe any valid claim in making, constructing, using or selling its Apotex product.
[17] The applicant argues that the allegations advanced by Apotex do not align with its NOA. This issue is addressed later in these reasons.
[18] The respondent, the Minister of Health, who has various responsibilities under the NOC Regulations, including the issuance of an NOC to a “second person” such as Apotex, took no active role in these proceedings.
IV. THE ‘287 PATENT GENERALLY [19] Canadian Letters Patent 2,129,287 were applied for by an application deemed to be filed with the Canadian Patent Office on August 2, 1994. The Patent is therefore governed by the provisions of the new Patent Act, RSC 1985 c P-4, that governs patents applied for after October 1, 1989.
[20] The application was filed under the provisions of the Patent Cooperation Treaty [PCT] and claims priority from a first application filed in the United States Patent Office on August 3, 1993. This is the date upon which the issues of anticipation and obviousness will be determined.
[21] The date of filing in Canada, August 2, 1994, is the date upon which the issue of (utility) sound prediction will be determined.
[22] The publication date, i.e. the date at which the patent was open to the public for inspection, was February 4, 1995. This is the date that is to be used for the purposes of the construction of the claims.
[23] The ‘287 Patent lists the inventors as Paul W Zinke, Peter G Klimko, John E Bishop, Verney L Sallee, and Louis Desantis Jr, all of the United States of America. Only Peter Klimko provided evidence in these proceedings.
[24] The ‘287 Patent was issued to Alcon Laboratories Inc, US.
[25] The term of the ‘287 Patent, unless declared as invalid, will expire 20 years from the date of the filing of the application in Canada, which is August 2, 2014.
[26] There are 54 claims in the ‘287 Patent, four of which are at issue in this proceeding (Claims 12, 27, 35 and 46). The construction of the claims and the inventive concept of the patent are addressed below.
V. THE EVIDENCE [27] The evidence in this proceeding was provided in the form of affidavits and transcripts of cross-examinations of experts along with their exhibits. All of the experts were cross-examined. Each party also submitted as evidence the affidavits of law clerks to place documents on the record and attest to facts.
[28] The evidence on the record includes the following:
A. For the applicant, Alcon: (1) Kingsley Koo: [29] Kingsley Koo is a law clerk at Alcon’s solicitor’s office. His affidavit attaches a variety of documents, such as the ‘287 patent, Apotex’s Notice of Allegation, Apotex’s prior art references, and the Travatan Z product monograph.
(2) Dr Peter Klimko: [30] Dr Peter G Klimko is an inventor on the ‘287 patent. Dr Klimko is a medicinal chemist at Alcon Research, Ltd, in Fort Worth, Texas. He has worked at Alcon since 1993, after earning his PhD in organic chemistry from Texas A&M University in May 1992. He discussed the work conducted by Alcon leading to the filing of the ‘287 patent, including biological test results. His affidavit reiterates, to a great extent, the contents of the ‘287 and sets out his role in the development of the patent.
(3) Dr Mitchell deLong: [31] Dr deLong is an adjunct professor in the department of chemistry at Duke University, and holds a PhD in synthetic organic and medicinal chemistry. He is vice-president of chemistry at Aerie Pharmaceuticals Inc, a company which specializes in the development of ocular drugs. Dr deLong has 20 years experience in medicinal chemistry with prostaglandins and glaucoma treatments. For 13 years, he was a senior scientist at Procter & Gamble, from 1992 to 2005, researching the use of prostaglandins to treat a variety of illnesses.
[32] Dr deLong was called upon by the applicant to review the ‘287 patent and provide an opinion on its construction, as well as utility and novelty. His opinion is detailed, and sets out the person skilled in the art, prior art, and the promise of the patent, among other opinions. He also provides a chemistry primer, explaining prostaglandins, their therapeutic effects, and the type of drug in issue in this case.
B. For the respondent, Apotex: (1) Lisa Ebdon: [33] Lisa Ebdon is a law clerk at the respondent, Apotex’s, solicitor’s office. Her affidavit attaches a variety of documents, including Apotex’s Notice of Allegation, the prior art references, and a copy of the ‘287 patent.
(2) Dr Manfred Wolff: [34] Dr Manfred E Wolff is a pharmacist and a patent agent. He holds a PhD in medicinal chemistry, and is currently president and CEO of Intellepharm Inc. Dr Wolff was asked to comment on the person skilled in the art, and what that person would have understood as the subject matter in the ‘287 patent, as well as the claims of the patent. He also examines the state of the art and common general knowledge of the skilled person at the relevant date, the inventive concept of the ‘287 patent, and the difference between the two. His affidavit focuses on anticipation and obviousness. He also commented on the evidence of Alcon’s experts.
(3) Dr Thomas Mittag: [35] Dr Thomas W Mittag is a professor emeritus of ophthalmology and pharmacology at the Mount Sinai School of Medicine. Dr Mittag was asked to provide an overview of the state of the art as of the relevant date, how the patent would have been understood as of February 4, 1994, as well as to comment on who the skilled person is. He also examined the inventive concept of the claims of the ‘287 patent, the differences between the state of the art and the inventive concept as of the relevant date, and whether the skilled person would have considered this routine work or inventive. His affidavit focuses on anticipation, obviousness, and utility, in the form of sound prediction.
VI. ISSUES [36] The principal issue is whether to grant an Order prohibiting the Minister of Health from granting a Notice of Compliance to Apotex for its generic product (Apo-Travoprost) until the expiry of the '287 Patent. This determination depends upon whether the allegations raised by Apotex as to the invalidity of the '287 Patent (and non-infringement) are justified.
[37] Apotex alleges the ‘287 patent is invalid on the basis of utility, anticipation, and obviousness.
[38] The key area of disagreement between the applicant and respondent (and from which the other issues depend) is the meaning of the patent i.e., what is the promise of the patent and what is the inventive concept (of each claim).
[39] The parties also disagree on the characterisation of the ‘287 patent as a “selection patent”. The applicant, Alcon, does not assert that the ‘287 is a selection patent from the genus in the ‘417; rather, it argues that it is a novel compound or invention with a promised utility of being useful in the treatment of glaucoma and ocular hypertension.
A. Alcon’s overall position [40] Alcon markets Travatan Z, which is travoprost, described by Alcon as the isopropyl ester of (+)-fluprostenol, structurally a “16-phenoxy” type of prostaglandin for the treatment of glaucoma.
[41] The claims of the ‘287 Patent at issue (12, 27, 35 and 46) relate to pharmaceutically acceptable esters of fluprostenol for the treatment of glaucoma.
[42] Alcon submits that the claims are valid: they were not anticipated by ‘417 Application; they were not obvious; and, the use of fluprostenol esters for the treatment of glaucoma was soundly predicted.
[43] Alcon submits that the ‘417 references a huge genus of 800 billion compounds, but it only evaluated 11 compounds and only one of those compounds, Compound 4, is a 16-phenoxy (which Alcon submits is the most closely related to fluprostenol). This evaluation revealed that Compound 4 displayed an unacceptable therapeutic profile. Alcon submits that the ‘417 specifically excludes (or “functionally carves out”) from its invention all non-therapeutically useful compounds. Therefore, Compound 4 was not included in the ‘417 and the ‘287 could not be anticipated by a compound which was excluded (or “carved out”). Alcon argues that for the same reason, the ‘287 could not be a selection from the ‘417.
[44] Alcon acknowledges that fluprostenol is within the huge genus of the ‘417, but it is not referenced in any way in the ‘417 and was not disclosed.
[45] Alcon submits that the ‘287 is not obvious because a Person of Ordinary Skill in the Art [POSITA] could not predict the side effect profile between structurally different PGs without testing the usefulness of the fluprostenol esters to treat glaucoma. This testing had not been done and, therefore, it was not obvious.
[46] Alcon submits that the utility of travoprost was soundly predicted, based on the test results of the ‘287 combined with the common general knowledge; there was a reasonable hypothesis that it would be useful for the treatment of glaucoma in humans.
B. Apotex’s overall position [47] Apotex submits that the ‘287 has all the hallmarks of a selection patent. The ‘417 application disclosed a genus of compounds all noted as being useful in the treatment of glaucoma and IOP with reduced side effects. The ‘287 Patent acknowledges that the ‘417 genus included fluprostenol (travoprost). The ‘287 also states that travoprost has substantial advantages over the compounds of the ‘417. Although Alcon does not assert that the ‘287 is a selection from the ‘417, Apotex submits that it appears to be a selection.
