HOFFMAN-LA ROCHE LIMITED Applicant v. APOTEX INC., 2013 FC 718

Date: 20130712 Docket: T-1247-11 Citation: 2013 FC 718 Ottawa , Ontario , July 12, 2013 PRESENT: The Honourable Madam Justice Kane BETWEEN: HOFFMAN-LA ROCHE LIMITED Applicant and APOTEX INC. and THE MINISTER OF HEALTH Respondents and F. HOFFMAN-LA ROCHE AG Respondent Patentee PUBLIC REASONS FOR JUDGMENT AND JUDGMENT (Confidential Reasons for Judgment and Judgment Issued June 27, 2013) INDEX PARA

INTRODUCTION.............................................................................................................. 4 THE PARTIES.................................................................................................................. 12 THE ‘721 PATENT GENERALLY................................................................................. 19 THE EVIDENCE.............................................................................................................. 26 ISSUES............................................................................................................................. 28 THE NOTICE OF ALLEGATION.................................................................................. 44 BURDEN.......................................................................................................................... 57 PERSON SKILLED IN THE ART.................................................................................. 65 THE ‘721 PATENT IN DETAIL...................................................................................... 71 CONSTRUCTION OF THE CLAIMS............................................................................ 90 THE INVENTION ........................................................................................................... 99 IS IT A SELECTION PATENT?................................................................................... 133 ANTICIPATION............................................................................................................ 179 OBVIOUSNESS............................................................................................................. 243 CLAIMS BROADER THAN THE INVENTION MADE OR DISCLOSED............. 355 INFRINGEMENT.......................................................................................................... 365 CONCLUSIONS AND COSTS..................................................................................... 400 [ 1 ] This is an application brought under the provisions of the Patented Medicines (Notice of Compliance) Regulations SOR/93- 133, as amended [ NOC Regulations ] to prohibit the Minister of Health from issuing a Notice of Compliance to Apotex in respect of its

valganciclovir hydrochloride 450mg tablets (the Apotex product) until the expiry of Canadian Letters Patent No 2154721 (the '721 Patent) on July 26, 2015. [ 2 ] For the reasons that follow, I find that the allegations with respect to invalidity are justified and the allegation with respect to non-infringement of claim 4 is justified. [ 3 ] The application is dismissed with costs to Apotex. INTRODUCTION [ 4 ] In the 1990s, ganciclovir was recognized as the leading drug for the treatment of certain herpes viruses, particularly cytomegalovirus [CMV], a type of herpes virus.

The parties and the experts described ganciclovir as an antiviral nucleoside, which is a compound that disrupts DNA synthesis in, for example, virally-infected cells. Disrupting viral replication induces the death of the infected cell. A nucleoside is a compound formed by joining a base moiety with a sugar moiety. A disadvantage of ganciclovir was its limited oral bioavailability. Although it could be more effective when administered intravenously [IV], this mode had other disadvantages including inconvenience for patients and potential infections, particularly in immunocompromised patients.

An improvement in the bioavailability of ganciclovir for oral administration was, therefore, desired. [ 5 ] Acyclovir and penciclovir were other antiviral nucleosides that were also effective against various strains of the herpes virus. However, they also shared the disadvantage, when orally administered, of poor absorption across the gut (small intestine) into the blood stream. These drugs were, therefore, also generally administered by IV (directly into the bloodstream). Several research groups were seeking to improve the oral bioavailability of these compounds in the 1980s and 90s.

As explained by the experts, one of the several possible approaches for improving the bioavailability of a drug like ganciclovir was to link the molecule to another compound, referred to as a pro-moiety, (often an amino acid) and to thereby create a prodrug.

A prodrug is a compound that has improved absorption and is metabolized to the active drug after absorption (valganciclovir is a prodrug formed by the molecular combination of ganciclovir with the amino acid, mono-L-valine). [ 6 ] The intended mechanism of action of a prodrug is that the pro-moiety will help deliver the active medicine more effectively to the site of action.

Prodrugs are designed such that the pro-moiety (in this case, the amino acid ester) is hydrolyzed, or cleaved, from the active drug compound at an appropriate point after absorption into the body. [ 7 ] Doctor McGuigan, an expert for Apotex, noted at paragraph 54 of his affidavit that by 1994 it was well known that prodrugs are often used where a drug has suboptimal bioavailability. He described a prodrug as a molecular derivative of the parent drug which requires structural transformation to the active drug in vivo (in the body). Once activated in the body it can then exert its pharmacological action.

A prodrug often results in improved tissue penetration by altering the lipophilicity and/or the water solubility of the drug. Prodrugs can also take advantage of the various active transport mechanisms available in the body, in particular when the prodrug resembles natural metabolites, such as with amino acid esters. The prodrug form is better absorbed, and after biotransformation, results in a greater exposure to the active drug that would have occurred had the parent drug form been administered. [ 8 ] He also noted that the majority of produgs are esters (para 55).

An ester is a compound produced through the reaction of an acid (with a -COOH functional group) with a compound having a hydroxyl group (-OH). [ 9 ] Dr McGuigan indicated that in order to be suitable, a nucleoside prodrug would need improved bioavailability (assuming that the desired improvement is higher oral bioavailability) and would have to be: soluble enough to be dissolved in the stomach; stable enough to survive the acidic environment of the stomach; have the ability to pass through the gut; reach the blood stream; and, release the active agent.

Additionally, a suitable prodrug would have to be acceptable for use as a pharmaceutical. [ 10 ] Roche holds the patent for valganciclovir, which is more fully described below, and which the inventors claim meets these desired characteristics. [ 11 ] In GlaxoSmithKline Inc v Pharmascience Inc , 2011 FC 239 , [2011] FCJ 287 , Justice Hughes explained the nomenclature of NOC proceedings and the requirements of the Notice of Allegation [NOA] as follows: [38] The NOC Regulations identify two groups of persons, a “first person”, commonly called the “brand”, who is the person owning or licensed under a patent and who has received permission to sell a drug somehow relating to that patent in Canada (section 4(1)).

A

“second person”, commonly called a “generic” is a drug company wanting to take advantage of much of the material submitted by the first person in order to obtain approval itself to sell the drug. The second person must notify the first person providing particulars of its application to secure approval and to state that the patent will not be infringed or is invalid or that the second person will wait for the patent to expire.

That notification takes the form of a “Notice of Allegation” (NOA). [39] That Notice of Allegation (NOA) is required by subsection 5(3) (b)(ii) of the NOC Regulations to include “a detailed statement of the legal and factual basis for the allegations”… . THE PARTIES [ 12 ] The applicant, Roche, is a “first person” as described in the NOC Regulations . It has listed the '721 Patent in accordance with those Regulations .

Roche has obtained a Notice of Compliance [NOC] to sell valganciclovir hydrochloride, which it does under the brand name Valcyte, from the Minister of Health. [ 13 ] The applicant, Roche, claims to be the owner of the '721 Patent and this is not contested in these proceedings. [ 14 ] The respondent, Apotex, is a “second person” as described in the NOC Regulations . It seeks to sell a generic version of Roche’s valganciclovir drug. To do so, it must receive a NOC from the Minister of Health.

In accordance with the NOC Regulations , Apotex served Roche with a Notice of Allegation [NOA] dated June 14, 2011. [ 15 ] In the NOA, Apotex alleges that claims 4-8 and 10 of the ‘721 Patent would not be infringed, and that the patent is invalid on the grounds of anticipation, obviousness, and overbreadth or claims broader than the invention made or disclosed.

Apotex also alleges that it does not infringe any valid claim in making, constructing, using or selling its Apotex product. [ 16 ] 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. [ 17 ] The respondent, Apotex, submits that the applicant, Roche, has not honored its part of the bargain upon which the ‘721 Patent is based.

The nature of this bargain was described in Apotex Inc v H Lundbeck A/S , 2013 FC 192 , [2013] FCJ 274 by Justice Harrington, as follows: [7] A patent represents a bargain between the inventor and the state. In consideration of the grant of a monopoly, the inventor must fully and properly disclose the invention so that when the monopoly expires, others may reproduce the product or process involved without undue difficulty. The Patent Act requires the applicant to provide a specification which discloses what has been invented and how to replicate it.

