Date: 20000508
Docket: T-2592-97
IN THE MATTER OF an application for an order pursuant
to section 55.2(4) of the Patent Act and Section 6 of the
Patented Medicines (Notice of Compliance) Regulations
BETWEEN:
NOVARTIS AG and
NOVARTIS PHARMACEUTICALS CANADA INC.
Applicants
- and -
APOTEX INC. and
THE MINISTER OF HEALTH
Respondents
REASONS FOR ORDER
REED, J.:
[1] The applicants seek an injunction, pursuant to the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133, prohibiting the Minister of Health from issuing a Notice of Compliance to the respondent Apotex Inc. for the drug terbinafine hydrochloride. Terbinafine hydrochloride is used for the treatment of fungal infections of the skin and nails.
[2] The procedure and burden of proof applicable to the present proceeding has been described in many cases and need not be repeated here. See, for example, Hoffmann LaRoche v. Canada (1996), 70 C.P.R. (3d) 20 (F.C.A.).
[3] The applicants seek to show that Apotex's allegation that its manufacture and sale of terbinafine hydrochloride would not infringe Canadian patent 1,157,023 ("the U023 patent") is not justified. The applicants also originally relied upon Canadian patent 1,111,852, but no longer do so. Dr. Giasson states in his affidavit that none of the processes claimed in the U852 patent lead to the preparation of terbinafine.
Principles of Patent Construction
[4] The principles to be applied when construing patents are well known. It is the claims of the patent that define the monopoly granted by the patent. Those claims as well as the rest of the specification are to be given a purposive construction. The text of a claim should not be subjected to the kind of meticulous verbal analysis in which lawyers are too often tempted by their training to indulge. At the same time, the Court must be careful to "construe and not reform a claim". The claims are read from the perspective of a person skilled in the art to whom the patent is addressed. A more exhaustive description of the relevant principles can be found elsewhere, and I will not repeat it here. See for example: Visx Incorporated v. Nidek Co., Ltd. et al. (T-195-94, December 16, 1999, paragraphs 9-11), and W.L. Hayhurst, "The Art of Claiming and Reading a Claim", in G.F. Henderson, ed., Patent Law in Canada (Toronto: Carswell, 1994) 177.
[5] In this case, a person skilled in the art to whom the patent is addressed is not a first or second year chemistry student. It is someone who has an advanced knowledge in the field of organic chemistry.
The U023 Patent
[6] The U023 patent is a product by process patent, as was required when it was issued, to comply with subsection 41(1) of the Patent Act, R.S.C. 1970, c. 203. [This section was repealed effective January 1, 1994, by An Act to Amend the Patent Act, S.C. 1993, c. 2, s. 3]. That subsection reads:
41(1) In the case of invention relating to substances prepared or produced by chemical processes and intended for food or medicine, the specification shall not include claims for the substance itself, except when prepared or produced by the methods or processes of manufacture particularly described and claimed or by their obvious chemical equivalents. [Emphasis added.]
[7] The U023 patent relates to propenylamines and covers many, many compounds (perhaps millions). The patent describes these compounds by way of a general formula in which the letters R1, R2 etc. stand for different substituents. The general formula (formula I) is written as:
[8] Terbinafine falls within that formula when:
R1 is a 1-napthyl group;
R2, R3, R5 are each hydrogen (H);
R4 is methyl (CH3);
R6 is a carbon triple bond carbon (C/C) bonded to R11,
and R11 is a tert.butyl (C(CH3)3);
and the C=C double bond has a trans (E) configuration.
[9] The carbon-carbon double bond (C=C), allows the chemical structure to exist in two different spatial configurations known as isomers. One configuration is known as the trans (or E) configuration and the other is known as the cis (or Z) configuration. Terbinafine is the trans or E isomer of the chemical structure.
[10] Organic chemists depict the structure of compounds in several ways. Sometimes they use the letters of the various elements (e.g. C designating carbon, H designating hydrogen), perhaps, together with letter designations for groups (e.g., Dr. McClelland uses Ar for the 1-naphthyl group of the terbinafine molecule); sometimes they use a diagrammatic presentation, omitting the obvious hydrogen and carbon atoms; sometimes they use a combination of the two. Among the different depictions of terbinafine found in the evidence are the following:
et
et
The superscript numbers 1-7 are used to identify the location of the carbon elements. Two additional superscripts could be added to the above diagram, an 8 and a 9 to the carbons lacking a superscript on the right hand side of the diagram. Everything to the right of the N-bond is sometimes referred to in the evidence as "the nine carbon chain".
[11] The only claims of the patent that are relevant for the purposes of this application are claims 1, 2, 14 and 15. Claims 1 and 14 are process claims. Claims 2 and 15 are product by process claims. Claims 2, 14 and 15 read:
2. A compound of the formula I or an acid addition salt thereof according to claim 1 whenever prepared by a process as claimed in Claim 1 or by an obvious chemical equivalent thereof
14. A process according to Claim 1 wherein:
R1 represents naphthyl
R2, R3 and R5 each represents hydrogen
R4 represents methyl and
R6 represents -C/C-R11, where R11 is n. butyl to produce N-methyl-N-(1-naphthylmethyl)-6,6-dimethyl-hept-2(trans)-en-4-ynyl-1-amine [terbinafine] or a hydrochloride salt thereof. [The reference to n.butyl is an error and was corrected to tert.butyl. by a certificate of correction, dated May 13, 1998.]
15. N-methyl-N-(1-naphthylmethyl)-6,6-dimethyl-hept-2(trans)-en-4-ynyl-1-amine [terbinafine] or its hydrochloride, whenever produced by the process according to Claim 14 or an obvious chemical equivalent.
[12] N-methyl-N-(1-naphthylmethyl)-6,6-dimethyl-hept-2(trans)-en-4-ynyl-1-amine is the chemical name for terbinafine. Claim 14 thus claims a process to make terbinafine and terbinafine hydrochloride; and claim 15 claims terbinafine and terbinafine hydrochloride when produced by the process claimed in claim 14.
[13] The focus of the within application, then, is claim 1 since it is that claim on which claim 14 (expressly), and claim 15 (by relying on claim 14), as well as claim 2 (expressly) rely.
[14] It is terbinafine hydrochloride, not terbinafine, that is sold as a pharmaceutical preparation. Claims 2, 14 and 15 all claim either an acid addition salt of terbinafine or the hydrochloride. Terbinafine hydrochloride is an acid addition salt of terbinafine. Also, claim 1 ends with: "... and if desired converting a compound of the formula I or an acid addition salt thereof thus obtained into or into another acid addition salt thereof or vice versa." The making of a hydrochloride salt is included in the Apotex process as the last step (i.e., step 2) and thus falls under the last part of the claims referred to above.