[48] Apotex submits that while the ‘287 promises substantial advantages over the ‘417, Alcon could not demonstrate these advantages or soundly predict them at the time it filed the patent.
[49] Apotex argues that Alcon has advanced the notion of a “functional carve out” from the ‘417 and proposed a construction of the promise of the patent and the inventive concept to avoid the fact that it cannot demonstrate the advantages. However, if there are no substantial advantages, the ‘287 is not new and basically no different than the ‘417 – and is anticipated by the ‘417 and obvious.
[50] Apotex submits that the ‘287 either fails for anticipation and/or obviousness, or if the inventive concept and promise is its substantial advantages over the ‘417, it fails for lack of soundly predicted utility.
[51] As noted above, the construction of the claims, the inventive concept and the promise of the patent will guide the analysis of the allegations and must be determined first.
VII. THE NOTICE OF ALLEGATION [52] Alcon submits that Apotex in its NOA asserted that the inventive concept was the compounds, compositions and uses claimed. But in the alternative, Apotex argues that the ‘287 is a selection patent. Alcon also notes that the NOA included other allegations no longer pursued by Apotex.
[53] Alcon submits that Apotex’s memo of argument in response to its Notice of Application and Memo is not aligned with its Notice of Allegation. Apotex has changed its approach and now argues that the ‘287 must be a selection patent, otherwise it would be invalid and, in the alternative, that if the ‘287 is not a selection patent then it is anticipated by the ‘417 and it was obvious.
[54] In the present case, the non–alignment of the NOA and the memorandum of argument is not an issue. Alternative arguments are simply alternatives, and all arguments were raised in the NOA, were argued and will be addressed. The allegations of anticipation, obviousness and inutility will be addressed whether or not the patent is a selection.
VIII. BURDEN [55] The jurisprudence has clearly established who bears the burden of proof of the allegations.
[56] As a starting point, where the validity of a patent is at issue, the patent will be presumed to be valid. However, where a generic manufacturer (a second person), in this case Apotex, raises allegations of invalidity and adduces some evidence capable of establishing the invalidity of the patent, the generic is said to put the issue “into play”. The burden then moves to the brand or applicant (first person), in this case, Alcon, to establish on a balance of probabilities that all of the allegations of invalidity are not justified: see Lundbeck Canada Inc v Ratiopharm Inc, 2009 FC 1102, [2009] FCJ No 1466; Abbott Laboratories v Canada (Minister of Health), 2007 FCA 153, [2007 ] FCJ No 543 at paras 9-10; Pfizer v Canada (Minister of Health), 2007 FCA 209, [2007] FCJ No 767 at para 109; Allergan Inc v Canada (Minister of Health), 2012 FC 767 at para 42 aff’d in the result 2012 FCA 308; Pfizer Canada Inc v Pharmascience Inc, 2013 FC 120, [2013] FCJ No 111 at paras 24-27.
[57] Justice O’Reilly set out the approach to be followed with respect to the burden of proof in Pfizer Canada Inc v Apotex Inc, 2007 FC 26, [2007] FCJ No 36 (aff’d 2007 FCA 195, leave to appeal refused 32169 (November 1, 2007)) at paragraphs 9 and 12, characterizing the burden on the respondent as “an ‘evidential burden’, a burden merely to adduce evidence of invalidity”. The respondent must adduce evidence to give its allegations an air of reality, and if it does so, it has put the issues “into play” and the presumption of validity no longer applies. The applicant must then discharge its legal burden of proof to the satisfaction of the court.
[58] If the generic (second person, Apotex) does not adduce any evidence with respect to a ground of invalidity alleged, then the presumption is not rebutted. Similarly, if Apotex adduces some evidence but that evidence is insufficient to meet its evidential burden or does not have an “air of reality”, the issues would not be put into play and Alcon would continue to rely on the presumption of validity to obtain its prohibition order.
[59] However, if Apotex presents sufficient evidence to give its allegations an air of reality, then the presumption of validity is rebutted and the issue becomes whether Alcon has established that Apotex's allegations of invalidity are unjustified.
[60] The brand (first person, Alcon) bears the burden with respect to allegations of non- infringement. Allegations of non-infringement of specific claims in the Notice of Allegation are presumed to be true. Alcon must, therefore, demonstrate on a balance of probabilities that any allegations of non-infringement are not justified.
[61] In the present case, Apotex has raised allegations in its NOA and has led sufficient evidence as to the invalidity of the Patent on the basis of anticipation, obviousness and lack of demonstrated or soundly predicted utility to put those issues into play. The applicant, Alcon bears the burden of establishing, on a balance of probabilities, that these allegations are not justified.
[62] Apotex also alleges that it will not infringe claims 12, 27, 35 and 46.
IX. PERSON SKILLED IN THE ART [63] As I noted in Hoffman-La Roche Limited v Apotex Inc, 2013 FC 718, [2013] FCJ No 844 at paras 65-66:
[65] The person skilled in the art (or person of ordinary skill in the art – a “POSITA”) provides the lens through which the patent is construed and many other issues are assessed. As described by Justice Hughes in Pfizer Canada Inc v Pharmascience Inc, 2013 FC 120, [2013] FCJ 111:
28 The person skilled in the art, or as sometimes described, the person of ordinary skill in the art (POSITA) is the notional person, which may include a team of persons, through whose eyes a patent is to be construed, the prior art is to be considered. This notional person may be pertinent to other issues that arise in respect of a patent under consideration by the Court.
[66] In Apotex Inc v Sanofi-Aventis, 2011 FC 1486, [2011] FCJ 1813, Justice Boivin (as he then was) noted:
[64] In assessing the hypothetical POSITA, the Court must define the person or group to whom the ‘777 Patent is addressed. This person is obviously not a real person. As explained by Justice Hughes in Merck & Co v Pharmascience Inc., 2010 FC 510, 85 CPR (4th) 179, at para 42: “[T]hat person is to be unimaginative, but that does not mean that the person is slow-witted or graduated (if at all) at the bottom of the class. Nor is the person the gold medalist who graduated at the top of the class. That person is the average person in the group. Just as a “reasonable man” is expected to be reasonable, the POSITA is expected to possess the ordinary skill in the art”.
[65] The Supreme Court of Canada considered such a person in Whirlpool, above, at para 74, where Justice Binnie for the Court wrote that the POSITA refers to the hypothetical “ordinary worker” who is reasonably diligent in keeping up with advances in the field to which the patent relates.
[64] In this case, there is no major dispute as to the Person of Ordinary Skill in the Art (POSITA, and also referred to as the person of skill or skilled person). The applicant and respondent agreed that the POSITA (the composite person or team of persons) includes a medical doctor specializing in eye diseases, ocular hypertension and glaucoma and persons with a background in pharmacology, medicinal chemistry, biochemistry or organic chemistry, preferably with a degree at the BSc level or higher, and with the ability to understand prostaglandin chemistry. Equally such a person or persons would have experience or an understanding of the pre-clinical evaluation of potential drugs in living animals.
[65] Alcon’s expert noted that if the person has a lower degree, they would have relevant practical experience. The POSITA would have some experience with prostaglandin chemistry and be familiar to some extent with the art relating to the potential therapeutic usefulness of prostaglandins, including testing models.
X. THE ‘287 PATENT IN DETAIL [66] The title of the Patent is the “Use of Cloprostenol, Fluprostenol and Their Analogues to Treat Glaucoma and Ocular Hypertension”.
[67] The Patent begins with the Background to the Invention, noting:
The present invention relates to the treatment of glaucoma and ocular hypertension. In particular, the present invention relates to the use of cloprostenol, fluprostenol, their analogues and their pharmaceutically acceptable salts and esters to treat glaucoma and ocular hypertension.
Cloprostenol and fluprostenol, both known compounds, are synthetic analogues of PGF2α, a naturally-occurring F-series prostaglandin (PG).
[68] The Patent then depicts the chemical structures for PGF2α, cloprostenol and fluprostenol.