The specification ends with a claim or series of claims over which a monopoly is asserted. According to Apotex, the specification is fatally defective. [ 18 ] In the present case, Apotex makes this same allegation. THE '721 PATENT GENERALLY [ 19 ] Canadian Letters Patent 2,154,721 (the ‘721 Patent) was applied for by an application deemed to be filed with the Canadian Patent Office on July 26, 1995.

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 July 28, 1994. This is the date upon which the issues of anticipation and obviousness will be determined. [ 21 ] The publication date, i.e. the date at which the public could inspect the patent, was January 29, 1996.

This is the date that is to be used for the purposes of the construction of the claims.

[ 22 ] The ‘721 Patent lists the inventors as John J Nestor, Scott W Womble and Hans Maag, all of the United States of America. None of the inventors provided evidence in these proceedings. [ 23 ] The ‘721 Patent was issued to F Hoffman-LaRoche AG, CH. [ 24 ] The term of the ‘721 Patent, unless declared as invalid, will expire 20 years from the date of the filing of the application in Canada, which is July 26, 2015. [ 25 ] There are 17 claims in the ‘721 Patent, 14 of which are at issue in this proceeding. The construction of the claims and the inventive concept of the patent are addressed below.

THE EVIDENCE [ 26 ] 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 and specific communications between the parties. [ 27 ] The evidence on the record includes the following: For the applicant (Roche)

i) Dr Ronald Sawchuk Dr Sawchuk is a Professor of Pharmaceutics, Emeritus, and Morse Alumni Distinguished Teaching Professor and the Director of the Bioanalytic and Pharmacokinetic Services Laboratory at the University of Minnesota. Dr Sawchuk was called on by the applicants for his extensive experience in the areas of pharmaceutical research, pharmacokinetics, and drug development.

Dr Sawchuk was asked to review Apotex’s Notice of Allegation and provide an opinion as to the content of the ‘721 Patent, and the validity of the ‘721 Patent. ii) Dr Youla S Tsantrizos Dr Tsantrizos is a Professor of Chemistry at the Faculty of Science at McGill University and an Associate Member of the Biochemistry Department at the Faculty of Medicine at McGill University.

Dr Tsantrizos spent 10 years at the Medicinal Chemistry Department of the pharmaceutical company Boehringer Ingelheim where she participated in pre-development and development committees that moved compounds through the different stages of drug discovery, pre-clinical and clinical development. She was called by the applicant for her expertise in human pharmaceuticals for the treatment of viral infections. Dr.

Tsantrizos was asked to comment on the claims of the ‘721 Patent and explain what is understood as the subject matter involved; to review and consider the allegations in the NOA; including anticipation, obviousness, the proper scope of the invention, and non- infringement. iii) Dr Jeffrey Manthorpe Dr Manthorpe is a Professor of Chemistry at Carleton University. His current academic research interests include synthetic chemistry and particularly synthetic organic chemistry, the development of new synthetic chemistry techniques and their application to biologically relevant molecules.

Dr Manthorpe was asked to design and perform an experiment to determine whether the Apotex crystallization process produces amorphous or crystalline material. iv) Dr Ilia Korobkov Dr Korobkov is an X-ray diffraction scientist, crystallographer, and supervisor at the X-ray Core Facility of the Faculty of Science at the University of Ottawa. His work is focused on single crystal X-ray diffraction, but he has also conducted analyses using other instruments such as powder X-ray and fluorescence.

Dr Korobkov was called by the applicant to analyze Dr Manthorpe’s experiment and to provide an opinion whether some samples were crystalline or amorphous.

v) Richard Killworth Richard Killworth is a Partner at Dinsmore & Shohl LLP in Dayton, Ohio, USA. Mr Killworth was called as an expert by the applicant as a US patent attorney and because of his extensive knowledge of US patent law and the United States Patent Office [“USPTO”] practices, requirements, and procedures. vi) Erin McIntomny Erin McIntomny is a law clerk for the office of the applicant’s solicitors, Gowling Lafleur Henderson LLP, and was asked to attest to the truth of various procedural facts relating to motions, orders, letters, and email correspondence between Apotex and Roche. For the respondent (Apotex)

i) Dr Chris McGuigan Dr McGuigan is a Professor of Medicinal Chemistry and Deputy Pro-Vice Chancellor (Research) at the Cardiff School of Pharmacy & Pharmaceutical Sciences at Cardiff University. Dr McGuigan has an extensive research background in new drug discovery and development, particularly for the treatment of viral and retroviral diseases, for diseases associated with viruses, and for osteoarthritis.

Dr McGuigan was asked to explain the state of the art in the pharmaceutical treatment of herpes virus infections, including cytomegalovirus infections [HCMV], from the perspective of an ordinary medicinal chemist. Dr McGuigan was asked to comment on the ‘721 Patent, to address its scope, the allegations of invalidity, the inventive concept and related issues.

Dr McGuigan was also asked to provide comments on the statements in the affidavits of Dr Ronald Sawchuk and Dr Youla Tsantrizos. ii) Dr George G Zhanel Dr Zhanel is a Professor of Medicinal Microbiology/Infectious Diseases at the Faculty of Medicine at the University of Manitoba, and is the Coordinator of the antimicrobial resistance program in the Departments of Medicine (Section of Infection Control) and Clinical Microbiology at the Health Sciences Center in Winnipeg, Manitoba. Dr Zhanel is also the Research Director of the Canadian Antimicrobial Resistance Alliance [CARA] in Winnipeg, Manitoba.

Dr Zhanel was asked by Apotex to state what a skilled pharmacologist would have known about acyclovir and ganciclovir, and their use in treating herpes viruses, as of July 28, 1994. Dr Zhanel was also asked to comment on the ‘721 Patent to address its scope, the allegations of invalidity, the inventive concept and related issues and to address several questions from the perspective of a skilled pharmacologist.

Dr Zhanel was also asked to provide comments on the opinions of Dr Ronald Sawchuk and Dr Youla Tsantrizos in their affidavits. iii) Dr Siddegowda Dr Siddegowda has a PhD in organic chemistry from the University of Mysore. Since April 2010, Dr Siddegowda has worked as Team Leader of Quality Assurance and Regulatory Affairs for Apotex Pharmachem India Private Limited [APIPL], in the City of Bangalore, India. Before that, he was the Group Leader II of Process Development R&D at APIPL, and from 2004 to 2009 was the Assistant Manager.

Dr Siddegowda was called by Apotex to explain specific terminology, statements and passages within APIPL’s Drug Master File [DMF] for valganciclovir. iv) Dr Robert K Boeckman, Jr Dr Boeckman is the Marshall D Gates Jr Professor of Chemistry and the Chair of the Chemistry Department at the University of Rochester. Dr Boeckman is an active researcher in the area of synthetic chemistry applied to medicinal chemistry, and is also a trained

X-ray crystallographer. Dr Boeckman was asked to provide his opinion on what the EP 329 patent taught and disclosed to the synthetic chemist reading it as of July 28, 1994. Dr Boeckman was asked to comment on the ‘721 Patent to address its scope, the allegations of invalidity, the inventive concept, crystallinity, and related issues and to address several questions from the perspective of a synthetic chemist. Dr Boeckman was also asked to review and comment on the affidavits of Dr Tsantrizos and Dr Manthorpe.

v) Dr Jonathan Steed Dr Steed is a Professor of Chemistry at Durham University, with considerable expertise in crystallography, crystallization, solid-state chemistry, coordination chemistry and intermolecular interactions in solids. Dr Steed established and ran the first X-ray crystallographic facility in the UK to be based on a particular new area detector technology. He was called by Apotex as an expert in the structures and solid state behavior of organic and molecular solids, and in the methods and techniques used to study and characterize them.

He was also asked to comment on the ‘721 Patent and answer several questions from the perspective of the solid state chemist including the scope, allegations of invalidity, inventive concept and the allegations of infringement, particularly regarding whether the product was crystalline. Dr Steed was also asked to review and comment on the affidavits of Dr Tsantrizos, Dr Manthorpe and Dr Korobkov. vi) Dr Richard Christian Moreton Dr Moreton is a pharmaceutical formulation scientist, and Vice-President of FinnBrit Consulting, a pharmaceutical consulting company.