[15] Dr. Olah gave evidence that "[terbinafine] hydrochloride is a salt derivative which has nothing to do with the chemical composition of the molecule"[i] and "to make from an amine an amine hydrochloride is one of the most common phenomena in chemistry".[ii] Thus, it is not surprising that it is the making of the terbinafine molecule that is the main focus of the evidence and these reasons.
[16] Claim 1 of the patent claims five alternative processes. Each is the last step in a synthetic pathway that leads to the making of compounds within formula I of the patent. Only three of these, claims 1(a), 1(c) and 1(e), can lead to the making of terbinafine. While claim 1(e) was originally asserted, by the applicants, as being one of the claims that would be infringed by Apotex, this assertion was abandoned on the hearing of the application. The applicants assert that claims 1(b) and 1(d) are relevant because they give content to the claims in the patent for obvious chemical equivalents. The full text of the claims are set out as an appendix to these reasons.
[17] The process claimed in claim 1(a) is the reaction of a compound described as formula IV with a compound described as formula V. It is depicted in claim 1(a) as illustrated below:
That process makes terbinafine, as noted above, when:
R1 is 1-naphthyl;
R2, R3, R5 are each hydrogen (H);
R4 is methyl (CH3);
R6 is -C/-C(CH3)3; and
A is a leaving group.
Another depiction of the process claimed in 1(a) is:
In this depiction a specific leaving group has been chosen, that is bromine (Br.).
[18] Claim 1(c) claims a process step in which the molecule is completed with the creation of the carbon-carbon double bond. That step is accomplished by the conversion of the triple bond, C2/C3 into a double bond, HC2=C3H. This process step involves reducing compound VIII with diisobutylaluminiumhydride (DIBAL). The process can be depicted as:
It makes terbinafine where
R1 is 1-naphthyl;
R2, R3, R5 are each hydrogen (H);
R4 is methyl (CH3); and
R6 is -C/-C(CH3)3.
Another depiction of this process, found in the evidence, is:
[19] In summary, the most pertinent claims of the U023 patent each claim a single (and final) step by which terbinafine is made. More particularly: claim 1(a) is directed to the bond between the central nitrogen(N) and the C1 carbon of the nine carbon chain when all other aspects of the molecule are completely in place; claim 1(c) is directed to the creation of the requisite C2=C3 carbon double bond when all other aspects of the molecule are completely in place.
[20] Claim 1(b) claims the last step of a process that does not make terbinafine, and that last step adds an hydroxyalkyl group to the carbon-carbon triple bond where the tert.butyl is in terbinafine. Claim 1(d) claims the last step in a process that does not make terbinafine, and that last step converts a carbon-carbon single bond into a carbon-carbon double bond in the R6 group (in a different position). Claim 1(e) claims the last step in a process that can be used to make terbinafine, and that last step is the adding of the methyl group to the molecule.
[21] The scope of claims 1(a), 1(c) and 1(e) (although the last is not in issue) cannot be expanded by relying on claims 1(b) and 1(d). The five subclaims are drafted as discrete and final steps of alternative syntheses for producing the various compounds. The earlier steps of each process are not claimed. The patentee chose to claim in this way, perhaps to avoid overbreadth, perhaps because so many compounds were being claimed within one patent that it was necessary to do so. The Court does not speculate as to why claims are drafted in a particular manner but must give effect to the claims as drafted by the patentee.
[22] A person skilled in the art, a person willing to understand would read the reference to claim 1 in claim 14 as referring only to those processes described in claim 1 that lead to the making of terbinafine. Similarly the reference to claim 1 in claim 2, when the substituents of the general formula are such that terbinafine is the compound under consideration, would be read by a person skilled in the art, with a mind willing to understand, as referring only to those processes described in claim 1 that lead to the making of terbinafine. Indeed, if they were more broadly interpreted one can question whether they would be void as inoperable, since if a patent claims a process that does not in fact work, the claim is too broad, because its promise fails.
[23] This does not mean, of course, that in order to infringe claims 1(a) or 1(c), any infringing step has to be exactly identical to claim 1(a) or 1(c), or that it has to be the last step in the process, or that steps in the Novartis processes that precede the claimed steps do not need to be considered when assessing whether the claimed steps are infringed by the Apotex process.
[24] Claim 1(a) provides that the UAUin formula V "is a leaving group". The patent instructs, on pages 7-8, that the leaving group A is "conveniently iodine or preferably chlorine or bromine, or an organic sulphonyloxy group having 1 to 10 carbon atoms, alkylsulphonyloxy, preferably having 1 to 4 carbon atoms such as mesylosy, or alkylphenylsulphonolxy preferable, having 7 to 10 carbon atoms such as tosyloxy". The only specific reference to the making of terbinafine in the disclosure is found in example 16[iii], where bromine is used.[iv] In that example, A leaves the molecule.
[25] Dr. McClelland's evidence was that an organic chemist skilled in the art would read "a leaving group" as referring to a substituent that leaves the molecule as a result of the reaction. Dr. McClelland was shown an excerpt from an undergraduate textbook, J. March, Advanced Organic Chemistry, 4th ed. (Toronto: John Wiley & Sons, 1992) at 353, which was attached to the affidavit of Dr. Giasson, in which the following sentence is found: "... Another circumstance that increases leaving group power is ring strain ...", followed by a discussion of various three - membered rings.[v] This sentence is found under the heading "The Effect of the Leaving Group", which heading appears on the preceding page, and was not part of Dr. Giasson's affidavit. Dr. McClelland commented that he did not think the passage from the textbook "makes a lot of sense".[vi] When Dr. Olah was referred to the same passage, he explained that the text meant that "when you react the reagent with an epoxide because epoxide is strained, you have a higher reactivity".[vii] He stated that "[t]he sentence unfortunately is not correctly formulated".[viii]
[26] Dr. Giasson stated that "a leaving group is either an atom or a group of atoms that have the property of being quite stable, under the form it will leave the molecule".[ix] In the terms of the patent he agreed that A has to be a good leaving group stating that "otherwise the reaction won't occur"[x]. He noted that when one talks about leaving groups, it is generally implied that one means a good leaving group.[xi]
[27] I conclude that a person skilled in the art would understand "a leaving group"to mean a substituent that leaves the molecule.
Apotex Process
[28] Apotex served its Notice of Allegation on October 14, 1997, alleging that its process for making [terbinafine or] terbinafine hydrochloride would not infringe the U023 patent. No details of the Apotex process were provided at that time. After the present application was commenced, and a protective order obtained from the Court, Apotex provided the following flow chart of its process.
[29] This process is described by Dr. McClelland as follows:
Step 1:
(i) Reaction of N-methyl-N-napthylmethylamine with epichlorohydrin to form a tertiary amine, thus joining the nitrogen to the appropriate carbon of the group that ultimately will become the nine carbon fragment;
(ii) Reaction of the lithium salt of tert-butylacetylene with the epoxide to introduce the carbon-carbon triple bond at the correct position, thus completing the framework of the nine carbon fragment;
(iii) Elimination of a water molecule to introduce the necessary carbon-carbon double bond contained in the molecule of terbinafine;
(iv) Formation of the hydrochloride salt; and
Step 2: Separation of the E and Z isomers.