[69] The Patent also notes the chemical names for both cloprostenol and fluprostenol, and notes that both differ from the natural product in that an oxygen atom is embedded within the lower (omega) chain.
[70] The Background continues at page 2 of the Patent stating:
Naturally-occurring prostaglandins are known to lower intraocular pressure (IOP) after topical ocular instillation, but generally cause inflammation, as well as surface irritation characterized by conjunctival hyperemia and edema. Many synthetic prostaglandins have been observed to lower intraocular pressure, but such compounds also produce the aforementioned side effects. Various methods have been used in attempting to overcome the ocular side effects associated with prostaglandins. Stjernschantz et al. (EP 364 417 A1) have synthesized derivatives or analogues of naturally-occurring prostaglandins in order to design out selectively the undesired side effects while maintaining the IOP-lowering effect. Others, including Ueno et al. (EP 330 511 A2) and Wheeler (EP 435 682 A2) have tried complexing prostaglandins with various cyclodextrins.
The Stjernschantz et al. publication is of particular interest, as it demonstrates that certain synthetically-modified PGF2α analogues retain the potent IOP-lowering effect of the parent (PGF2α isopropyl ester) while decreasing the degree of conjunctival hyperemia. In this publication, the only modification to the PG structure is to the omega chain: the chain length is 4-13 carbon atoms “optionally interrupted by preferably not more than two heteroatoms (O, S, or N)” and includes a phenyl ring (substituted or unsubstituted) on the terminus (see page 3, line 44 to page 4, line 7). Stjernschantz et al. exemplify two subclasses within this definition: (1) carbon-only omega chains [and a depiction is set out] and (2) heteroatom-interrupted omega chains [and a depiction is set out].
In particular, the 17-phenyl-18,19,20-trinor analogue of PGF2α isopropyl ester (formula 1, n=2) displayed a superior separation of toward and untoward activities. Furthermore, the 13,14-dihydro analogue of 17-phenyl-18,19,20-trinor PGF2α isopropyl ester. displayed an even more favorable separation of activities. Both 17-phenyl PGF2α and its 13,14-dihydro congener fall into the former (formula 1, carbon-only omega chain) subclass. Additional synthetic analogues employing the phenyl substituent on the end of the omega chain explored the effects of chain elongation, chain contraction, and substitution on the phenyl ring, However, such analogues showed no apparent therapeutic improvement over the preferred formulation, 13,14-dihydro-17-phenyl-18,19,20-trinor PGF2α isopropyl ester.
Because they contain heteroatom (O) interruption of the omega chain, both cloprostenol and fluprostenol are generically included in the subclass defined in formula 2 by Stjernschantz et al. However, neither compound is specifically mentioned by Stjernschantz et al. and the disclosure is primarily related to carbon-only omega chains. The only example of a heteroatom- interrupted omega chain disclosed by Stjernschantz et al. is 16-phenoxy-17,18,19,20-tetranor PGF2α isopropyl ester (see formula 2, n=1). The IOP data revealed Stjernschantz et al for 16-phenoxy-17,18,19,20 tetranor PGF2α isopropyl ester (see Stjernschantz et al., page 17, Table V) indicate an initial increase in IOP (1-2 hours after administration) followed by a decrease. Moreover, this compound displays unacceptable hyperemia (see Stjernschantz et al., Table IV, line 40). In short, data from Stjernschantz et al. demonstrate that the oxygen-interrupted omega chain subgeneric class of compounds (see formula 2) displays an unacceptable therapeutic profile.
[Emphasis in original]
SUMMARY OF THE INVENTION
It has now been unexpectedly found that cloprostenol, fluprostenol, and their pharmaceutically acceptable salts and esters show significantly greater IOP reduction than the compounds of Stjernschantz et al., while having a similar or lower side effect profile. In particular, it appears that the addition of a chlorine atom or a trifluoromethyl group to the meta position on the phenoxy ring at the end of the omega chain provides a compound having excellent IOP reduction without the significant side effects found with other, closely related compounds.
In addition, it has also been unexpectedly found that certain novel cloprostenol and fluprostenol analogues are useful in treating glaucoma and ocular hypertension. In particular, topical application of ophthalmic compositions comprising these novel cloprostenol and fluprostenol analogues result in significant IOP reduction.
[71] The Patent does not set out other Prior Art, apart from several references to Stjernschantz et al, and the single reference to Ueno and Wheeler.
[72] At pages 5-6, a detailed description of the formula (Formula IV) of the compounds useful in the invention is provided.
[73] At page 6, the preferred salts and esters are described.
[74] At page 7, the patent notes the preferred compounds which include cloprostenol isopropyl ester (Table 11, Compound A) and fluprostenol isopropyl ester (Compound B), and a number of analogues of cloprostenol and fluprostenol.
[75] The patent notes that “The compounds of formula (IV) are useful in lowering Intraocular pressure and thus are useful in the treatment of glaucoma”.
[76] At page 7-8 the patent notes that the preferred route is topical, sets out the dosage range, formulation details, and other desirable ingredients including preservatives, co-solvents and viscosity building agents.
[77] Table 1, at page 9, depicts compounds 5-8.
[78] Examples 1-4 detail the synthesis of the compounds, which are described at pages 10-27.
[79] Examples 5-9 compared the IOP lowering activity and side effects of five compounds including cloprostenol isopropyl ester (Compound A) and fluprostenol isopropyl ester (Compound B), 16-Phenoxy-17,18,19,20-tetranor PGF2α isopropyl ester (Compound C), 17-Phenyl-18,19,20-trinor PGF2α isopropyl ester (Compound D) and 13,14-Dihydro-17-phenyl-18,19,20-trinor PGF2α isopropyl ester (latanoprost) (Compound E).
[80] Table 2 at page 29 depicts the structures of these compounds (A-E). The testing compares cloprostenol (A) and fluprostenol (B) to three compounds that were tested in the ‘417 – that are said to “differ only slightly in structure” (Patent, p. 30). These are 16-phenoxy (C), 17-phenyl-trinor (D) and latanoprost (E)
[81] The Patent notes at page 30 that the examples demonstrate that, although the compounds are structurally similar, slight structural differences produce greatly different IOP lowering effects and levels of hyperemia.
[82] Example 5 tested for hyperemia in the guinea pig. The Patent notes that the goal of this model is to provide a primary screening indication of the potential of a prostaglandin for inducing conjunctival hyperemia in humans.
[83] The testing for hyperemia and IOP lowering generally compares cloprostenol isopropyl ester and fluprostenol isopropyl ester to the three compounds tested in Stjernschantz et al (the 417).
[84] At page 32, the results are set out and note that the hyperemia produced by Compound A (cloprostenol) and Compound B (fluprostenol) appear to be intermediate between that of Compound D (latanoprost) and Compound E, but this degree of hyperemia is also mild and cannot be distinguished from that produced by Compound E (latanoprost).
[85] Example 6 tested the IOP-lowering effect in cynomolgus monkey eyes with the results were set out in Tables 4 and 5 (page 33-34). The Patent notes that Compounds A, B, C, and D produce similar degrees of IOP reduction with 0.3µg doses, but Compound E is inactive at this dose. Table 5 depicts only compounds A and E and notes that Compound A is more potent and produces a greater maximum response for IOP reduction than Compound E.
[86] Example 7 tested contraction in the cat eye. Example 8 tested only one compound (6) for IOP lowering in the monkey eye. Example 9 set out various formulations for the compositions of the invention for topical use in lowering intraocular pressure.
[87] The ‘287 ends with 54 claims. Only the claims that are asserted and the claims upon which they depend are noted below.
• Claim 1 - Use of a therapeutically effective amount of a compound (of the formula depicted and described, and referred to as IV) for the treatment of glaucoma and ocular hypertension.
• Claim 12 - The use of claim 9, wherein the compound of formula (IV) is selected from the group consisting of the pharmaceutically acceptable esters of fluprostenol.
(Claim 9 is dependent on claim 8 which traces its dependency back to claim 1. Claim 9 is the use of claim 8, wherein the compound of formula (IV) is selected from the group consisting of the pharmaceutically acceptable esters of cloprostenol and fluprostenol.)
• Claim 27 - The composition of claim 24, wherein the compound of formula (IV) is selected from the group consisting of the pharmaceutically acceptable esters of fluprostenol.