Dr Moreton has over 30 years experience in the pharmaceutical industry and throughout his industrial career has worked in formulation, pre-formulation, formulation development and scale-up, drug development and optimization, including the study and design of prodrug strategies, and the technical transfer of products into commercial manufacture. He also has experience with antiviral drugs, including antiviral drug formulations and prodrugs.

Dr Moreton was asked to review the ‘721 Patent and answer several questions from the perspective of the pharmaceutical formulator including the scope, allegations of invalidity, inventive concept and the allegations of infringement, particularly regarding whether the product was crystalline. Dr Moreton was also asked to review and comment on the affidavits of Dr Tsantrizos and Dr Sawchuk. vii) Duane Terrill Duane Terrill is a long time employee of Apotex and is currently Associate Director of Regulatory Affairs.

From 2005 until 2012, Mr Terrill was Manager for Apotex’s Regulatory Affairs Department, which regulates all of Apotex’s interactions with Health Canada regarding Apotex’s submissions for approval to promote and sell new drugs as well as its compliance obligations. Mr Terrill was called by Apotex to comment on Health Canada’s requirements for regulatory approval of new drugs in Canada, and to provide specifications on the procedure followed by Apotex while seeking approval for the sale of Apo-Valganciclovir tablets.

He was also asked to comment on the contents of the tablets. viii) Lisa Ebdon Lisa Ebdon is a law clerk at the office of the respondent’s solicitors, Goodmans LLP. She was called to testify as to the truth of various documents sent by Apotex to the applicant, specifically those relating to Apotex’s drug submissions and filings.

THE ISSUES [ 28 ] 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 valganciclovir until the expiry of the '721 Patent.

This determination depends upon whether the allegations raised by Apotex as to the invalidity of the '721 Patent and non-infringement are justified. [ 29 ] Apotex alleges that the ’721 Patent is invalid on the basis of anticipation, obviousness and overbreadth (insufficiency of claims or claims broader than the invention made or disclosed). [ 30 ] Apotex also claims in the alternative, that if the patent is valid, they do not infringe the patent because their product is non- crystalline (it is amorphous).

This flows from the submission by Apotex that the invention of the ‘721 is its crystallinity. [ 31 ] The key area of disagreement between the applicant and respondent (and from which many issues depend) is the meaning of the patent – i.e. what is the invention or what is the inventive step. [ 32 ] The applicant, Roche, asserts that the invention of the ‘721 Patent is the identification that the mono-L-valine ester of ganciclovir (referred to as “L-valganciclovir” or simply “valganciclovir”) has unexpectedly better bioavailability over the previously known esters of ganciclovir, most importantly the bis-valine ester.

This improvement is not only over the closest prior art (i.e. the bis- ester of EP 329), but also over other known ganciclovir esters and over ganciclovir itself. Roche notes that the bioavailabilities of the invention are specifically compared with EP 329 and other esters and ganciclovir in the ‘721 Patent. [ 33 ] The applicant also asserts that the ‘721 Patent is probably, likely, or is definitely a selection patent from the genus of EP 329. [ 34 ] The applicant asserts that the allegations of invalidity due to anticipation and obviousness are not justified.

The applicant argues that the respondent, Apotex, did not provide any evidence whether it was obvious that L-valganciclovir would have improved bioavailability over the other known ganciclovir esters, and, in particular, the bis-valine ester and the bis-propyl ester. [ 35 ] With respect to overbreadth, Roche submits that the ‘721 Patent teaches and claims both amorphous and crystalline valganciclovir (and that crystallinity is merely an additional advantage). [ 36 ] With respect to infringement, Roche submits that there is evidence to establish that the Apotex product is not limited to amorphous (i.e. non-crystalline) valganciclovir.

As a result, Roche submits that Apotex infringes all claims. [ 37 ] The respondent, Apotex, asserts that the applicant’s position is based on a flawed construction of the ‘721 Patent. Apotex maintains that the ‘721 Patent neither claims nor indicates in its disclosure that its invention is “the identification that the mono -L-valine ester of ganciclovir … has unexpectedly better bioavailability over the previously known esters of ganciclovir, most importantly the bis - valine ester”, as indicated by Roche in their memorandum.

Apotex argues that no witness stated that this was the inventive concept of any of the claims of the ‘721 Patent. [ 38 ] Apotex submits that the invention relates to valganciclovir, a prodrug of ganciclovir, and its pharmaceutically acceptable salts, methods and intermediates used to prepare these compounds, and compositions of these compounds for use to treat viral diseases in humans.

Apotex’s position is that the invention is the crystalline compound and submits that the patent distinguishes its invention from the prior knowledge by identifying its compounds as crystalline, which it says provides a “decisive advantage” in characterization and processing. [ 39 ] With respect to anticipation, Apotex submits that EP 329 disclosed the subject matter of the claims of the ‘721 Patent, including valganciclovir, as a medicine to treat herpes virus infections with improved oral bioavailability over ganciclovir. [ 40 ] With respect to obviousness, and to the extent that EP 329 did not explicitly make crystalline valganciclovir, Apotex submits that this was obvious from the art.

[41] With respect to overbreadth, Apotex submits that most of the claims in the ‘721 Patent cover all solid forms of valganciclovirhydrochloride rather than being limited to the crystalline form (which Apotex submits is the inventive concept).

In its written argument,Apotex also argued that other claims are overbroad for claiming the use of valganciclovir to treat all viral diseases, rather than beinglimited to those diseases against which ganciclovir had been shown to be effective. [42] Apotex also asserts that it will not infringe any claim of the ‘721 Patent because all of the claims are invalid. [43] Alternatively, Apotex submits that it does not infringe claims 4 to 8 and 10 of the ‘721 Patent.

All of the details of thepreparation and testing of Apo-Valganciclovir are included in its abbreviated new drug submission [“ANDS”] and its supplier’s drugmaster file [“DMF”]. These documents establish that Apotex’s valganciclovir is never crystalline and contains a mixture of the (

R) and(

S) forms of the compound. Apotex notes that it produced all of these details to the applicant. NOTICE OF ALLEGATION [44] As a preliminary issue, the applicant, Roche, asserts that the respondent raised new issues in its argument that it had not setout in the Notice of Allegation [NOA]. [45] The applicant notes that the respondent is limited to the factual and legal basis set out in its NOA and that any new non-infringement and invalidity allegations cannot be considered.

The applicant further notes that the NOA does not assert or suggest that theadvantages set out or information provided in the ‘721 Patent are not true. [46] More particularly, the applicant asserts that Apotex in its NOA indicated that the question to be answered was whether“making the mono-ester instead of the diester (bis-ester) would have been obvious” but then “shifted ground” and changed the question,which is central to the allegation of obviousness, to whether the mono-ester was obvious over ganciclovir. [47] Roche asserts that the NOA is deficient because it fails to make any allegations relating to whether Apotex’s supplier makescrystalline valganciclovir during the manufacturing process. [48] Roche also asserts that because the respondent did not raise an allegation pursuant to

section 53 of the Patent Act, itswitnesses could not question whether the statements in the Patent were true, particularly with respect to Examples 9 and 10. Jurisprudence / Principles regarding NOA [49] In GlaxoSmithKline Inc v Pharmascience Inc, 2011 FC 239, [2011] FCJ 287, Justice Hughes summarized the requirements ofsubsection 5(3)(b)(ii) of the NOC Regulations governing the contents of the NOA which must include “a detailed statement of the legaland factual basis for the allegations”. He noted at para 40: [40] Without comment as to whether they are right or wrong as a matter of “fairness”, certain principles have emerged as a result ofjudicial

interpretation as to an NOA, including: i. The NOA cannot be amended once legal proceedings have commenced except that certain allegations made can be omitted or no longer relied upon (e.g. Hoffmann-La Roche Ltd v. Canada(Minister of National Health and Welfare) (1996), 70 C.P.R. (3d) 1, (FCA); Bayer A/G v. Novopharm Ltd. (2006), 2006 FC 379 , 48 C.P.R. (4th) 46 (FC) at paras 72 to 84). ii. The Notice of Allegation must be sufficient so as to make the “first person” fully aware of the grounds raised as to invalidity or non-infringement (Mayne Pharma (Canada) Inc. v. Aventis Pharma Inc. (2005), 2005 FCA 50 , 38 C.P.R. (4th) 1 (FCA), at paras. 19-21).

iii. A second person cannot, in proceedings taken in Court, present argument and evidence relating to an issue that is outside the scope of its NOA (e.g. Ratiopharm Inc. v. Canada (Minister of Health) (2007), 2007 FCA 83 , 58 C.P.R. (4th) 97 (FCA), atpara. 25. iv. The second party may not shift ground or raise a new ground during the legal proceedings that has not been raised in its NOA (Pfizer Canada Inc. v. Canada (Minister of Health) (2006), 2006 FC 1471 , 54 C.P.R. (4th) 279 (FC), at paras 70 – 71).