The reaction (i) of Step 1 proceeds as follows:
The initial step makes the nitrogen-carbon bond through the opening of the epoxide ring by the amine. The epoxide ring then recloses due to the presence of the nearby chlorine. During the ring closure, H-Cl is expelled.
In Step 1(ii), the epoxide ring reopens through the reaction with the acetylide anion. This reaction results in the formation of nine carbon group required for terbinafine, with its carbon-carbon triple bond at the correct position. The oxygen of the epoxide is still present after the reaction, but as an alcohol.
Step 1(iii) leads to the formation of the carbon-carbon double bond by the net elimination of a water molecule. The OH group of the alcohol formed in Step 1(ii) is the key, since this provides the means for the
introduction of the carbon-carbon double bond:
Step 1(iii) results in the formation of two isomers. The formation of the hydrochloride salts (Step 1(iv)) followed by purification (Step 2) removes the Z isomer.
[30] Apotex states in its Notice of Allegation that its process does not infringe the U023 patent. The burden of proof rests with the applicants to demonstrate that that allegation is not justified.
The Affiants
[31] In this case, it is necessary to comment on the affiants of the affidavit evidence filed by each party. Novartis filed two expert affidavits, one by Dr. Stütz, the inventor and long time employee of Novartis; the other by Dr. Acheson, a person who has had a professional relationship with Novartis, having consulted for it, and having received research money from it. Dr. Acheson retired professionally in 1986, and since that time he has been largely inactive in his professional life, although he has continued to be interested in chemistry. He utilizes the Novartis library for his research, and writes, speaks and consults with Novartis personnel.
[32] The evidence filed on behalf of Apotex, in response to the affidavits of Drs. Stütz and Acheson, consists of the affidavits of: Dr. Robert McClelland, a professor of chemistry at the University of Toronto and a frequent affiant for Apotex; Dr. Richard Giasson, an associate professor of chemistry at the University of Montreal; and Dr. George Olah, the 1994 Nobel Prize chemist and a distinguished professor of organic chemistry at the University of Southern California. As is usual in these cases, the experts proffered by the respective parties take opposite positions.
[33] In addition to the obvious interest that Dr. Stütz would have in seeing the patent interpreted as broadly as possible, there are other factors that lead me to give his affidavit less weight than those filed in support of the respondent's position: Dr. Stütz's affidavit was drafted without him ever having read the U023 patent (he used the European patent or patent application, which at the time was not identical to the Canadian patent because the latter contained an error);[xii] his affidavit was drafted as a joint effort with a colleague in the Novartis patent department who was "responsible for this particular issue".[xiii] That colleague, Dr. Vallet did not give evidence.
[34] Dr. Acheson was also assisted by Dr. Vallet. This factor, together with Dr. Acheson's close connection with Novartis and his professional inactivity for many years, lead me to accord his affidavit less weight than the affidavits filed in support of the respondent's position.
[35] In addition, there are inconsistencies in the positions taken. In Dr. Stütz's opinion, as set out in his affidavit, the three most relevant chemical processes to consider when assessing whether Apotex's process infringes that patent are claims 1(a), 1(b) and 1(d). Surprisingly he does not identify either 1(c) or 1(e) as being among the most relevant, although they lead to the making of terbinafine, while 1(b) and 1(d) do not. On cross-examination, after he had seen the affidavits filed by others, he sought to increase his reliance on 1(c) for his opinion.[xiv] Dr. Acheson relies on claims 1(a), 1(c) and 1(e).[xv] Then, Novartis at the hearing abandoned any reliance on 1(e) as relevant to the conclusion that the Apotex process was an obvious chemical equivalent. It is strange to see such uncertainty and inconsistency in opinions proffered to establish that the two processes are obvious chemical equivalents.
Obvious Chemical Equivalents
[36] The doctrine of equivalence has long been a feature of patent law. In addition, subsection 41(1) of the Patent Act, which was added to the Act as section 17, in 1923, specifically provides that "obvious chemical equivalents" of the processes of manufacture claimed under that section fall within such claims. Also, it is not unusual to see the express claiming of obvious equivalents in patents, as is found in the U023 patent. It is found in claim 2 (in reference to the processes claimed for making all compounds falling under the general formula) and in claim 15 (in reference to the processes claimed for making terbinafine specifically).
[37] Counsel for Novartis seemed to suggest that since each of claims 2, 14 and 15 claim "obvious chemical equivalents", that phrase must be given some content and thus affiants who on cross-examination did not provide content for it should be treated with scepticism and their evidence accorded less weight. I do not accept that argument. The burden of proof rests with the applicants. It is not for the Court or the respondent's affiants to provide content to those words in the patent. As noted, they repeat what would in any event have been required by the applicable common law principles and the statutory provisions of section 41. The question the Court must address is whether the particular process that Apotex plans to use is an obvious chemical equivalent to that claimed in the patent. Whether other processes might be obvious chemical equivalents to the process claimed is not relevant to the present analysis.
[38] The context within which section 41 was added to the Patent Act is relevant to its interpretation. As noted, what is now section 41 was added in 1923. It was modelled on the corresponding section of the British Patent Act, which section had been added to that Act in 1919. The object of that provision was to enable British chemical manufacturers to make useful compounds, especially dyes, discovered by others, provided they could devise a non-infringing method of manufacture. The limitation was designed to protect the British domestic industry. The purpose of the limitation and the reasons for its eventual repeal are discussed in H.T. Brown, "Patents in Pharmacy and Medicine"(1960), 34 C.P.R. 117 at 143.
[39] When the amendment to the Canadian Patent Act was introduced, it was explained as being designed to ensure that no one could patent any article used for human food or having a medical purpose. (For a discussion see, House of Commons Debates (20 April 1923) at 2076-2078.) The inventive process could be patented, but not the substance itself. In Dairy Foods Inc. v. Co-opérative Agricole de Granby, [1976] 2 S.C.R. 651, at 663, the Court explained:
The object of section 41(1) is to prevent a patentee from monopolizing a food or a medicine. He indeed must be content with a monopoly for his way of making it. If someone else develops a different process which will result in a similar product, then he is free to use it.
[40] Both Dr. Stütz and Dr. Acheson, in their affidavits, state that it is the compounds, not the processes for making them that are the essence of the U023 patent. Both say they are aware that at the relevant time Canadian patent law required process claims to be included.[xvi] The implication that is left by these statements is that the only reason the process claims were included was to comply with Canadian law; that is, the process part of the claims are non-essential and from this one should conclude that a variation in the process used to make the compound is a non-essential element.