(Claim 24 traces its dependency back to claim 16 which is a topical ophthalmic composition for the treatment of glaucoma and ocular hypertension comprising a therapeutically effective amount of a compound of the formula described (IV)).
• Claim 35 - The use of claim 34, wherein for the compound (IV): Z = CF3.
(Claim 34 traces back to claim 33 which claims the use of a therapeutically effective amount of a compound having the absolute stereochemical structure of the following formula (IV) (which is described and depicted) and being substantially free of the enantiomer of said compound).
• Claim 46 - The composition of claim 45, wherein for the compound (IV): Z = CF3.
(Claim 45 is dependent on claim 44 which claims a topical ophthalmic composition for the treatment of glaucoma and ocular hypertension comprising an opthalmically acceptable carrier and a therapeutically effective amount of a compound having the absolute stereochemical structure of the following formula (IV) (as described and depicted) and being substantially free of the enantiomer of said compound).
[88] I observe that the experts had differing views on some aspects of the disclosure, including the summary of the invention, the promised utility, whether the references to Stjernschantz regarding the 16-phenoxy were misleading and whether fluprostenol was racemic, all of which are explored later in these reasons.
[89] Dr deLong expresses his opinion on the claims at paragraphs 141-154 of his affidavit.
[90] His evidence is similar in most respects to that of Dr Wolff.
[91] Dr deLong notes that Claim 12 covers the use of pharmaceutically acceptable esters of fluprostenol for the treatment of glaucoma and ocular hypertension.
[92] Claim 27 claims a topical ophthalmic composition for the treatment of glaucoma and ocular hypertension comprising a therapeutically effective amount of a compound of formula (IV) wherein the compound of formula (IV) is selected from a group consisting of “the pharmaceutically acceptable esters of fluprostenol”.
[93] Claim 35, claims the use of claim 34, which claims the use of claim 33, with additional limitations on the substituents. At para 150 of his affidavit, Dr deLong provides the substitutions in formula (IV) that result from reading claims 33 and 35.
[94] Claim 46 claims the composition of claim 44 and places additional limitations on the substituents. Dr deLong states, “When claim 46 is read in conjunction with claims 45 and 44, and the appropriate substitutions are made, it describes the compounds as claim 35 and compounds in which R1 is a cationic salt moiety.”
[95] Of note, Dr deLong explains the meaning of fluprostenol in claims 12 and 27. At para 158 he opines that the skilled reader would understand fluprostenol (in claims 12 and 27 and more broadly in the patent) “as (+)-fluprostenol, a single stereoisomer […]”. Dr deLong sets out his reasons at para 158-170.
[96] Dr deLong’s reasons include that the use of PGF2α indicates the same absolute stereochemistry as the naturally-occurring prostaglandins, that there is no indication in the ‘287 that the compounds are racemic and that there are several indications that the compounds are single isomers.
[97] As noted below, Dr Wolff‘s evidence is that the skilled person would understand the word “fluprostenol” in claims 12 and 27 to encompass both racemic and enantiomeric forms. He notes that the Patent does not specify (+)-fluprostenol nor does the patent add any stereochemical designations that a POSITA would customarily use to describe the absolute stereochemistry of a compound, and if this were intended, the inventors would have so indicated.
[98] For similar reasons, the two experts reach different conclusions. However, Apotex agrees that this is not a material issue. As this is not a factor in the determination of any of the allegations of invalidity, the construction of the claims will encompass both racemic and enantiomeric forms.
[99] In the summary of his opinions, Dr Wolff states that the ‘287 discloses a class of compounds defined by Formula (IV) that are said to be useful to treat glaucoma and ocular hypertension without causing significant ocular side effects. The person skilled in the art would understand Formula (IV) of the ‘287 to encompass racemic forms of the compound. He adds at para 32 that each of the claims at issue “encompasses within its scope the isopropyl ester of fluprostenol, or the isopropyl ester of one of the specific enantiomers of the [sic] of fluprostenol.”
[100] With respect to the construction of the claims, Dr Wolff sets out his opinion beginning at para 97 of his affidavit.
Claim 1 is directed to the use of a therapeutically effective amount of a compound of formula (IV) [depicted] for the treatment of glaucoma and ocular hypertension. Claim 1 includes a definition of the various substituents in formula (IV). Importantly for the purposes of my opinions below, the isopropyl ester of fluprostenol is one of the compounds encompassed by formula (IV) in claim 1.
[101] Dr Wolff notes that claims 2, 3, 7-9 and 12-15 are all dependent on claim 1. He notes that each of the claims 2, 3, 7-9 narrow the scope of the compounds of formula (IV) but the isopropyl ester of fluprostenol is included in each of those claims.
[102] Claim 12, a claim at i

Source text

Alcon Canada Inc. v. Apotex Inc. Court (s) Database Federal Court Decisions Date 2014-08-08 Neutral citation 2014 FC 699 File numbers T-1666-12 Decision Content Date: 20140808 Docket: T-1666-12 Citation: 2014 FC 699 Ottawa, Ontario, August 8, 2014 PRESENT: The Honourable Madam Justice Kane BETWEEN: ALCON CANADA INC. and ALCON RESEARCH, LTD. Applicants and APOTEX INC. and THE MINISTER OF HEALTH Respondents PUBLIC JUDGMENT AND REASONS (Confidential Judgment and Reasons issued July 15, 2014) TABLE OF CONTENTS Page I. OVERVIEW... 4 II. INTRODUCTION.. 4 III. THE PARTIES. 6 IV. THE ‘287 PATENT GENERALLY.. 7 V. THE EVIDENCE.. 9 A. For the applicant, Alcon: 9 (1) Kingsley Koo: 9 (2) Dr Peter Klimko: 9 (3) Dr Mitchell deLong: 10 B. For the respondent, Apotex: 10 (1) Lisa Ebdon: 10 (2) Dr Manfred Wolff: 11 (3) Dr Thomas Mittag: 11 VI. ISSUES. 11 A. Alcon’s overall position. 12 B. Apotex’s overall position. 14 VII. THE NOTICE OF ALLEGATION.. 15 VIII. BURDEN.. 16 IX. PERSON SKILLED IN THE ART. 18 X. THE ‘287 PATENT IN DETAIL.. 19 XI. CONSTRUCTION OF THE CLAIMS. 33 A. Jurisprudence and Principles Governing the Construction of a Patent and its Claims. 33 B. Claims 12, 27, 35 and 46. 34 XII. THE INVENTION.. 36 A. Is it a selection patent?. 36 B. Jurisprudence and Principles on Selection Patents. 38 C. The ‘287 is not a selection patent 43 XIII. INVENTIVE CONCEPT. 45 A. Alcon’s position. 45 B. Apotex’s position. 46 C. What do the experts say?. 46 D. The inventive concept 48 XIV. UTILITY / SOUND PREDITION.. 49 A. Jurisprudence and Principles on the Promise of the Patent 50 B. Alcon’s position. 53 C. Apotex’s position. 57 D. What do the experts say?. 61 E. The Promised Utility was Soundly Predicted. 66 XV. ANTICIPATION.. 68 A. Jurisprudence and Principles on Anticipation. 69 B. Alcon’s position. 73 C. Apotex’s position. 80 D. What do the Experts Say?. 86 E. The ‘417 anticipates the invention of the ‘287. 92 XVI. OBVIOUSNESS. 98 A. Jurisprudence and Principles on Obviousness. 100 B. Alcon’s position. 102 C. Apotex’s position. 105 D. What do the Experts say?. 113 E. The ‘287 was Obvious. 119 XVII. CONCLUSIONS AND COSTS. 124 I. OVERVIEW [1] This application is brought under the provisions of the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133, as amended [NOC Regulations] by Alcon to prohibit the Minister of Health from issuing a Notice of Compliance to Apotex in respect of its generic product (the Apotex product) until the expiry of Canadian Letters Patent No 2,129,287 (the '287 Patent) on August 3, 2014. [2] For the reasons that follow, I find that the allegations with respect to the invalidity of the claims at issue for anticipation and obviousness are justified and the allegations with respect to invalidity for lack of utility are not justified. [3] The application is dismissed with costs to the respondent. II. INTRODUCTION [4] Glaucoma is a disease of the eye resulting in a progressive loss of vision due to increased intraocular pressure [“IOP”], which is the pressure within the aqueous humour of the eye. There is no cure for glaucoma, however, it can be managed by reducing IOP. Such treatment is ongoing or “chronic” and requires the patient to take medication daily, generally for life, to maintain the IOP at a reduced level. [5] According to the inventors of the ‘287, drugs were available to treat glaucoma and ocular hypertension prior to the invention of the ‘287, but they had undesirable effects. [6] As the experts, Dr deLong and Dr Wolfe, described, prostaglandins [PGs] are a large class of biologically active chemical compounds with many different roles in the body. PGs, and in particular PGF2α and their derivatives, were known to reduce IOP since at least the mid 1980s (and Dr deLong