Conclusion re NOA [50] I have considered these principles and do not agree that there was any deficiency in the NOA. [51] The NOA sufficiently set out the allegations of invalidity and non-infringement to make Roche fully aware and to permitRoche to respond. Apotex did not raise any new ground or new argument or lead any evidence that was beyond the NOA or that was notresponsive to arguments raised by the applicant.

In addition, as noted by Apotex, the applicant did not bring any earlier motions, exceptfor the production order as noted below, to resolve any concerns it had about the NOA. [52] Apotex served the NOA alleging that the ‘721 Patent and each of its relevant claims are invalid and will not be infringed byApotex’s making, constructing, using or selling of Apotex’s Apo-Valganciclovir product. Apotex noted that the details of itsvalganciclovir and its formulation would be provided once a confidentiality order was in place.

The applicant, Roche, obtained a CourtOrder requiring Apotex to produce those portions of its ANDS and associated DMF that provide information on the solid state form ofApotex’s valganciclovir at each stage of its manufacture and formulation into tablets. [53] Apotex’s NOA gave sufficient notice that its allegation of non-infringement was not limited to the fact that Apotex’svalganciclovir hydrochloride will not be crystalline when sold. Apotex’s NOA states that Apotex will not infringe the ‘721 Patent in its“making” or “using” of its product.

The applicant, Roche, was aware of how to seek Apotex’s process information and pursued theproduction order.

Moreover, the experts for Roche considered whether Apotex’s product might become crystalline at any point in itsprocessing, handling or subsequent storage. [54] With respect to Roche’s assertion that Apotex changed the key question on obviousness, from whether “making the mono-ester instead of the diester (bis-ester) would have been obvious” to whether making the mono-ester instead of ganciclovir would havebeen obvious, I find that the words quoted are taken out of the context of the full sentence and the part of the NOA in which they arefound. [55] This issue relates to the inventive concept of the ‘721 Patent which is a significant point of disagreement between the parties.It was fully addressed in argument by both parties. [56] With respect to the concern that

section 53 was not raised, I agree with Apotex that its submissions with respect to the data setout in Examples 9 and 10 respond to evidence on the record submitted by the applicant. BURDEN [57] There is extensive jurisprudence with respect to who bears the burden of proof of the allegations and there is no dispute onthis issue. [58] Where the validity of a patent is at issue, the patent will be presumed to be valid.

However, where a generic manufacturer (asecond person), in this case Apotex, raises allegations of invalidity and adduces some evidence capable of establishing the invalidity ofthe patent, the generic is said to put the issue “into play”.

This puts the burden on the brand or applicant (first person), in this case,Roche, to establish on a balance of probabilities that all of the allegations of invalidity are not justified: see Lundbeck Canada Inc vRatiopharm Inc, 2009 FC 1102, [2009] FCJ 1466; Abbott Laboratories v Canada (Minister of Health), 2007 FCA 153, 59 C.P.R. (4th)30 at paras 9-10; Pfizer v Canada (Minister of Health), 2007 FCA 209, 60 C.P.R. (4th) 81 at para 109 (FCA); Pfizer v Canada (Ministerof Health), 2012 FC 767 at para 42 affirmed in the result 2012 FCA 308; Pfizer Canada Inc v Pharmascience Inc, 2013 FC 120, [2013]FCJ 111 at paras 24-27.

[59] If the generic (second person) does not adduce any evidence with respect to a ground of invalidity alleged, then thepresumption is not rebutted. [60] The burden is also on the brand (first person), Roche, with respect to allegations of non- infringement. The genericmanufacturer, Apotex, has alleged non-infringement of specific claims in its NOA. These statements are presumed to be true. The onus ison the brand, Roche, to demonstrate, on a balance of probabilities, that the allegations of non-infringement are not justified.

Theapplicant cannot simply raise the possibility of infringement: see Novopharm Limited v Pfizer Canada Inc, 2005 FCA 270, 42 CPR (4th)97, at paras 19-20 and 24. [61] In Pfizer Canada Inc v Apotex Inc, 2007 FC 26, 59 CPR (4th) 183 (aff’d 2007 FCA 195, leave to appeal refused [2007] SCCANo. 371) Justice O’Reilly set out the approach to be followed with respect to the burden of proof at paragraphs 9 and 12: 9 In my view, the burden on a respondent under the Regulations is an "evidential burden" -- a burden merely to adduce evidence ofinvalidity.

Once it has discharged this burden, the presumption of validity dissolves and the Court must then determine whether theapplicant has discharged its legal burden of proof. I believe this is what is meant in those cases where the Court has stated that therespondent must put its allegations "into play". It must present sufficient evidence to give its allegations of invalidity an air of reality. . . . 12 To summarize, Pfizer bears the legal burden of proving on a balance of probabilities that Apotex's allegations of invalidity areunjustified.

Apotex merely has an evidentiary burden to put its case "into play" by presenting sufficient evidence to give its allegations ofinvalidity an air of reality. If it meets that burden, then it has rebutted the presumption of validity. I must then determine whether Pfizerhas established that Apotex's allegations of invalidity are unjustified.

If Apotex does not meet its evidential burden, then Pfizer cansimply rely on the presumption of validity to obtain its prohibition order. [62] As noted above, Justice Hughes summarized the requirements of subsection 5(3)(b)(ii) of the NOC Regulations governing thecontents of the Notice of Allegation [NOA] in GlaxoSmithKline Inc v Pharmascience, 2011 FC 239, [2011] FCJ 287, and also noted atpara 41: [41] In the Court proceedings, a first person is required to demonstrate, in accordance with subsection 6(2) of the NOC Regulations,that “none of those allegations is justified”.

Thus, the object of the proceedings is to look at the allegations, consider the evidence, applythe law, and determine whether an allegation made in the NOA is justified. Such a determination, for instance, whether an allegation asto invalidity is justified or not, does not preclude that issue from being litigated in an ordinary action respecting the patent, in other words, there is no res judicata (Aventis Pharma Inc. v.

Apotex Inc. (2006), 2006 FCA 64 , 46 C.P.R. (4th) 401(FCA), at para.7). [63] In the present case, Apotex has raised allegations in its NOA and has led evidence as to the invalidity of the Patent on thebasis of anticipation, obviousness and overbreadth which is sufficient to put those issues into play. As a result, the applicant, Roche bearsthe burden of establishing, on a balance of probabilities, that these allegations are not justified. [64] Apotex also alleges that it will not infringe claims 4-8 and claim 10.

As noted above at paragraph 60, the law is well-settledthat where a generic has alleged non-infringement, the statements that it makes in that regard in its NOA are presumed to be true. Theapplicant, Roche, therefore bears the burden of proof, on a balance of probabilities, to satisfy the Court that the allegations of non-infringement are not justified; merely to raise the possibility of infringement is insufficient.

PERSON SKILLED IN THE ART [65] The person skilled in the art (or person of ordinary skill in the art – a “POSITA”) provides the lens through which the patentis construed and many other issues are assessed. As described by Justice Hughes in Pfizer Canada Inc v Pharmascience Inc, 2013 FC120, [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 notionalperson 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 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 (4 th ) 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. [ 67 ] In my view, it is difficult to characterize the POSITA as an ordinary person possessing ordinary skill in the art given the expertise, experience and educational qualifications of the scientists engaged in this research; even if they are considered ordinary vis–à- vis their peers, they are far from ordinary.

In this case, these highly qualified experts were in disagreement on most issues, but there was general agreement on the POSITA. [ 68 ] The experts called by both parties expressed their opinions on the qualifications of the proposed person skilled in the art and why such qualifications and experience would be necessary.