[41] A minor variant of a non-essential element of a patent will not justify a finding of non-infringement. Thus, the assertions concerning Canadian patent law found in the affidavits of Drs. Stütz and Acheson feed into the argument that the essence of the invention is the compound terbinafine itself, and any change to the process by which it is made is a change to a non-essential aspect, and thus a minor non-infringing variant. This argument carried to its logical conclusion, of course, undercuts the whole purpose of section 41. If the processes are non-essential elements, then the inventor is being allowed to claim the substance itself - the result that section 41 was designed to prevent.
[42] As noted, both Drs. Stütz and Acheson, in their affidavits, indicate that the process for making terbinafine was not essential. Yet on cross-examination they were not as categorical in this regard. When Dr. Stütz was asked what he considered to be the essence of the patent he said it was "The essence of the patent is the novel compounds, the novel and the preferred compounds terbinafine and processes to make them ... as well as the biological activity"(emphasis added). When asked whether he agreed that the processes were unessential he stated that he did not agree.[xvii] When it was pointed out to him that this seemed to contradict what he had said in his affidavit, he revised his answer to accord with the affidavit. Dr. Acheson's explanation as to why he stated in his affidavit that the invention resided in the creation of the substance, and that the process was added only to comply with Canadian law is also not very convincing.[xviii]
[43] I find it necessary, in this case, to refer to the distinction between the purposive construction of a patent, which is an approach to the reading of the words found in the text of the patent (including of course the diagrams in chemistry patents) and the purpose of a given chemical reaction. In asking what is the purpose of a given chemical step, process or reaction, the answer may indeed be that it is to make the same molecule as that to which the patent relates, (or the same bond in a particular location) but this does not mean that the given step, process or reaction falls within the text of the patent, purposively construed.
[44] The processes under discussion in this kind of a case, will always have the same purpose in that they build the same molecule. And, that molecule must have a certain structure, with elements in certain places, joined by particular bonds. Thus, an identity of purpose or function at a high level of generality, without further analysis, may not be useful in determining whether one process is the chemical equivalent of another. The relevance of a description at any given level of generality will always depend on the particular facts of the individual case.
[45] The affiants were sometimes asked if they had ever heard of the principle of purposive construction (or the non-literal approach to patent construction). While they were unfamiliar with this language, it is clear that they understood that they were not to interpret the patent literally. When asked whether he understood that a chemical process could differ from what was literally claimed in a patent, Dr. Giasson responded that when "talking about chemical equivalents some variability is allowed"[xix]; he understood the distinction as to what was included in and what was outside a patent to depend upon "what the variations are".[xx] The affiants had been asked whether the Apotex process was the obvious chemical equivalent of the patented process? They were not taking a literal approach to the claims.
[46] In applying a purposive construction to patents, one is asking what did the inventor intend to claim as disclosed in the text of the patent - what is the purpose of the written text. This is a question for the court, on which expert evidence with respect to what constitutes obvious chemical equivalents is relevant.
[47] Dr. Stütz first notes that some of the starting compounds are the same in the two processes, and some of the end compounds are the same (terbinafine and terbinafine hydrochloride). He describes the first process claimed in very general terms, as a reaction of an amine of formula IV with a carbon chain of formula V carrying a leaving group "A". He states that the nature of this type of reaction is a nucleophilic substitution reaction involving the non-bonded pair of elections of the nitrogen displacing the leaving group A to form a new nitrogen-carbon bond.[xxi] He states that the essence of process (a), when the process described therein is used to make terbinafine, involves an alkylation reaction[xxii] (modified in cross-examination to an N-alkylation reaction)[xxiii] to produce a tertiary amine from a secondary amine by the formulation of a new nitrogen-carbon bond.
[48] Dr. Giasson's evidence was that "the synthesis of a "target molecule" such as terbinafine is always achieved by linking together a number of "building blocks" or "synthons" in order to generate the "skeleton" of the molecule".[xxiv] A "synthon" is a particular type of building block, Dr. Giasson is not using the word in any comparative sense. He states that some of the starting building blocks may be the same, but this does not mean that the two syntheses are chemically equivalent:
... two very different synthesis will often have common building blocks. This is the case here. Not only are the building blocks assembled in a different order in these processes, but they are linked together using distinct synthetic methodologies based on unrelated chemical principles ... These differences are fundamental ...[xxv]
[49] The fact that some of the end compounds are the same (terbinafine and terbinafine hydrochloride) does not assist the analysis. If they were not, there would be no litigation. The expert affiants state that what is important is the chemical strategy that is involved. For example, Dr. McClelland states:
Although the same final product is obtained, it is my conclusion that the overall strategies involve different reactions which perform different functions and lead to different intermediates.[xxvi]
[50] With respect to the description of claim 1(a) as a nucleophilic substitution reaction involving the non-bonded pair of electrons of the nitrogen displacing the leaving group A to form a new nitrogen-carbon bond, the respondent's affiants state that this is an overly simplistic and overly general description. Dr. McClelland states:
Q. ... the terminal carbon of the epoxide ... that is the electrophilic site?
A. In a very simple sense, yes, it is.[xxvii]
. . .
A ... Any reaction we do to make that carbon-nitrogen bond will involve that nitrogen as a nucleophile reacting as an electrophile on the other side.[xxviii]
. . .
A. Almost every reaction that one does in organic chemistry is an electrophile/nucleophile reaction.[xxix]
When asked to explain what he meant by "simple sense", Dr. McCelland answered:
A. ... any reaction that one does in organic chemistry where elections flow in pairs, probably 90 per cent of the reactions we do they flow in pairs, one of their reagents can be viewed as having a nucleophilic site that supplies the election pairs and the other can be viewed as having an electrophilic site that accepts the election pairs.
A. ... Any reaction one does, almost any reaction, one does, is a nucleophile/electrophile reaction.[xxx]
The following excerpt from Dr. Giasson's cross-examination is also instructive:
Q. But they are both nucleophilic substitutions?
A. Nucleophilic substitutions, but nucleophilic substitution includes a lot of chemistry. I mean, there's a lot of different reaction that could be labelled as nucleophilic substitution in organic chemistry.[xxxi]
[51] Counsel for the applicants sought to draw a parallel between the role of the "leaving group"in the patented process and the epoxide of the epichlorohyrin. Dr. McClelland was very clear that in his opinion an epoxide is not a leaving group as described in the patent.[xxxii] He agreed that if one were to define a leaving group as something that left the reaction site but remained attached to the molecule, a definition of leaving group he clearly did not consider as falling within the meaning of "leaving group" in the patent, the oxygen of the epoxide acted in that way.[xxxiii] He was quite emphatic on this point, stating "I don't consider an epoxide as a leaving group ... the oxygen does leave the reaction site but it remains attached to the molecule and it plays an important function".[xxxiv]
[52] Dr. Olah also stated repeatedly that an epoxide was not a leaving group.[xxxv] Counsel refers to an answer given by Dr. Olah on cross-examination as evidence that he agreed that an epoxide was a leaving group.[xxxvi] However, there is a question mark at the end of that sentence. He agreed that if you were to define a leaving group as something that left the reaction site rather than the molecule, then the oxygen of the epoxide would fit into that description.[xxxvii] But he also stated "if you teach chemistry, you wouldn't call an epoxide a leaving group".[xxxviii] Dr. Giasson was also very clear that an epoxide was not a leaving group.[xxxix]
[53] Dr. Stütz sets out the details of his analysis in his affidavit, which I do not find it necessary to repeat here, and then concludes that the two processes are chemical equivalents:
37. ... The Apotex Process forms the allylamine system in the last part of Step 1, while in the U023 Patent the allylic system is already present in precursor compound V for process a).