suggests as early as 1977). [7] Although naturally occurring prostaglandins were known to reduce IOP, there were side effects, particularly irritation and hyperemia (blood shot eyes). The goal was therefore to develop a compound that reduced IOP without the side effects. Synthetic prostaglandins also led to side effects, however, various methods may be used to reduce or eliminate the side effects. [8] Fluprostenol is a PG, more specifically, a synthetic analogue of PGF2α, a naturally occurring prostaglandin. Alcon notes that the isopropyl ester of (+)-fluprostenol, known as travoprost, is the active ingredient in Travatan Z marketed by Alcon for the treatment of glaucoma. Apotex seeks to market its own product, Apo-Travoprost, also for the treatment of glaucoma. [9] Apotex alleges that it does not infringe the claims of the Patent at issue, the ‘287, because the claims are invalid. Apotex alleges that the patent is a selection patent from the genus of European Patent Application, (EP 0 364 417, referred to as the ‘417), and that it has not lived up to its promise of the substantial advantages over the ‘417 and specifically that its utility was not demonstrated or soundly predicted. Apotex alternatively alleges that if the ‘287 is not a selection patent, but a species patent as Alcon asserts, then it is not novel as it does only what the ‘417 promised, it is anticipated by the ‘417, and it is obvious. [10] Apotex argues that Alcon cannot characterize the ‘287 as a novel compound with unstated advantages, rather than a selection patent, yet rely on its unstated advantages to support its novelty. If it is novel then it will fail for want of utility because it does not meet its promise. [11] Alcon acknowledges that the ‘417 application discloses a huge genus of compounds, and that travoprost is included generically in this genus, but argues that the ‘417 application describes what Alcon refers to as a “functional carve out” of compounds that are not useful due to their side effects. Fluprostenol (and its esters) was carved out, therefore fluprostenol (travoprost) does not fall within the ‘417 and it is not anticipated or obvious due to the reference in the ‘417. Alcon also argues that the promised utility of the ‘287 was soundly predicted. [12] The construction of the claims at issue is not in dispute. However, the determination of the allegations of invalidity is dependant upon the promise of the patent and the inventive concept of the claims, which are in dispute. III. THE PARTIES [13] The applicant, Alcon, is a “first person” as described in the NOC Regulations. It has listed the '287 Patent in accordance with the Regulations. Alcon obtained a Notice of Compliance [NOC] to sell travoprost, which it does under the brand name Travatan Z, from the Minister of Health. [14] The applicant, Alcon, is the owner of the '287 Patent and this is not contested. [15] The respondent, Apotex, is a “second person” as described in the NOC Regulations. In order to sell a generic version of travoprost, as Apo-Travoprost, it must receive a NOC from the Minister of Health. In accordance with the NOC Regulations, Apotex served Alcon with a Notice of Allegation [NOA] dated July 25, 2012. [16] In the NOA, Apotex alleges that claims 12, 27, 35 and 46 of the ‘287 Patent would not be infringed, and that the patent is invalid on the grounds of anticipation, obviousness, and lack of utility (alternative). Apotex also alleges that it does not infringe any valid claim in making, constructing, using or selling its Apotex product. [17] The applicant argues that the allegations advanced by Apotex do not align with its NOA. This issue is addressed later in these reasons. [18] The respondent, the Minister of Health, who has various responsibilities under the NOC Regulations, including the issuance of an NOC to a “second person” such as Apotex, took no active role in these proceedings. IV. THE ‘287 PATENT GENERALLY [19] Canadian Letters Patent 2,129,287 were applied for by an application deemed to be filed with the Canadian Patent Office on August 2, 1994. The Patent is therefore governed by the provisions of the new Patent Act, RSC 1985 c P-4, that governs patents applied for after October 1, 1989. [20] The application was filed under the provisions of the Patent Cooperation Treaty [PCT] and claims priority from a first application filed in the United States Patent Office on August 3, 1993. This is the date upon which the issues of anticipation and obviousness will be determined. [21] The date of filing in Canada, August 2, 1994, is the date upon which the issue of (utility) sound prediction will be determined. [22] The publication date, i.e. the date at which the patent was open to the public for inspection, was February 4, 1995. This is the date that is to be used for the purposes of the construction of the claims. [23] The ‘287 Patent lists the inventors as Paul W Zinke, Peter G Klimko, John E Bishop, Verney L Sallee, and Louis Desantis Jr, all of the United States of America. Only Peter Klimko provided evidence in these proceedings. [24] The ‘287 Patent was issued to Alcon Laboratories Inc, US. [25] The term of the ‘287 Patent, unless declared as invalid, will expire 20 years from the date of the filing of the application in Canada, which is August 2, 2014. [26] There are 54 claims in the ‘287 Patent, four of which are at issue in this proceeding (Claims 12, 27, 35 and 46). The construction of the claims and the inventive concept of the patent are addressed below. V. THE EVIDENCE [27] The evidence in this proceeding was provided in the form of affidavits and transcripts of cross-examinations of experts along with their exhibits. All of the experts were cross-examined. Each party also submitted as evidence the affidavits of law clerks to place documents on the record and attest to facts. [28] The evidence on the record includes the following: A. For the applicant, Alcon: (1) Kingsley Koo: [29] Kingsley Koo is a law clerk at Alcon’s solicitor’s office. His affidavit attaches a variety of documents, such as the ‘287 patent, Apotex’s Notice of Allegation, Apotex’s prior art references, and the Travatan Z product monograph. (2) Dr Peter Klimko: [30] Dr Peter G Klimko is an inventor on the ‘287 patent. Dr Klimko is a medicinal chemist at Alcon Research, Ltd, in Fort Worth, Texas. He has worked at Alcon since 1993, after earning his PhD in organic chemistry from Texas A&M University in May 1992. He discussed the work conducted by Alcon leading to the filing of the ‘287 patent, including biological test results. His affidavit reiterates, to a great extent, the contents of the ‘287 and sets out his role in the development of the patent. (3) Dr Mitchell deLong: [31] Dr deLong is an adjunct professor in the department of chemistry at Duke University, and holds a PhD in synthetic organic and medicinal chemistry. He is vice-president of chemistry at Aerie Pharmaceuticals Inc, a company which specializes in the development of ocular drugs. Dr deLong has 20 years experience in medicinal chemistry with prostaglandins and glaucoma treatments. For 13 years, he was a senior scientist at Procter & Gamble, from 1992 to 2005, researching the use of prostaglandins to treat a variety of illnesses. [32] Dr deLong was called upon by the applicant to review the ‘287 patent and provide an opinion on its construction, as well as utility and novelty. His opinion is detailed, and sets out the person skilled in the art, prior art, and the promise of the patent, among other opinions. He also provides a chemistry primer, explaining prostaglandins, their therapeutic effects, and the type of drug in issue in this case. B. For the respondent, Apotex: (1) Lisa Ebdon: [33] Lisa Ebdon is a law clerk at the respondent, Apotex’s, solicitor’s office. Her affidavit attaches a variety of documents, including Apotex’s Notice of Allegation, the prior art references, and a copy of the ‘287 patent. (2) Dr Manfred Wolff: [34] Dr Manfred E Wolff is a pharmacist and a patent agent. He holds a PhD in medicinal chemistry, and is currently president and CEO of Intellepharm Inc. Dr Wolff was asked to comment on the person skilled in the art, and what that person would have understood as the subject matter in the ‘287 patent, as well as the claims of the patent. He also examines the state of the art and common general knowledge of the skilled person at the relevant date, the inventive concept of the ‘287 patent, and the difference between the two. His affidavit focuses on anticipation and obviousness. He also commented on the evidence of Alcon’s experts. (3) Dr Thomas Mittag: [35] Dr Thomas W Mittag is a professor emeritus of ophthalmology and pharmacology at the Mount Sinai School of Medicine. Dr Mittag was asked to provide an overview of the state of the art as of the relevant date, how the patent would have been understood as of February 4, 1994, as well as to comment on who the skilled person is. He also examined the inventive concept of the claims of the ‘287 patent, the differences between the