There is no significant difference among the experts about the attributes and range of qualifications and expertise of the person skilled in the art in the mid-1990s to whom the ‘721 Patent would be addressed. [ 69 ] This composite person or team of persons would have expertise in medicinal chemistry, solid state chemistry, synthetic chemistry, pharmaceutical formulation, pharmacology and pharmacokinetics at the Masters or PhD level. [ 70 ] The medicinal chemist would be necessary to provide expertise in the discovery and design of drugs, and the understanding of organic synthesis, including issues related to chirality and stereoisomerism and pharmacokinetics, including familiarity with the design of prodrugs.

The solid state chemist would address the aspects of the ‘721 that involve the solid state of the L-valine mono-ester of ganciclovir, including its crystalline nature and its properties. The synthetic chemist would address the process aspects of the ‘721 Patent. The pharmaceutical formulator would address the making of the patent formulations. The pharmacologist would address the pharmacokinetic aspects of the patent.

THE ‘721 PATENT IN DETAIL [ 71 ] The ‘721 Patent appears to have no title except, 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl) methoxy-1,3-propane-diol derivative. [ 72 ] It is generally described, beginning at page 1 as a novel antiviral drug: [ 73 ] The prior art is acknowledged at pages 1-8.

The Patent identifies several other patents, patent applications and published research, including: US Patent 4 355 032, published in 1982 , which discloses ganciclovir and notes that it is highly efficacious against viruses of the herpes family (e.g. herpes simplex and cytomegalovirus), however, it has relatively low rate of absorption when administered orally.

Ganciclovir is most commonly administered intravenously, which has disadvantages. Therefore, it has been highly desirable to provide ganciclovir with an improved oral absorption profile. European Patent 375 329 (EP 329), published in 1990, which discloses prodrug compounds described as having advantageous bioavailability when administered the oral route resulting in high levels of the parent compound in the body. The examples described are all bis-esters, except example 6(

b) which discloses a bis-(L-alininate) ester of ganciclovir as a syrup containing 90% bis-ester and 19% mono-ester. The described bis-esters are non-crystalline materials which are difficult to process for the manufacture of oral pharmaceutical dosage forms. EP 329 discloses amino acid esters of the compounds of the formula indicated and the physiologically acceptable salts. Examples of preferred amino acids include aliphatic acids, e.g. containing up to 6 carbon atoms such as glycine, alanine, valine and isoleucine. The amino acid esters include both mono and diesters.

However, this patent application and US Patent No 5,043,339 (which is ganciclovir) do not disclose the preparation of mono-esters, much less any data suggesting their usefulness. Martin et al (1982 ) J Pharm Sci 76(2) which discloses the mono- and diacyl esters of ganciclovir and indicate that the dipropionate ester is about 43% more bioavailable than ganciclovir itself. There are also several references to patent applications and research regarding acyclovir, which is also used for the treatment of herpetic viruses, again at pages 1-8.

British Patent (BP) 1 523 865 published in 1978 describes derivatives which include acyclovir, which has been found to have good activity against herpes simplex and is very effective upon topical or parenteral administration, but it is only moderately absorbed upon oral administration. Maudgal et al, Arch Ophthalmal, 102 (1984) discloses esters of acyclovir and the advantages of the glycine ester for administration as eye drops. Colla et al , J Med Chem 98 (1983) discloses several water soluble ester derivatives of acyclovir and their salts as prodrugs of acyclovir.

The authors suggest that these acyclovir esters should be more practical for clinical use than the parent compound (acyclovir) for topical treatment as eye drops and for treatment of herpes virus infections that respond well to intravenous acyclovir treatment. European Patent Application 308 065, published in 1989, discloses the valine and isoleucine esters of acyclovir, preferably in the L- form , as showing a large increase in absorption from the gut after oral administration when compared with other esters and acyclovir.

Beauchamp et al, Antiviral Chemistry and Chemotherapy 3 (1992) discloses 18 amino esters of acyclovir and their efficiencies as prodrugs. The L-amino acid esters were better prodrugs than the corresponding D-, or D, L-isomers, suggesting the involvement of a stereoselective transporter. According to the authors, the L-valyl ester of acyclovir was the best prodrug, in terms of bioavailability, of the esters investigated. [ 74 ] The Patent notes that, currently, ganciclovir is the leading drug for the treatment of cytomegalovirus infection.

It also notes that ganciclovir has limited oral bioavailability and needs slow daily intravenous infusion of the drug. This indicates the “urgent need” for an oral dosage form with improved bioavailability. [ 75 ] The invention of the ‘721 Patent and its promise are described at page 9 of the Patent specification as follows: The present invention provides a stable prodrug formulation of ganciclovir with improved oral absorption and low toxicity.

Such characteristics are especially valuable for suppression of herpetic infections in immunocompromised patients where oral administration therapeutically is the preferred choice. In addition, the active ingredients exhibit pharmacopoeial properties which permit their improved characterization and pharmaceutical processing. Surprisingly, it was found that the L-monovaline ester of ganciclovir and its pharmaceutically acceptable salts exhibit these desired characteristics.

[ 76 ] The compound is described in more detail at pages 9-11 and

definitions of terms are provided at pages 9-19. [ 77 ] The processes to prepare the compound are described at pages 20-22 and later in the Patent. The uses of the compound are set out at pages 22-24. [ 78 ] At page 24 the utility of ganciclovir as a proven antiviral drug is noted to have been established by determining the blood level concentrations of ganciclovir in test animals (the rat and monkey) following oral administration of the prodrug.

The concentrations were determined according to the methods described in Examples 9 and 10 (which appear later in the Patent at pages 51-55). [ 79 ] The modes of administration of the compound are noted at page 24 as any of the usual and acceptable modes known in the art, noting that oral pharmaceutical compositions are preferred. [ 80 ] The preferred acids, compounds, and compositions are described at pages 24-28.

The most preferred compounds are described on page 27 and it is noted that these compounds can be prepared as crystalline materials and therefore can be easily manufactured into stable oral formulations. Oral and intravenous formulations are preferred. The oral formulations have the advantage of high bioavailability; the intravenous formulations have the advantage that the prodrug of the invention, unlike intravenous ganciclovir formulations, can be prepared using a physiologically more acceptable ph (4-6).

The intravenous formulation of ganciclovir requires a ph of 11 which results in irritation. [ 81 ] At pages 31-39, the Patent describes the steps for the preparation of the mono-L-valine ganciclovir. [ 82 ] On page 39 under a separate heading, The Manufacture of Crystalline 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3- hydroxy-1-propanyl-L-valinate, (i.e. valganciclovir), it is noted that: The compound of the invention can be, and has been, produced in crystalline form. This is a decisive advantage over the compounds disclosed in the prior art which have been described as non-crystalline materials.

The advantage resides in the fact that pharmaceutical formulations can be more easily produced with a crystalline material. A crystalline material can be processed efficiently and is susceptible of being more reproducibly characterized than a non-crystalline material, and the quality of the crystalline materials of the invention can be much more readily ascertained than that of non-crystalline materials. [ 83 ] Examples are described at pages 40-57 .

None of the examples, except Examples 9 and 10, indicate their purpose and none state or summarize a conclusion. [ 84 ] Examples 9 and 10, which were first referred to at page 24, are more fully described at pages 51-55. [ 85 ] Example 9 indicates it was used to determine the oral absorption (oral bioavailability) of the compound of Formula I (L- monovaline ester of ganciclovir) and of other ganciclovir amino acid esters and other ganciclovir esters and ethers examined for comparative purposes.

It provides bioavailability results for ganciclovir, other esters of ganciclovir, EP 329 and the G-L-valinate ester of the invention and the G-L-valinate hydrochloride of the invention. The example indicates that ganciclovir had oral bioavailability of 7.9%, G-bis (L-valine) ester ganciclovir (EP 329) had oral bioavailability of 52% and the amino acid ester of the present invention (G-L- valinate hydrochloride) had a 98% oral bioavailability. [ 86 ] Example 10 indicates that it was used to determine the oral bioavailability of valganciclovir in the monkey.

This suggests that the invention, mono L- valine/valganciclovir, had an oral bioavailability of 35.7%, whereas the bis-L-valinate (EP 329) had a 23.5% oral bioavailability and ganciclovir had 9.9 %. [ 87 ] The ‘721 Patent ends with 17 claims. [ 88 ] Claim 1 is the broad compound. Claims 2-3 are directed at the compound and its diastereomers and salts. Claim 4 is directed to the crystalline form of the compound. Claims 5-8 cover specific salts and diastereomers. Claims 9-10 cover pharmaceutical compositions. Claim 11 covers intermediates and Claim 15 covers their use to make the compounds in Claims 1-8.