38. Essentially, the Apotex Process repeats process a) of the U023 Patent, but does this in a different order of reaction steps, using information available from the U023 Patent, such as processes b) and d).
39. Overall, the Apotex process does not show significant differences regarding synthetic strategy or starting materials. It carries out the same types of reactions that are described and claimed in the U023 Patent. The same types of bonds are formed in each of the reactions. For process a), the bond that is formed is in the same location as that in both the Apotex and the U023 Patent process. For processes b) and d), the bonds that are formed are merely on the opposite side of the alkynyl (acetylene) group but as noted above, it is the same type of bond (conjugated ene-yne system) using the same type of reaction with only the location of the bond being different.
. . .
41. Furthermore, it is clear that the alkynyl group is the critical functional group for the formation of terbinafine and processes b) and d) as carried out by the Apotex Process are merely applying the chemistry that is specifically taught in the U023 Patent to analogous bonds in the terbinafine structure. For the above reasons, it is my belief that overall, the Apotex Process has merely put together the same types of reactions in a different order involving analogous bonds as those that are specifically described and claimed in the U023 Patent and for this reason, I believe it is an obvious chemical equivalent: the portion of the claims that Apotex are utilizing is process a), all they have done is made terbinafine through an equivalent type of reaction and merely started with one of the two initial reagents in the form of a simpler molecule, but which was then subsequently completed by using the reactions of processes b) and d) of the Novartis patent to arrive at the complete terbinafine molecule.[xl]
[54] Dr. Giasson writes with respect to Dr. Stütz's analysis of why the two processes are chemical equivalents:
42 Dr. Stuetz is the inventor of the U023 Patent. The gist of his affidavit is based on the fallacious premise that the Apotex Process simply repeats, in a different order, the reaction steps of process (a) using information available from processes (b) and (d) and therefore the Apotex Process is an obvious chemical equivalent to the processes claimed in the U023 Patent.
43 I disagree totally with Anton Stuetz's superficial analysis and clearly biased opinion. As stated in paragraphs 19 to 21 of my affidavit it is obviously normal that different syntheses of a simple molecule like terbinafine have some common features imposed by chemical limitations and the logic of chemical synthesis. In this present case, an in-depth comparison reveals important differences between the processes.
44 Some examples of where Anton Stuetz amplifies apparent similarities to the detriment of real significant differences follow:
45 In paragraph 27 of his affidavit, Stuetz declares that the same carbon-nitrogen bond is being made in exactly the same manner in process (a) of the U023 Patent and in the Apotex Process. While the formation of this carbon-nitrogen bond is a common feature adopted in both processes because of chemical considerations, the methodologies used are clearly different and it is a gross exaggeration to say that the bonds are made in exactly the same manner. Indeed, as stated in paragraph 22 of my affidavit, the chemical principles behind the two methods are completely different.[xli]
[55] Dr. Giasson also points out that the fact that the same bond is being made does not automatically lead to a conclusion that the two processes are chemically equivalent:
22. ... while a carbon-nitrogen bond is created in both processes, the chemical methodology used to make this bond is very different ... In process (a) of Claim 1 of the U023 Patent, this carbon-nitrogen bond is created by the nucleophilic displacement of an allylic bromide or other excellent leaving groups at the allylic position. Such a reaction takes place because the departing group is, by its chemical nature, a good leaving group and its departure is facilitated by the fact that it is located at an allylic position.
The Apotex Process, on the other hand, relies on a totally different chemical principle to facilitate the formation of the carbon-nitrogen bond. Indeed, the nucleophilic opening of an oxirane ring occurs because much ring-strain energy is released by the opening of a three-membered ring.[xlii]
[56] Dr. Giasson comments on Dr. Stütz's affidavit:
46 In paragraph 28 of his affidavit, Stuetz states that the second reaction of the Apotex Process is the reaction of a metalated alkyne, i.e. the lithium salt of 3,3-dimethyl-1-butyne, with an activated carbon atom and that it is the same type of reaction that what is found in process (b) of the U023 Patent. He then adds that the electronegativity effects of an epoxide (i.e. oxirane) and a carbonyl are analogous and permit those two reactions. This is a blatant misrepresentation knowingly made.
The polarisation of the carbon-oxygen bond of an oxirane is not what makes the reaction in the Apotex Process work. Indeed, tetrahydrofuran, which is a five-membered ring analog of the three-membered oxirane ring, comprises identical polarized carbon-oxygen bonds and is quite inert toward metalated alkynes. Anton Stuetz certainly knows this since, at page 42 of the U023 Patent, he describes a reaction between the lithium salt of 3,3-dimethyl-1-butyne and a carbonyl compound where tetrahydrofuran is used as an inert solvent!
47 Anton Stuetz points out in paragraphs 30 and 31 of his affidavit to similarities that not only do not exist but are also irrelevant. He draws a parallel between reactions in the Apotex Process and process (b) of the U023 Patent and another parallel between the water elimination step of the Apotex Process and process (d). These well known reactions claimed in processes (b) and (d) cannot be used for the synthesis of terbinafine and from the disclosed chemical methodology used in the U023 Patent were not even contemplated for the synthesis of terbinafine.
48 Although I can understand that Anton Stuetz as inventor of processes to prepare terbinafine is anxious to broaden the scope of the U023 Patent to in fact protect terbinafine per se (indeed he so states in paragraph 9 of his affidavit) the arguments presented above show that, contrary to what Anton Stuetz declares in paragraph 36 of his affidavit, the differences between what is claimed in claim 1 of the U023 Patent and the Apotex Process are numerous and significant.
49 The Apotex Process does not repeat, in a different order, process (a) using information available from processes (b) and (d), as stated in paragraph 38. In reality, processes (b) and (d) cannot be used for the preparation of terbinafine, as candidly admitted by the inventor in paragraph 10 of his affidavit, and should be considered irrelevant. The Apotex Process, therefore, cannot be considered a chemical equivalent, nor an obvious chemical equivalent, of any of the processes claimed in the U023 Patent.[xliii]
[57] The following critique of Dr. Acheson's affidavit is made by Dr. Giasson:
50 Richard Morrin Acheson repeats basically the same arguments as Anton Stuetz in his affidavit. The core of his argumentation is the Apotex Process simply repeats, in a different order, the reaction steps of process (a) of the U023 Patent using information available in processes (b) and (d) and, therefore, constitutes an obvious chemical equivalent. To avoid redundancy, I will not repeat my objections raised to the affidavit of Stuetz and will only concentrate instead on two somewhat new and certainly imaginative arguments raised in the affidavit of Richard Morrin Acheson.