state of the art and the inventive concept as of the relevant date, and whether the skilled person would have considered this routine work or inventive. His affidavit focuses on anticipation, obviousness, and utility, in the form of sound prediction. VI. ISSUES [36] The principal issue is whether to grant an Order prohibiting the Minister of Health from granting a Notice of Compliance to Apotex for its generic product (Apo-Travoprost) until the expiry of the '287 Patent. This determination depends upon whether the allegations raised by Apotex as to the invalidity of the '287 Patent (and non-infringement) are justified. [37] Apotex alleges the ‘287 patent is invalid on the basis of utility, anticipation, and obviousness. [38] The key area of disagreement between the applicant and respondent (and from which the other issues depend) is the meaning of the patent i.e., what is the promise of the patent and what is the inventive concept (of each claim). [39] The parties also disagree on the characterisation of the ‘287 patent as a “selection patent”. The applicant, Alcon, does not assert that the ‘287 is a selection patent from the genus in the ‘417; rather, it argues that it is a novel compound or invention with a promised utility of being useful in the treatment of glaucoma and ocular hypertension. A. Alcon’s overall position [40] Alcon markets Travatan Z, which is travoprost, described by Alcon as the isopropyl ester of (+)-fluprostenol, structurally a “16-phenoxy” type of prostaglandin for the treatment of glaucoma. [41] The claims of the ‘287 Patent at issue (12, 27, 35 and 46) relate to pharmaceutically acceptable esters of fluprostenol for the treatment of glaucoma. [42] Alcon submits that the claims are valid: they were not anticipated by ‘417 Application; they were not obvious; and, the use of fluprostenol esters for the treatment of glaucoma was soundly predicted. [43] Alcon submits that the ‘417 references a huge genus of 800 billion compounds, but it only evaluated 11 compounds and only one of those compounds, Compound 4, is a 16-phenoxy (which Alcon submits is the most closely related to fluprostenol). This evaluation revealed that Compound 4 displayed an unacceptable therapeutic profile. Alcon submits that the ‘417 specifically excludes (or “functionally carves out”) from its invention all non-therapeutically useful compounds. Therefore, Compound 4 was not included in the ‘417 and the ‘287 could not be anticipated by a compound which was excluded (or “carved out”). Alcon argues that for the same reason, the ‘287 could not be a selection from the ‘417. [44] Alcon acknowledges that fluprostenol is within the huge genus of the ‘417, but it is not referenced in any way in the ‘417 and was not disclosed. [45] Alcon submits that the ‘287 is not obvious because a Person of Ordinary Skill in the Art [POSITA] could not predict the side effect profile between structurally different PGs without testing the usefulness of the fluprostenol esters to treat glaucoma. This testing had not been done and, therefore, it was not obvious. [46] Alcon submits that the utility of travoprost was soundly predicted, based on the test results of the ‘287 combined with the common general knowledge; there was a reasonable hypothesis that it would be useful for the treatment of glaucoma in humans. B. Apotex’s overall position [47] Apotex submits that the ‘287 has all the hallmarks of a selection patent. The ‘417 application disclosed a genus of compounds all noted as being useful in the treatment of glaucoma and IOP with reduced side effects. The ‘287 Patent acknowledges that the ‘417 genus included fluprostenol (travoprost). The ‘287 also states that travoprost has substantial advantages over the compounds of the ‘417. Although Alcon does not assert that the ‘287 is a selection from the ‘417, Apotex submits that it appears to be a selection. [48] Apotex submits that while the ‘287 promises substantial advantages over the ‘417, Alcon could not demonstrate these advantages or soundly predict them at the time it filed the patent. [49] Apotex argues that Alcon has advanced the notion of a “functional carve out” from the ‘417 and proposed a construction of the promise of the patent and the inventive concept to avoid the fact that it cannot demonstrate the advantages. However, if there are no substantial advantages, the ‘287 is not new and basically no different than the ‘417 – and is anticipated by the ‘417 and obvious. [50] Apotex submits that the ‘287 either fails for anticipation and/or obviousness, or if the inventive concept and promise is its substantial advantages over the ‘417, it fails for lack of soundly predicted utility. [51] As noted above, the construction of the claims, the inventive concept and the promise of the patent will guide the analysis of the allegations and must be determined first. VII. THE NOTICE OF ALLEGATION [52] Alcon submits that Apotex in its NOA asserted that the inventive concept was the compounds, compositions and uses claimed. But in the alternative, Apotex argues that the ‘287 is a selection patent. Alcon also notes that the NOA included other allegations no longer pursued by Apotex. [53] Alcon submits that Apotex’s memo of argument in response to its Notice of Application and Memo is not aligned with its Notice of Allegation. Apotex has changed its approach and now argues that the ‘287 must be a selection patent, otherwise it would be invalid and, in the alternative, that if the ‘287 is not a selection patent then it is anticipated by the ‘417 and it was obvious. [54] In the present case, the non–alignment of the NOA and the memorandum of argument is not an issue. Alternative arguments are simply alternatives, and all arguments were raised in the NOA, were argued and will be addressed. The allegations of anticipation, obviousness and inutility will be addressed whether or not the patent is a selection. VIII. BURDEN [55] The jurisprudence has clearly established who bears the burden of proof of the allegations. [56] As a starting point, where the validity of a patent is at issue, the patent will be presumed to be valid. However, where a generic manufacturer (a second person), in this case Apotex, raises allegations of invalidity and adduces some evidence capable of establishing the invalidity of the patent, the generic is said to put the issue “into play”. The burden then moves to the brand or applicant (first person), in this case, Alcon, to establish on a balance of probabilities that all of the allegations of invalidity are not justified: see Lundbeck Canada Inc v Ratiopharm Inc, 2009 FC 1102, [2009] FCJ No 1466; Abbott Laboratories v Canada (Minister of Health), 2007 FCA 153, [2007 ] FCJ No 543 at paras 9-10; Pfizer v Canada (Minister of Health), 2007 FCA 209, [2007] FCJ No 767 at para 109; Allergan Inc v Canada (Minister of Health), 2012 FC 767 at para 42 aff’d in the result 2012 FCA 308; Pfizer Canada Inc v Pharmascience Inc, 2013 FC 120, [2013] FCJ No 111 at paras 24-27. [57] Justice O’Reilly set out the approach to be followed with respect to the burden of proof in Pfizer Canada Inc v Apotex Inc, 2007 FC 26, [2007] FCJ No 36 (aff’d 2007 FCA 195, leave to appeal refused 32169 (November 1, 2007)) at paragraphs 9 and 12, characterizing the burden on the respondent as “an ‘evidential burden’, a burden merely to adduce evidence of invalidity”. The respondent must adduce evidence to give its allegations an air of reality, and if it does so, it has put the issues “into play” and the presumption of validity no longer applies. The applicant must then discharge its legal burden of proof to the satisfaction of the court. [58] If the generic (second person, Apotex) does not adduce any evidence with respect to a ground of invalidity alleged, then the presumption is not rebutted. Similarly, if Apotex adduces some evidence but that evidence is insufficient to meet its evidential burden or does not have an “air of reality”, the issues would not be put into play and Alcon would continue to rely on the presumption of validity to obtain its prohibition order. [59] However, if Apotex presents sufficient evidence to give its allegations an air of reality, then the presumption of validity is rebutted and the issue becomes whether Alcon has established that Apotex's allegations of invalidity are unjustified. [60] The brand (first person, Alcon) bears the burden with respect to allegations of non- infringement. Allegations of non-infringement of specific claims in the Notice of Allegation are presumed to be true. Alcon must, therefore, demonstrate on a balance of probabilities that any allegations of non-infringement are not justified. [61] In the present case, Apotex has raised allegations in its NOA and has led sufficient evidence as to the invalidity of the Patent on the basis of anticipation, obviousness and lack of demonstrated or soundly predicted utility to put those issues into play. The applicant, Alcon bears the burden of establishing, on a balance of probabilities, that these allegations are not