Claims 12-13 are

process claims which are not at issue. Claims 14, 16, and 17 cover the uses of the compounds claimed. [ 89 ] The claims of the ‘721 Patent are as follows: 1. The compound 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl-L-valinate or a pharmaceutically acceptable salt thereof, in the form of its (R)– or (S)–diastereomers, or in the form of mixtures of the two diastereomers. 2. The compound according to Claim 1 comprising said mixture containing equal amounts of its (R)- and (S)- diastereomers. 3.

The compound according to Claim 1 wherein the pharmaceutically acceptable salt is the hydrochloride or acetate. 4. A compound according to Claim 1 in crystalline form. 5. The compound of Claim 1 which is (R)-2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl-L-valinate and its pharmaceutically acceptable salts. 6. The compound of Claim 1 which is (S)-2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl-L-valinate and its pharmaceutically acceptable salts. 7. A compound according to Claim 5 or 6 wherein said salt is the hydrochloride. 8.

A compound according to Claim 5 or 6 wherein said salt is the acetate. 9. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 8 together with a pharmaceutically acceptable excipient or carrier material. 10. The pharmaceutical composition according to Claim 9 for intravenous administration. 11. A compound of the formula wherein

P 1 is hydrogen or hydroxy-protecting group and P 2 is an amino-protecting group. 12. A process for preparing the compound 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl-L-valinate or a pharmaceutically acceptable salt or diastereomers thereof which process comprises: (

a) removal of an amino- and/or hydroxy-protecting group from a compound with the formula wherein: P 1 is a hydroxy-protecting group or hydrogen, P 2 is an amino-protecting group, and P 3 is hydrogen or P 2 ; to afford the compound 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl- L-valinate or a pharmaceutically acceptable salt thereof; (

b) conversion of the compound 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl-L-valinate into a pharmaceutically acceptable salt thereof; or (

c) esterification of 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol (ganciclovir) or a salt thereof, with an activated derivative of L-valine; or (

d) condensation of an optionally substituted guanine of the formula

optionally in persilylated form, wherein: P 3 is hydrogen or an amino-protecting group, with an 2-substituted glycerol of the formula wherein: Y 1 and Y 2 independently are halo, lower acyloxy, lower alkyloxy, or aryl(lower)alkyloxy groups, and Z is a leaving group selected from lower acyloxy, methoxy, isopropyloxy, benzyloxy, halo, mesyloxy or tosyloxy; optionally in the presence of a Lewis acid catalyst, to provide the compound 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3- hydroxy-1-propanyl-L-valinate; or (

e) partial hydrolysis of the bis ester 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediyl bis (L-valinate) or a salt thereof to afford the monoester 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl-L-valinate or a pharmaceutically acceptable salt thereof; or (

f) diastereomeric separation of 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl-L-valinate into its (

R) and (

S) diastereomers. 13. The process of Claim 12, wherein the removal of amino- and hydroxy-protecting groups is carried out under acidic conditions. 14. A compound as claimed in any one of claims 1 to 8 as a therapeutically active agent for the treatment of viral diseases. 15. The use of a compound as claimed in claim 11 for the preparation of a compound as claimed in claims 1 to 8. 16. The use of a compound as claimed in any one of claims 1 to 8 for the preparation of a pharmaceutical composition. 17. The use of a compound as claimed in any one of claims 1 to 8 for the preparation of a pharmaceutical composition for the treatment of viral diseases.

CONSTRUCTION OF THE CLAIMS Jurisprudence / Principles re the Construction of a Patent [90] In Apotex Inc v Sanofi-Aventis, 2011 FC 1486, [2011] FCJ 1813, Justice Boivin noted: [59] The Court observes that claims construction is a question of law and must be addressed with a purposive approach in order “toachieve fairness and predictability and to define the limits of the monopoly” (Dimplex North America Ltd. v CFM Corp., 2006 FC 586, 54 CPR (4th) 435, at para 49, aff'd 2007 FCA 278, 60 CPR (4th) 277). In so doing, the Court is required to read the patent claims with “amind willing to understand” (Whirlpool, above). [91] Justice Hughes reviewed all the relevant case law and provided a useful

summary of the principles which govern claimconstruction in Pfizer Canada Inc and Warner Lambert Company LLC v Pharmascience Inc et al, 2013 FC 120, [2013] FCJ 111: [64] There have been many judicial instructions as to the construction of a claim.

To summarize: • construction must be done before considering the issues of validity and infringement; • construction is done by the Court alone, as a matter of law; • the Court is to construe the claim through the eyes of the person skilled in the art to which the patent pertains; • the Court may obtain the assistance of experts to explain the meaning of particular words and phrases, and as to the state of the artas of the date the claim was published; • the Court should read the claim in the context of the patent as a whole, including the description and other claims; • The Court should avoid importing this or that gloss from the description; • the Court should not restrict the claim to specific examples in the patent; • the Court should endeavour to interpret the claim in a way that gives effect to the intention of the inventor; • the Court should endeavour to support a meritorious invention. [92] Justice Hughes traced the current state of the law to Free World Trust v Électro-Santé Inc, 2000 SCC 66 , [2000] 2SCR 1024, [Free World Trust] where Justice Binnie noted that Canadian courts prefer the “peripheral claiming principle” – an approachwhereby the legal boundary of the monopoly of the patent is defined by the claims.

Justice Binnie wrote at para 68: The other school of thought supporting what is sometimes called the "peripheral claiming principle" emphasizes the language of theclaims as defining not the underlying technical idea but the legal boundary of the state-conferred monopoly. Traditionally, for reasons offairness and predictability, Canadian courts have preferred the latter approach. [93] Justice Binnie indicated that an informed and purposive construction was required to advance research while promotingcertainty, and generally, to reflect the patent bargain.

At para 50, he stated: I do not suggest that the two-stage approach necessarily ends at a different destination than the one-stage approach, or that the two-stageapproach has resulted in abuse. I think we should now recognize, however, that the greater the level of discretion left to courts to peerbelow the language of the claims in a search for "the spirit of the invention", the less the claims can perform their public notice function,

and the greater the resulting level of unwelcome uncertainty and unpredictability. "Purposive construction" does away with the first step of purely literal

interpretation but disciplines the scope of "substantive" claims construction in the interest of fairness to both the patentee and the public. In my view its endorsement by the Federal Court of Appeal in O'Hara was correct.

Construction of the ‘721 [ 94 ] Turning to the claims, I have endeavoured to construe those at issue in an informed and purposive way through the eyes of the POSITA with regard to the Patent as a whole and with the benefit of the evidence of the experts. [ 95 ] As noted above, the POSITA or “skilled person” is a composite person or a team of persons with expertise in medicinal chemistry, solid state chemistry, synthetic chemistry, pharmaceutical formulation, pharmacology and pharmacokinetics at the Masters or PhD level. [ 96 ] The experts for both parties expressed similar opinions with respect to how the patent should be construed. [ 97 ] I would construe the claims as follows: Claim 1 of the patent covers the compound, 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl-L-valinate, referred to as valganciclovir, or its pharmaceutically acceptable salts, either as the (

R) diastereomer or (

S) diastereomer separately, or as a mixture of the two diastereomers. The claim is not specific to the solid state form (crystalline or non-crystalline) of the compound and thus encompasses both. The claim is also not specific to the route of administration. In simple terms, claim 1 includes a mixture of the (

R) and (

S) diastereomers of the L-valganciclovir as well as the pharmaceutically acceptable salts of these compounds. Claim 2 covers the compounds of claim 1 (valganciclovir) where the compound contains equal amounts of the two diastereomers (i.e. 50% of the (

R) mono–L-valinate ganciclovir and 50% (

S) mono-L– valinate ganciclovir). Claim 3 covers the compounds of claim 1 (valganciclovir) but includes only the hydrochloride or acetate salts of mono-L–valinate ganciclovir. Claim 4 covers the compounds of claim 1 (valganciclovir) when the compound is in crystalline form. Claims 5 and 6 cover the two diastereomers individually. Claim 5 covers the compound of claim 1 (valganciclovir) but indicates only the (

R) diastereomer. Claim 6 covers the compound of claim 1 (valganciclovir) but indicates only the (

S) diastereomer. Claim 7 covers the compounds of claims 5 or 6 but limits the compounds to the hydrochloride salt. Claim 8 covers the compounds of claims 5 or 6 but limits the compounds to the acetate salt. Claim 9 covers a pharmaceutical composition (i.e. a mixture of active ingredient and inactive ingredients to form a drug for administration to a patient) that can contain any of the compounds of any of claims 1-8. Claim 10 covers a pharmaceutical composition of claim 9 for intravenous administration. Claim 11 covers an intermediate compound of the formula set out in that claim.