51 Richard Morrin Acheson states in paragraph 10 of his affidavit that the U023 Patent "discloses or suggests various routes for arriving at the terbinafine molecule, i.e. processes (a), (c) and (e), and further, that these routes possess a common pattern".
52 He then describes in detail the patterns in paragraph 12:
(1) The amino compound carrying the naphthyl group, i.e. N-methyl-N-(1-naphthylmethyl)amine, is invariably the starting material;
(2) The side chain can then be put on as one unit, which can be build up beforehand from a three carbon atom unit;
(3) Alternatively, the side chain can be put on in fragments, which can be a three carbon atom unit followed by the rest of the chain, or a one carbon atom unit and the rest of the chain.
53 The patterns Acheson sees in the U023 Patent are a product of his imagination that he created in order to make us believe that the synthetic strategy behind the Apotex Process was taught in that patent. Indeed, these so-called patterns are not even real:
(1) N-methyl-N-(1-naphthylmethyl)-amine is not the starting material in process (e) of the U023 Patent.
(2) The side chain is introduced as one until in processes (a) and (e), but the preparation of the side chain from a three carbon atom unit is disclosed only in the case of process (a).
(3) There are only two cases where the side chain is put on in fragments in the U023 Patent, i.e. the two variants or process (c).
In one case, it is a three carbon atom unit followed by the rest of the chain, in the other a one carbon unit followed by the rest of the chain. Where is the pattern?
54 In paragraphs 15.1 to 15.3, Acheson implies that once Apotex learned the so-called patterns of the U023 Patent, it became obvious for them to devise a synthesis which is a mere reordering of the steps of process (a), where the side chain is introduced in fragments instead of a single unit, one of those fragments being a three carbon atom until, and, most importantly, that the choice of three carbon atom unit, epichlorohydrin, was obvious. I previously discussed all these affirmations but the one on the apparently obvious three carbon atom unit, epichlorohydrin; let us see if it is a valid argument.
55 According to paragraphs 15.4 to 15.5 in Acheson's Affidavit, Oxford and Cambridge undergraduates, familiar with Stuart Warren's textbook entitled "Designing Organic Syntheses", would have no difficulty in deducing plausible syntheses of terbinafine and epichlorohydrin as a three carbon atom until. I cannot judge on the competence of Oxford and Cambridge undergraduates, but I would guess that their syntheses would most likely look like the ones in the U023 Patent than the Apotex one. Indeed, the examples found on page 14 of that book, attached as exhibit 18 in Acheson's Affidavit, teach a reaction used in process (b) of the U023 Patent, not the Apotex Process.
56 In conclusion, Acheson makes the same superficial analysis and uses the same irrelevant arguments than Stuetz in his affidavit. In addition, he sees patterns that do not exist in the U023 Patent, minimizes the originality of the Apotex Process and makes unsubstantiated comments about the synthetic knowledge of Oxford and Cambridge undergraduate students. All of this in order to convince us that the Apotex Process is an obvious chemical equivalent of the processes disclosed in the U023 Patent. I disagree with his opinion which does not resist an in-depth chemical analysis.[xliv]
[58] Dr. McClelland writes:
55 As a preliminary general comment, it is apparent that Stuetz and Acheson engage in a description of the process steps involved in the Apotex Process in the context of the U023 Patent at a very high level of generality. This disguises any chemical difference and totally ignores the logic of the chemical synthesis devised and used in the Apotex Process.
56 Both Stuetz and Acheson are of the opinion that the amine-epichlorohydrin reaction in the Apotex Process is the same as process (a). This over simplified analysis conveniently masks the fact that the chemistry and the chemical methodology are different.
58 Both Stuetz and Acheson see the Apotex Process as a simple re-ordering of the steps claimed in the U023 Patent. Again, this view does not take into account the logic of the chemical strategy followed in the U023 Patent which prevents the re-ordering of the steps.
59 More particularly when describing process (a) of Claim 1 of the U023 Patent in paragraphs 11 and 19 and comparing it with the first reaction of Step 1 in the Apotex flow sheet at paragraphs 26 and 27, Stuetz uses such general language that it masks any chemical difference.
While it is correct to say that in both processes a carbon-nitrogen bond is created, the chemical methodology employed to make this bond is very different.
In process (a) of Claim 1 of the U023 Patent the carbon-nitrogen bond is created by nucleophilic displacement at an allylic position. The departure of the leaving group A is facilitated by its location at any allylic position.
In the first reaction of Step 1 in the Apotex Process, the carbon-nitrogen bond is created by a nucleophilic opening of the oxirane ring which occurs because of ring strain energy present in a three membered ring.
An amine displacing an halide (i.e. process (a) of Claim 1) and an epoxide ring opening are not "the same type of reactions" and certainly do not create the carbon-nitrogen bond "in exactly the same manner".
61 Again in paragraphs 31-33 Stuetz is oblivious of the fact that process (d) of Claim 1 cannot create terbinafine as such process adds an additional carbon-carbon double bond.
62 Dr. Acheson shows in paragraphs 14.1 to 14.3 of his Affidavit with the aid of numerous articles that all the reactions in the Apotex Process that is:
(i) reaction of an amine with epichlorohydrin (an oxirane);
(ii) reaction of the oxirane with a 3-3 dimethylbut-1-ynyl lithium; and
(iii) dehydration
are well known. He also states for (ii) and (iii) that "this type of reaction" was disclosed in the U023 Patent. Although his review may be found of some interest, it is irrelevant to the issue of this proceeding. The Apotex Process represents a new strategy to prepare terbinafine.
63 In comparing at paragraph 15.1, acrolein, propargyl bromide and epichlorohydrin, Dr. Acheson completely fails to recognize an absolutely essential requirement, namely the ways that these units function so as to provide the carbon-carbon double bond of the propenylamine unit. As previously discussed in my Affidavit, these three units function in a completely different manner. In acrolein and propargyl bromide, the unsaturation is already present in the three carbon unit. Acrolein already contains the double bond, but it is situated in the wrong place so that an allylic rearrangement is required. In propargyl bromide, there is a triple bond, so that a reduction is required. In epichlorohydrin, there is no double bond or triple bond in the starting material. The manner in which the molecule functions so as to provide the propenylamine is completely different.