justified. [62] Apotex also alleges that it will not infringe claims 12, 27, 35 and 46. IX. PERSON SKILLED IN THE ART [63] As I noted in Hoffman-La Roche Limited v Apotex Inc, 2013 FC 718, [2013] FCJ No 844 at paras 65-66: [65] The person skilled in the art (or person of ordinary skill in the art – a “POSITA”) provides the lens through which the patent is construed and many other issues are assessed. As described by Justice Hughes in Pfizer Canada Inc v Pharmascience Inc, 2013 FC 120, [2013] FCJ 111: 28 The person skilled in the art, or as sometimes described, the person of ordinary skill in the art (POSITA) is the notional person, which may include a team of persons, through whose eyes a patent is to be construed, the prior art is to be considered. This notional person may be pertinent to other issues that arise in respect of a patent under consideration by the Court. [66] In Apotex Inc v Sanofi-Aventis, 2011 FC 1486, [2011] FCJ 1813, Justice Boivin (as he then was) noted: [64] In assessing the hypothetical POSITA, the Court must define the person or group to whom the ‘777 Patent is addressed. This person is obviously not a real person. As explained by Justice Hughes in Merck & Co v Pharmascience Inc., 2010 FC 510, 85 CPR (4th) 179, at para 42: “[T]hat person is to be unimaginative, but that does not mean that the person is slow-witted or graduated (if at all) at the bottom of the class. Nor is the person the gold medalist who graduated at the top of the class. That person is the average person in the group. Just as a “reasonable man” is expected to be reasonable, the POSITA is expected to possess the ordinary skill in the art”. [65] The Supreme Court of Canada considered such a person in Whirlpool, above, at para 74, where Justice Binnie for the Court wrote that the POSITA refers to the hypothetical “ordinary worker” who is reasonably diligent in keeping up with advances in the field to which the patent relates. [64] In this case, there is no major dispute as to the Person of Ordinary Skill in the Art (POSITA, and also referred to as the person of skill or skilled person). The applicant and respondent agreed that the POSITA (the composite person or team of persons) includes a medical doctor specializing in eye diseases, ocular hypertension and glaucoma and persons with a background in pharmacology, medicinal chemistry, biochemistry or organic chemistry, preferably with a degree at the BSc level or higher, and with the ability to understand prostaglandin chemistry. Equally such a person or persons would have experience or an understanding of the pre-clinical evaluation of potential drugs in living animals. [65] Alcon’s expert noted that if the person has a lower degree, they would have relevant practical experience. The POSITA would have some experience with prostaglandin chemistry and be familiar to some extent with the art relating to the potential therapeutic usefulness of prostaglandins, including testing models. X. THE ‘287 PATENT IN DETAIL [66] The title of the Patent is the “Use of Cloprostenol, Fluprostenol and Their Analogues to Treat Glaucoma and Ocular Hypertension”. [67] The Patent begins with the Background to the Invention, noting: The present invention relates to the treatment of glaucoma and ocular hypertension. In particular, the present invention relates to the use of cloprostenol, fluprostenol, their analogues and their pharmaceutically acceptable salts and esters to treat glaucoma and ocular hypertension. Cloprostenol and fluprostenol, both known compounds, are synthetic analogues of PGF2α, a naturally-occurring F-series prostaglandin (PG). [68] The Patent then depicts the chemical structures for PGF2α, cloprostenol and fluprostenol. [69] The Patent also notes the chemical names for both cloprostenol and fluprostenol, and notes that both differ from the natural product in that an oxygen atom is embedded within the lower (omega) chain. [70] The Background continues at page 2 of the Patent stating: Naturally-occurring prostaglandins are known to lower intraocular pressure (IOP) after topical ocular instillation, but generally cause inflammation, as well as surface irritation characterized by conjunctival hyperemia and edema. Many synthetic prostaglandins have been observed to lower intraocular pressure, but such compounds also produce the aforementioned side effects. Various methods have been used in attempting to overcome the ocular side effects associated with prostaglandins. Stjernschantz et al. (EP 364 417 A1) have synthesized derivatives or analogues of naturally-occurring prostaglandins in order to design out selectively the undesired side effects while maintaining the IOP-lowering effect. Others, including Ueno et al. (EP 330 511 A2) and Wheeler (EP 435 682 A2) have tried complexing prostaglandins with various cyclodextrins. The Stjernschantz et al. publication is of particular interest, as it demonstrates that certain synthetically-modified PGF2α analogues retain the potent IOP-lowering effect of the parent (PGF2α isopropyl ester) while decreasing the degree of conjunctival hyperemia. In this publication, the only modification to the PG structure is to the omega chain: the chain length is 4-13 carbon atoms “optionally interrupted by preferably not more than two heteroatoms (O, S, or N)” and includes a phenyl ring (substituted or unsubstituted) on the terminus (see page 3, line 44 to page 4, line 7). Stjernschantz et al. exemplify two subclasses within this definition: (1) carbon-only omega chains [and a depiction is set out] and (2) heteroatom-interrupted omega chains [and a depiction is set out]. In particular, the 17-phenyl-18,19,20-trinor analogue of PGF2α isopropyl ester (formula 1, n=2) displayed a superior separation of toward and untoward activities. Furthermore, the 13,14-dihydro analogue of 17-phenyl-18,19,20-trinor PGF2α isopropyl ester. displayed an even more favorable separation of activities. Both 17-phenyl PGF2α and its 13,14-dihydro congener fall into the former (formula 1, carbon-only omega chain) subclass. Additional synthetic analogues employing the phenyl substituent on the end of the omega chain explored the effects of chain elongation, chain contraction, and substitution on the phenyl ring, However, such analogues showed no apparent therapeutic improvement over the preferred formulation, 13,14-dihydro-17-phenyl-18,19,20-trinor PGF2α isopropyl ester. Because they contain heteroatom (O) interruption of the omega chain, both cloprostenol and fluprostenol are generically included in the subclass defined in formula 2 by Stjernschantz et al. However, neither compound is specifically mentioned by Stjernschantz et al. and the disclosure is primarily related to carbon-only omega chains. The only example of a heteroatom- interrupted omega chain disclosed by Stjernschantz et al. is 16-phenoxy-17,18,19,20-tetranor PGF2α isopropyl ester (see formula 2, n=1). The IOP data revealed Stjernschantz et al for 16-phenoxy-17,18,19,20 tetranor PGF2α isopropyl ester (see Stjernschantz et al., page 17, Table V) indicate an initial increase in IOP (1-2 hours after administration) followed by a decrease. Moreover, this compound displays unacceptable hyperemia (see Stjernschantz et al., Table IV, line 40). In short, data from Stjernschantz et al. demonstrate that the oxygen-interrupted omega chain subgeneric class of compounds (see formula 2) displays an unacceptable therapeutic profile. [Emphasis in original] SUMMARY OF THE INVENTION It has now been unexpectedly found that cloprostenol, fluprostenol, and their pharmaceutically acceptable salts and esters show significantly greater IOP reduction than the compounds of Stjernschantz et al., while having a similar or lower side effect profile. In particular, it appears that the addition of a chlorine atom or a trifluoromethyl group to the meta position on the phenoxy ring at the end of the omega chain provides a compound having excellent IOP reduction without the significant side effects found with other, closely related compounds. In addition, it has also been unexpectedly found that certain novel cloprostenol and fluprostenol analogues are useful in treating glaucoma and ocular hypertension. In particular, topical application of ophthalmic compositions comprising these novel cloprostenol and fluprostenol analogues result in significant IOP reduction. [71] The Patent does not set out other Prior Art, apart from several references to Stjernschantz et al, and the single reference to Ueno and Wheeler. [72] At pages 5-6, a detailed description of the formula (Formula IV) of the compounds useful in the invention is provided. [73] At page 6, the preferred salts and esters are described. [74] At page 7, the patent notes the preferred compounds which include cloprostenol isopropyl ester (Table 11, Compound A) and fluprostenol isopropyl ester (Compound B), and a number of analogues of cloprostenol and fluprostenol. [75] The patent notes that “The compounds of formula (IV) are useful in lowering Intraocular pressure and thus are useful in the treatment of