Claim 12 and 13 relate to processes for the manufacture of the compound of claims 1-8 (i.e. for the L-valine ester of ganciclovir).

Claim 14 covers the compounds of claims 1-8 as a therapeutically active ingredient for the treatment of viral diseases. Claim 15 covers the use of the compounds of claim 11 in the preparation of the compounds of claims 1-8. Claims 16 covers the use of a compound of claims 1 to 8 for the preparation of a pharmaceutical composition. Claim 17 covers the use of a compound of claims 1 to 8 for the preparation of a pharmaceutical composition for the treatment of viral diseases. [ 98 ] There are several dependent claims, such as claims 2-8, and all are dependent on claim 1.

THE INVENTION [ 99 ] The invention, or the inventive concept, is a point of major disagreement between the parties. The identification of the inventive concept is essential for the assessment of all the allegations and it should therefore be addressed at the outset. [ 100 ] The applicant, Roche, submits that the invention is the identification that valganciclovir has unexpectedly better bioavailability over the previously known esters of ganciclovir, most importantly the bis-valine ester (i.e. the EP 329). [ 101 ] Roche submits that the improvement is over not only the closest prior art (the bis-ester, i.e.

EP 329), but also over other known ganciclovir esters and over ganciclovir itself, the bioavailabilities of which are explicitly compared to L-valganciclovir in the Patent (the comparisons are set out in Examples 9 and 10 which are first referred to at page 24 of the Patent). [ 102 ] Apotex submits that the inventive concept described by Roche cannot be supported because the ‘721 Patent does not state that valganciclovir is an improvement over the bis-valine ester, rather that it is an improvement over ganciclovir.

Apotex also submits that the POSITA would not look to Examples 9 and 10 as disclosing the invention. [ 103 ] In addition, the Patent does not state that the L-valine bis-ester had any shortcomings in terms of oral bioavailability or that the ‘721 Patent was directed at overcoming such problems. [ 104 ] Apotex asserts that the invention as described in the ‘721 Patent is crystalline valganciclovir and its salts which has the advantage of being a stable prodrug of ganciclovir with low toxicity, having pharmacopoeial properties that will permit improved characterization and pharmaceutical processing, and when administered orally, have better oral bioavailability than ganciclovir.

The Expert Evidence [ 105 ] The experts addressed the issue of whether the ‘721 Patent claims that the mono-L-valine ester of ganciclovir (i.e. valganciclovir) is better (improved) than the bis-ester (EP 329) and other esters of ganciclovir or whether it claims that the mono-L- valine ester of ganciclovir (valganciclovir) is better (improved) than ganciclovir.

The experts are not ad idem with respect to the inventive concept. [ 106 ] Dr Sawchuk indicated at paragraph 66 of his affidavit that the POSITA would understand that the invention of the ‘721 Patent is the L-mono-valine ester of 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl) methoxy-1,3-propanediol and its pharmaceutically acceptable salts (i.e. valganciclovir) which has the advantages of: improved oral absorption and delivery of ganciclovir over the compounds in the prior art; a low toxicity profile; and, improved stability (which can include in vivo stability and stability for pharmaceutical processing). [ 107 ] Dr Tsantrizos indicated at paragraph 39 of her affidavit that the POSITA would understand that the ‘721 Patent relates to the L- valine mono-ester of ganciclovir which is a prodrug formulation of ganciclovir and has the advantages of

a) being stable,

b) having improved oral absorption; and

c) having low toxicity.

[ 108 ] Dr Tsantrizos also noted that making L-valganciclovir in the first place is a key inventive step in the ‘721 Patent. She added that while a chemist may prefer an amorphous or a crystalline compound (depending on the application) that does not take away from the fact that it is the compound itself that is the first inventive step; in this case, L-valganciclovir is the first inventive step. [ 109 ] Dr McGuigan provided a

summary of his opinion at para 31 of his affidavit, “The inventive concept/step of the claims of ‘721 patent valganciclovir and its salts and that they can [sic] prepared as crystals.” I note that a verb is missing. [ 110 ] Dr McGuigan conveyed his opinion on the inventive step in different ways. [ 111 ] At para 299 he notes that “The inventive concept/step of each claim is clear from the wording of the claims themselves and relates to the specific compounds claimed therein.

Additionally, the skilled person would understand from the disclosure of the 721 patent that the aspect of the invention that sets it apart from the prior art, thus comprising the inventive concept/step, is the crystalline nature of these compounds.” [ 112 ] Dr McGuigan also noted that the ‘721 Patent distinguishes its invention from those esters prepared in EP 329 by pointing out that they were non-crystalline in nature and therefore difficult to process for the manufacture of oral pharmaceutical dosage forms.

He noted that the ‘721 Patent indicates that the crystalline nature of the compounds provides a decisive advantage over those compounds of the prior art that were described as non-crystalline.

He concluded that the inventive concept of the ‘721 Patent is that which is said to set it apart from the prior art: i.e. the specific compounds set out in the claims and prepared in crystalline form. [ 113 ] Dr McGuigan indicated that a medicinal chemist would not understand that the improved bioavailability as compared to ganciclovir is part of the inventive concept because the ‘721 Patent is not limited to oral administration and many forms of administration do not need bioavailability. [ 114 ] I would note that I find it difficult to reconcile Dr McGuigan’s statement that crystallinity addressed the problem of processing ganciclovir for oral dosage forms and, hence, this is the inventive concept, with his opinion that oral bioavailability is not part of the inventive step because the patent is not limited to oral administration.

If crystallinity is a way to improve oral dosage forms, then it too would only be an advantage for that mode of administration and not for the other modes, for example, intravenous or parenteral administration. [ 115 ] The goal was to improve the bioavailability of ganciclovir for oral administration. All experts agreed that this was a problem with ganciclovir and also with acyclovir. [ 116 ] Dr Zhanel, in his

summary of opinion at para 34 of his affidavit, indicated that the inventive step is valganciclovir and its pharmaceutically acceptable salts in crystalline form. [ 117 ] Dr Zhanel indicated at para 177 of his affidavit that, “the skilled pharmacologist would appreciate that the inventive step/concept of the claims of the 721 Patent was valganciclovir, as well as its pharmaceutically acceptable salts, which (unlike prior art compounds) are crystalline.

The skilled pharmacologist would understand the inventive concept to include this crystalline form because it is the only quality described in the 721 Patent providing a “decisive advantage” over the prior art compounds.” [ 118 ] He also indicated that increased bioavailability is not an aspect of the inventive concept because the claims are not limited to the oral formulation and improved bioavailability is only achieved upon oral administration. [ 119 ] Dr Boeckman, Dr Steed and Dr Moreton all shared the view that the advantage was crystallinity for similar reasons as noted by Dr McGuigan and Dr Zhanel. [ 120 ] Dr Moreton also commented on Dr Sawchuk’s affidavit noting that the Patent does not say that the inventive concept is the “improved oral absorption and delivery of ganciclovir over the prior art” (para 111).

He asserts that the inventive concept does not relate

to bioavailability and adds that if bioavailability were the inventive concept, the patent is clear that this is an improvement in bioavailability over ganciclovir, not over the compounds of the prior art. [ 121 ] He expressed the view that Examples 9 and 10 should not be relied on as disclosing the advantage over the compounds of the prior art and that a formulator would expect the inventive concept to be plainly stated, not based on an inference (para 112). [ 122 ] Again, I would note my difficulty in reconciling the opinion that oral bioavailability is not part of the inventive concept because oral administration is not the only mode of administration with the common general knowledge which recognized the need to improve the bioavailability of ganciclovir for oral administration.