64 The difference between the Apotex Process and the U023 processes is seen in considering the fallacious statements made in paragraph 15.2 that the Apotex Process simply re-orders the reaction sequence presented in Exhibit 4. As previously discussed, the chemical nature of the three steps in the Apotex Process is very different from that of the three steps in Exhibit 4, especially in the way that the two sequences function so as to introduce the carbon-carbon double bond of the propenylamine unit. The difference is also seen in considering whether the chemistry in Exhibit 4 or in the Apotex Process is such that the reaction steps can be re-ordered. With respect to Exhibit 4, it is not possible with this strategy to re-order the steps. Starting with acrolein, the alkyne unit must be joined first, this must be followed by allylic rearrangement, and then in the last step the amine is added. Starting with epichlorohydrin, the amine can be added in the first step followed by the alkyne (as is done in the Apotex Process) or the alkyne could be added first followed by the amine. The last step however must be the dehydration to introduce the carbon-carbon double bond.[xlv]
[59] Not only must the two processes be chemical equivalents, they must be obvious chemical equivalents. Drs. Olah, McClelland and Giasson all refer to the Apotex process as being original and not obvious. Drs. Stütz and Acheson, of course, take the opposite view. There is, however, objective evidence that supports the views of Drs. Olah, McClelland and Giasson.
[60] In an article entitled "Allylamine Antimycotics: Recent Trends in Structure - Activity Relationships and Syntheses", (1991) 31 Pestic. Sci. 437, Dr. Stütz, et al., reviewed the methods that had been developed for the synthesis of terbinafine-related allylamine over the 1982 - 1991 period. The article summarises several synthetic methods that had been developed for terbinafine. Dr. Giasson notes that nine methods were described for the preparation of terbinafine and most of these were variants of the processes (a), (c) and (e) claimed in the U023 Patent. He points out that none of these nine methods contemplated the sequence devised in the Apotex process for the synthesis of terbinafine.
[61] Dr. McClelland makes the same point:
A review article published in 1991 by Stuetz, et al. ... clearly shows that among the different syntheses leading to terbinafine, not one bears any similarity to the strategy devised by Apotex for the manufacture of terbinafine. By 1991, eight different sequences had been developed for the preparation of terbinafine. None of the routes contemplates the use of an epoxide for the joining of an amine or/and an alkyne unit. Moreover, none of the routes uses a dehydration (i.e., elimination) reaction for the construction of the carbon-carbon double bond.[xlvi]
[62] Dr. Giasson refers to nine processes, while Dr. McClelland refers only to eight; Dr. Giasson considers that one of the eight can be treated as two separate processes.
[63] In addition, in an article entitled "A New Route to the Synthesis of Terbinafine", (1997) 18:11 Bull. Korean Chem. Soc. 1218, the authors, after reviewing the then current known synthetic methods for making terbinafine, describe a new route for the synthesis of terbinafine. Dr. McClelland writes:
More recently in an article published in 1997, ... the chemists from Daewong Pharmaceutical Co. describe "a new route to they synthesis of terbinafine" which strategy is based on the use of an epoxide. Such new route was considered worth publishing in peer-reviewed journal as an example of an inventive strategy for the synthesis of terbinafine.[xlvii]
Dr. Giasson writes:
... This new synthetic approach, which presents some similarity with the Apotex Process, is only available to the scientific community since 1997 and has not been considered among the methods reviewed in the above article by Stuetz, et al. ...[xlviii]
[64] Dr. Olah also refers to this literature.[xlix] He notes that Dr. Stütz is a leading expert in the field of the alkylamine synthesis and has authored and co-authored numerous scientific papers pertaining to the subject matter. Dr. Olah states that a reading of the 1991 paper demonstrates that the synthetic route of the Apotex process was neither contemplated, nor mentioned by Dr. Stütz, nor by his associates at that time. He also comments on the article in the November 1997 issue of the Bulletin of the Korean Chemical Society. Dr. Olah notes that this article begins with a review of the various synthetic routes that had been reported, and that review did not provide any other route from those previously discussed in the literature. Dr. Olah points out that the authors then describe a new route whereby epibromohydrin is first reacted with lithium tert-butylacetylide to form a substituted epoxide which is then reacted with N-methyl-1-naphthalenemethylamine and subsequently dehydrated to form terbinafine. This process has similarities to the Apotex process.
[65] Dr. Olah refers to the Apotex process as "a rather unique, ingenious simple synthesis" that is "even more remarkable when one considers that there can exist only a limited number of synthetic routes for the synthesis of a relatively simple compound".[l] He refers to some of the literature on the subject, of which Dr. Stütz was a co-author and comments, "it is only after Apotex disclosed its synthesis that it is claimed to be an "obvious equivalent".[li] Dr. Olah asserts that Apotex developed "an independent new synthetic route to prepare terbinafine in a two-step process from readily available materials", and this was done "in a way which clearly was not found or considered by Dr. Stütz or anybody else".
[66] Dr. Olah's affidavit, paragraph 17, reads:
I find Dr. Acheson's argument, after reciting his version of the claims to the effect that the Apotex Process must be an "obvious equivalent", as the type of reactions used by Apotex (alkylation, nucleophilic addition, elimination etc.) are well known and therefore the scheme must be an obvious chemical equivalent to be without merit. Adding many pages to the affidavit showing that these basic reactions are well discussed in text books makes the affidavit fatter, but not more relevant. Of course all chemists are using fundamental general reactions in the process to construct their compounds. In writing a novel or poem we all use the letters of the same alphabet. What differs is how we are putting them together. Apotex is not claiming that any new reaction was used in its synthesis (neither does Dr. Stutz). Apotex, however, did develop an independent new synthetic route to prepare terbinafine in a two-step process from readily available materials, in a way which clearly was not found or considered by Dr. Stutz or anybody else prior to Apotex.[lii]
[67] The presence of an article disclosing a new synthetic route for the preparation of terbinafine in a peer review journal, which route is similar to the Apotex process, and with respect to which the applicants did not file any rebuttal evidence, is very convincing evidence that the Apotex process is not an obvious chemical equivalent to those disclosed in the patent.
[68] Counsel for the applicants argue that obviousness and novelty should not be confused and that a novel process could still be obvious. The evidence establishes, however, that the Apotex process was not an obvious chemical equivalent. It may also have been novel, but this does not undercut the finding that it was not an obvious chemical equivalent to the claimed processes.
[69] It is always difficult to know how much detail should be included in reasons given for a decision in these kinds of cases. If reference is not made to parts of the evidence, there is a risk that a conclusion will be drawn that that evidence was ignored. On the other hand, extensive reference to the evidence, when such is not really necessary, unnecessarily lengthens the reasons and the amount of time required to both produce and read them. I have considered all the evidence that was presented even though I have not referred to some of it in these reasons.
Conclusion
[70] After having heard the oral submissions of counsel on this application and having reserved my decision, but before reasons and an order were issued, correspondence was received by the Court from counsel for the applicants suggesting that the application was now moot. Counsel for the respondent disagreed. No formal request from the applicants to re-open the hearing was received and, in any event, the circumstances described in the correspondence do not appear to render the application moot.