glaucoma”. [76] At page 7-8 the patent notes that the preferred route is topical, sets out the dosage range, formulation details, and other desirable ingredients including preservatives, co-solvents and viscosity building agents. [77] Table 1, at page 9, depicts compounds 5-8. [78] Examples 1-4 detail the synthesis of the compounds, which are described at pages 10-27. [79] Examples 5-9 compared the IOP lowering activity and side effects of five compounds including cloprostenol isopropyl ester (Compound A) and fluprostenol isopropyl ester (Compound B), 16-Phenoxy-17,18,19,20-tetranor PGF2α isopropyl ester (Compound C), 17-Phenyl-18,19,20-trinor PGF2α isopropyl ester (Compound D) and 13,14-Dihydro-17-phenyl-18,19,20-trinor PGF2α isopropyl ester (latanoprost) (Compound E). [80] Table 2 at page 29 depicts the structures of these compounds (A-E). The testing compares cloprostenol (A) and fluprostenol (B) to three compounds that were tested in the ‘417 – that are said to “differ only slightly in structure” (Patent, p. 30). These are 16-phenoxy (C), 17-phenyl-trinor (D) and latanoprost (E) [81] The Patent notes at page 30 that the examples demonstrate that, although the compounds are structurally similar, slight structural differences produce greatly different IOP lowering effects and levels of hyperemia. [82] Example 5 tested for hyperemia in the guinea pig. The Patent notes that the goal of this model is to provide a primary screening indication of the potential of a prostaglandin for inducing conjunctival hyperemia in humans. [83] The testing for hyperemia and IOP lowering generally compares cloprostenol isopropyl ester and fluprostenol isopropyl ester to the three compounds tested in Stjernschantz et al (the 417). [84] At page 32, the results are set out and note that the hyperemia produced by Compound A (cloprostenol) and Compound B (fluprostenol) appear to be intermediate between that of Compound D (latanoprost) and Compound E, but this degree of hyperemia is also mild and cannot be distinguished from that produced by Compound E (latanoprost). [85] Example 6 tested the IOP-lowering effect in cynomolgus monkey eyes with the results were set out in Tables 4 and 5 (page 33-34). The Patent notes that Compounds A, B, C, and D produce similar degrees of IOP reduction with 0.3µg doses, but Compound E is inactive at this dose. Table 5 depicts only compounds A and E and notes that Compound A is more potent and produces a greater maximum response for IOP reduction than Compound E. [86] Example 7 tested contraction in the cat eye. Example 8 tested only one compound (6) for IOP lowering in the monkey eye. Example 9 set out various formulations for the compositions of the invention for topical use in lowering intraocular pressure. [87] The ‘287 ends with 54 claims. Only the claims that are asserted and the claims upon which they depend are noted below. • Claim 1 - Use of a therapeutically effective amount of a compound (of the formula depicted and described, and referred to as IV) for the treatment of glaucoma and ocular hypertension. • Claim 12 - The use of claim 9, wherein the compound of formula (IV) is selected from the group consisting of the pharmaceutically acceptable esters of fluprostenol. (Claim 9 is dependent on claim 8 which traces its dependency back to claim 1. Claim 9 is the use of claim 8, wherein the compound of formula (IV) is selected from the group consisting of the pharmaceutically acceptable esters of cloprostenol and fluprostenol.) • Claim 27 - The composition of claim 24, wherein the compound of formula (IV) is selected from the group consisting of the pharmaceutically acceptable esters of fluprostenol. (Claim 24 traces its dependency back to claim 16 which is a topical ophthalmic composition for the treatment of glaucoma and ocular hypertension comprising a therapeutically effective amount of a compound of the formula described (IV)). • Claim 35 - The use of claim 34, wherein for the compound (IV): Z = CF3. (Claim 34 traces back to claim 33 which claims the use of a therapeutically effective amount of a compound having the absolute stereochemical structure of the following formula (IV) (which is described and depicted) and being substantially free of the enantiomer of said compound). • Claim 46 - The composition of claim 45, wherein for the compound (IV): Z = CF3. (Claim 45 is dependent on claim 44 which claims a topical ophthalmic composition for the treatment of glaucoma and ocular hypertension comprising an opthalmically acceptable carrier and a therapeutically effective amount of a compound having the absolute stereochemical structure of the following formula (IV) (as described and depicted) and being substantially free of the enantiomer of said compound). [88] I observe that the experts had differing views on some aspects of the disclosure, including the summary of the invention, the promised utility, whether the references to Stjernschantz regarding the 16-phenoxy were misleading and whether fluprostenol was racemic, all of which are explored later in these reasons. [89] Dr deLong expresses his opinion on the claims at paragraphs 141-154 of his affidavit. [90] His evidence is similar in most respects to that of Dr Wolff. [91] Dr deLong notes that Claim 12 covers the use of pharmaceutically acceptable esters of fluprostenol for the treatment of glaucoma and ocular hypertension. [92] Claim 27 claims a topical ophthalmic composition for the treatment of glaucoma and ocular hypertension comprising a therapeutically effective amount of a compound of formula (IV) wherein the compound of formula (IV) is selected from a group consisting of “the pharmaceutically acceptable esters of fluprostenol”. [93] Claim 35, claims the use of claim 34, which claims the use of claim 33, with additional limitations on the substituents. At para 150 of his affidavit, Dr deLong provides the substitutions in formula (IV) that result from reading claims 33 and 35. [94] Claim 46 claims the composition of claim 44 and places additional limitations on the substituents. Dr deLong states, “When claim 46 is read in conjunction with claims 45 and 44, and the appropriate substitutions are made, it describes the compounds as claim 35 and compounds in which R1 is a cationic salt moiety.” [95] Of note, Dr deLong explains the meaning of fluprostenol in claims 12 and 27. At para 158 he opines that the skilled reader would understand fluprostenol (in claims 12 and 27 and more broadly in the patent) “as (+)-fluprostenol, a single stereoisomer […]”. Dr deLong sets out his reasons at para 158-170. [96] Dr deLong’s reasons include that the use of PGF2α indicates the same absolute stereochemistry as the naturally-occurring prostaglandins, that there is no indication in the ‘287 that the compounds are racemic and that there are several indications that the compounds are single isomers. [97] As noted below, Dr Wolff‘s evidence is that the skilled person would understand the word “fluprostenol” in claims 12 and 27 to encompass both racemic and enantiomeric forms. He notes that the Patent does not specify (+)-fluprostenol nor does the patent add any stereochemical designations that a POSITA would customarily use to describe the absolute stereochemistry of a compound, and if this were intended, the inventors would have so indicated. [98] For similar reasons, the two experts reach different conclusions. However, Apotex agrees that this is not a material issue. As this is not a factor in the determination of any of the allegations of invalidity, the construction of the claims will encompass both racemic and enantiomeric forms. [99] In the summary of his opinions, Dr Wolff states that the ‘287 discloses a class of compounds defined by Formula (IV) that are said to be useful to treat glaucoma and ocular hypertension without causing significant ocular side effects. The person skilled in the art would understand Formula (IV) of the ‘287 to encompass racemic forms of the compound. He adds at para 32 that each of the claims at issue “encompasses within its scope the isopropyl ester of fluprostenol, or the isopropyl ester of one of the specific enantiomers of the [sic] of fluprostenol.” [100] With respect to the construction of the claims, Dr Wolff sets out his opinion beginning at para 97 of his affidavit. Claim 1 is directed to the use of a therapeutically effective amount of a compound of formula (IV) [depicted] for the treatment of glaucoma and ocular hypertension. Claim 1 includes a definition of the various substituents in formula (IV). Importantly for the purposes of my opinions below, the isopropyl ester of fluprostenol is one of the compounds encompassed by formula (IV) in claim 1. [101] Dr Wolff notes that claims 2, 3, 7-9 and 12-15 are all dependent on claim 1. He notes that each of the claims 2, 3, 7-9 narrow the scope of the compounds of formula (IV) but the isopropyl ester of fluprostenol is included in each of those claims. [102] Claim 12, a claim at i

Alcon Canada Inc. v. Apotex Inc.

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