Moreover, the need to improve the bioavailability of ganciclovir was the motivation for most of the prior art, including that relied on by the Apotex experts as the most promising research, notably, acyclovir. Although Dr Moreton conveyed the opinion that the inventive concept was crystallinity, he indicated that if bioavailability was the inventive concept, it would be bioavailability over ganciclovir.

Inventive concept [ 123 ] Based on my review of the Patent and of the views of the experts, I find that the ‘721 Patent does not assert that the invention is an improvement over the bis-ester (EP 329) and other prior art but only over ganciclovir. [ 124 ] The Patent does not assert that the invention is an improvement over the bis-ester (EP 329) and other prior art but only that it is an improvement over ganciclovir. There is no clear reference to an improvement in bioavailability over the ‘329. All of the problems which the invention sought to solve related primarily to the oral bioavailability of ganciclovir.

The disclosure does not indicate any problems associated with EP 329 that would suggest a need for improvement that the present invention then addressed. [ 125 ] The only reference to improvements over EP 329 and over the other prior art, including over ganciclovir, is in Examples 9 and 10. However, even these examples compare the invention of the ‘721 to ganciclovir as the key comparator, although the results of testing of the other esters are included. [ 126 ] Only through a very creative

interpretation could a POSITA understand that the invention of the mono-L-valine ester of ganciclovir (i.e. valganciclovir) is that it is an improvement over the bis-ester (EP 329) and over ganciclovir and other esters. [ 127 ] The Patent refers to the prior art, including EP 329 which is acknowledged to be the closest prior art, and which is noted as having “advantageous” bioavailability. The ‘721 indicates that it has “improved” bioavailability. There is no indication of what the ‘721 is improved from.

Roche would argue that the POSITA could deduce that the ‘721 is an improvement over the “advantageous” EP 329 and that the reference to the examples and deductions to be made from the data support such an

interpretation. However, this is not a clearly stated improvement and all of the examples note the comparison to ganciclovir. Not crystallinity [ 128 ] I do not share the view that the inventive concept is the compound as a crystalline product.

The Apotex experts advanced this opinion but I cannot conclude from the testimony of the experts and the manner in which they described the crystallinity advantage that the crystalline product can exist and can have the key advantages of the compound without first making the compound. [ 129 ] Although crystallinity is described more clearly as an advantage and it does address an identified shortcoming in the prior art for oral administration, it should be construed as an additional advantage rather than the only advantage or the stand-alone advantage.

Crystallinity is not the inventive concept; it is a manner of making the invention. [ 130 ] The Patent describes how to make the mono-L-valine ester, outlines several steps, and also describes other methods of preparation. It then refers to how to manufacture the invention as crystalline, under a separate heading and after several pages describing the steps to make the mono-L-valine ester and other methods.

The earlier parts of the disclosure refer to the invention, whether amorphous or not. [ 131 ] Apotex submits that Dr Tsantrizos agreed on cross-examination that the Patent did not teach amorphous valganciclovir. This is not an accurate portrayal of her testimony. Dr Tsantrizos indicated that it was not necessary to teach amorphous valganciclovir. She

expressed the view that the Patent covered both forms and that the inventive step was the compound which could then be prepared as crystalline. [ 132 ] I have, therefore, concluded that the inventive concept of the ‘721 Patent is the invention of valganciclovir, a stable prodrug with low toxicity and improved oral bioavailability over ganciclovir. IS IT A SELECTION PATENT? [ 133 ] To adopt the words of Justice Layden-Stevenson in Eli Lilly Canada v Novapharm , 2010 FCA 197 , [2010] FCJ 951 , the Court should know “the nature of the beast” when considering allegations with respect to a patent (para 28).

In the present case, the applicant, Roche, raised the issue that the ‘721 could be a selection patent. [ 134 ] Although it is not essential that I make a finding that the ‘721 is or is not a selection patent, as there is no attack on utility, the characterisation as a selection patent will inform the analysis, particularly with respect to anticipation and obviousness. [ 135 ] The assertions of the applicant and respondent and the words of the claims themselves are not determinative of whether this is a selection patent.

The applicant, Roche, over the course of its oral argument, progressed from submitting that the ‘721 was probably or likely a selection patent to asserting that it was clearly a selection patent. Roche submitted that EP 329 disclosed a class that encompassed valganciclovir (i.e. it disclosed both the mono- and the bis-ester) and that the ‘721 was a selection from this class. [ 136 ] Roche submitted in its written argument that EP 329 provides a large class of compounds that include both mono- and bis- amino acid esters of different nucleosides and their derivatives and would have at least 500,000 compounds.

Roche maintains that EP 329 only specifically discloses bis -esters and does not disclose any mono-esters, “although they are encompassed within the disclosed class”. In addition, Roche referred to the Supreme Court of Canada’s decision in Apotex v Sanofi-Synthelabo , 2008 SCC 61 , [2008] 3 SCR 265 [ Sanofi ] , regarding the disclosure requirements of selection patents. [ 137 ] The respondent, Apotex, referred to genus and selection patents in its NOA in the context of setting out the test for anticipation, suggesting that the ‘721 could be so characterised.

Apotex submits that the applicant seeks to retroactively characterize the ‘721 Patent as a selection patent, which it is not, at least with respect to oral bioavailability.

Apotex maintains that the ‘721 Patent does not clearly define the bioavailability advantage which Roche asserts as the basis for the selection nor does it indicate that a significant number of other esters of ganciclovir would not have oral bioavailabilities comparable to valganciclovir. [ 138 ] Apotex submits that the ‘721 did not meet the criteria of a selection patent as it did not disclose the special advantages of the selected compound. [ 139 ] In addition, regardless of whether the ‘721 is a selection patent, Apotex asserts that the advantages claimed were over ganciclovir and not over EP 329.

No advantages or improvements were disclosed over EP 329 other than crystallinity. [ 140 ] A selection patent is like all other patents; the same principles will apply. However, as noted, the characterisation will inform the analysis of anticipation and obviousness. [ 141 ] While the applicant, Roche, sought to draw analogies between the ‘721 Patent and the patent at issue in Sanofi , such analogies may not be appropriate. [ 142 ] I have, therefore, considered whether the ‘721 is a selection from EP 329.

Jurisprudence / Principles of Selection Patents [ 143 ] The Supreme Court of Canada considered the issue of selection patents in Sanofi and the principles affirmed in that case have been subsequently applied in several recent cases.

[ 144 ] In Sanofi , Justice Rothstein adopted the conditions that must be satisfied for a selection patent as set out below by Justice Maugham in In re I G Farbenindustrie AG’s Patents (1930), 47 RPC 289 (Ch D) [ Farbenindustrie ] and which he noted were a useful starting point for the analysis: 1. There must be a substantial advantage to be secured or disadvantage to be avoided by the use of the selected members. 2. The whole of the selected members (subject to “a few exceptions here and there”) possess the advantage in question. 3.

The selection must be in respect of a quality of a special character peculiar to the selected group. If further research revealed a small number of unselected compounds possessing the same advantage, that would not invalidate the selection patent.

However, if research showed that a larger number of unselected compounds possessed the same advantage, the quality of the compound claimed in the selection patent would not be of a special character. [ 145 ] In Eli Lilly Canada Inc v Novopharm Limited , 2010 FCA 197 , [2010] FCJ 951 , Justice Layden-Stevenson held that the failure of a patent to meet the conditions for a selection patent does not constitute an independent basis for challenge or invalidity, but informs the analysis of other bases for invalidity: [ 27] In my view, a challenge directed to a determination that the conditions for a selection patent have not been met does not constitute an independent basis upon which to attack the validity of a patent.

Rather, the conditions for a valid selection patent serve to characterize the patent and accordingly inform the analysis for the grounds of validity set out in the Act – novelty, obviousness, sufficiency and utility. In short, a selection patent is vulnerable to attack on any of the grounds set out in the Act. I arrive at this conclusion for a variety of reasons. [28] As noted in Sanofi , the conditions set out in I.G. Farbenindustrie describe selection patents (para. 9). In other words, the conditions are akin to a definition. Rothstein J. found I.G.

Farbenindustrie to be a useful starting point for the analysis to be conducted (para. 11). It only stands to

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