[71] I conclude that the applicants have not demonstrated that Apotex's allegation is not justified. Accordingly, the application will be dismissed.
Judge
OTTAWA, ONTARIO
May 8, 2000
A P P E N D I X
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of a compound of formula I,
wherein a) R1 represents a group of formula
and R2 represents hydrogen or lower alkyl, or R1 and R2 together represent a group of formula
whereby in the formulae IIa to Iii,
R7 and R8 represent, independently, hydrogen, halogen, trifluoromethyl, hydroxy, nitro, lower alkyl or lower alkoxy,
R9 represents hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy,
X represents oxygen, sulphur, imino, lower alkyl imino or a radical of formula - (CH2)r -,
p is 1, 2 or 3,
r is 1, 2 or 3,
s is 3, 4 or 5,
t is 2, 3 or 4, and
v is 3, 4, 5 or 6;
R3 and R5 represent, independently, hydrogen or lower alkyl, and
R4 represents C1-6alkyl or C3-8 cycloalkyl - (C1-6)-alkyl; and
R6 represents a group of formula
wherein R11 represents hydrogen, optionally α-hydroxy substituted alkyl; alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, phenyl, phenalkyl or thienyl,
R12, R13 and R14 represent, independently, hydrogen or lower alkyl, and
b) R1 represents a group of formula IIa to IIg as defined under a),
R2 represents hydrogen or lower alkyl,
R3 and R4 together form a group - (CH2)u-,
wherein u is an integer of 1 to 8, and
R5 and R6 have the meanings given under a),
or an acid addition salt thereof,
which comprises
a) when R6 represents a group of formula IIIa, as defined above, (compound Ia), reacting
a compound of formulaIV,
wherein R1 to R4 are as defined above, with a compound of formula V,
wherein A is a leaving group, R5 is as defined above,
b) when R6 represents a group of formula IIIa, wherein R11 represents α-hydroxyalkyl
(compounds Ib), reacting a metalated compound of formula Ic,
wherein R1 to R5 are as defined above, with a carbonyl compound of formula VII,
wherein R15, R16 and R17 represent independently hydrogen or lower alkyl, or
c) when the double bond between R6 and the nitrogen atom is in trans configuration (compounds Id) reducing a compound of formula VIII,
wherein R1 to R6 are defined above, with diisobutyl-aluminiumhydride, or
d) when R6 represents a group of IIIb or IIIc as defined above or a group of formula IIId,
wherein R15, R16 and R17 are as defined above (compounds Ie) splitting off water from a compound of formula
wherein R1 to R5 are as defined above,
wherein R11 to R17 and Z are as defined above, or
and if desired converting a compound of the formula I or an acid addition salt thereof thus obtained into or into another acid addition salt thereof or vice versa.
2. A compound of the formula I or an acid addition salt thereof according to Claim 1 whenever prepared by a process as claimed in Claim 1 or by an obvious chemical equivalent thereof.
3. A process according to Claim 1 wherein:
R1 represents a group of the formula
R2 represents hydrogen
R3 represents hydrogen
R4 represents lower alkyl
R5 represents hydrogen or lower alkenyl, and
R6 has the meaning of claim 1
or R3 and R4 together form a group (CH2)u wherein u is an integer of 1 to 8.
4. A compound of the formula I or an acid addition salt thereof according to Claim 1
wherein R1 represents a group of the formula
R2 represents hydrogen
R3 represents hydrogen
R4 represents lower alkyl
R5 represents hydrogen or lower alkenyl, and
R6 has the meaning of claim 1
or R3 and R4 together form a group (CH2)u wherein u is an integer of 1 to 8,
whenever prepared by a process as claimed in Claim 3 or by an obvious chemical equivalent thereof.
5. A process according to Claim 1 wherein R1 and R2 together represent a group of
the formula
R3 represents hydrogen
R4 represents lower alkyl
R5 represents lower alkyl and
R6 has the meaning of claim 1.
6. A compound of the formula I or an acid addition salt thereof according to Claim 1 wherein R1 and R2 together represent a group of the formula
R3 represents hydrogen
R4 represents lower alkyl
R5 represents lower alkyl and
R6 has the meaning of claim 1,
whenever prepared by a process as claimed in Claim 5 or by an obvious chemical equivalent thereof.
7. A process according to Claim 3 wherein R6 is a group of the formula
- C / C-R11
wherein R11 represent hydrogen, alkyl, α-hydroxy substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, phenyl, phenalkyl or thienyl.
8. A process according to Claim 5 wherein R6 is a group of the formula
- C / C-R11
wherein R11 represent hydrogen, alkyl, α-hydroxy substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, phenyl, phenalkyl or thienyl.
9. A process according to Claim 3 or 7 wherein R1 is a group of formula
10. A process according to Claim 5 or 8 wherein R1 is a group of formula
11. A process according to Claim 1 wherein the double bond between R6 and the nitrogen atom has the trans-configuration.
12. A process according to Claim 1 wherein:
R1 represents naphthyl
R2, R3 and R5 each represents hydrogen
R4 represents methyl and
R6 represents -C/C-R11, where R11 is tert. butyl to produce N-methyl-N-(1-naphthylmethyl)-non-2 (trans) - en-4-ynyl-1-amine or a hydrochloride salt thereof.
13. N-methyl-N-(1-naphthylmethyl)-non-2 (trans) - en-4-ynyl-1-amine or its hydrochloride, whenever produced by the process according to Claim 12 or an obvious chemical equivalent.
14. A process according to Claim 1 wherein:
R1 represents naphthyl
R2, R3 and R5 each represents hydrogen
R4 represents methyl and
R6 represents -C/C-R11, where R11 is n. butyl to produce N-methyl-N-(1-naphthylmethyl)-6, 6-dimethyl-hept-2 (trans) - en-4-ynyl-1-amine or hydrochloride salt thereof.
15. N-methyl-N-(1-naphthylmethyl)-6, 6-dimethyl-hept-2 (trans) - en-4-ynyl-1-amine or its hydrochloride, whenever produced by the process according to Claim 14 or an obvious chemical equivalent.
FEDERAL COURT OF CANADA TRIAL DIVISION
NAMES OF SOLICITORS AND SOLICITORS ON THE RECORD
COURT FILE NO.: T-2592-97
STYLE OF CAUSE: Novartis AG and Novartis Phamaceuticals Canada Inc. V. Apotex Inc. and The Minister of Health
PLACE OF HEARING: Ottawa, Ontario Toronto, Ontario
DATE OF HEARING: Ottawa - January 10,11,12 13, 2000 Toronto- January 25, 2000
REASONS FOR ORDER OF The Honourable Madame Justice Reed
DATED: May 8, 2000
APPEARANCES:
Mr. Anthony Creber FOR APPLICANT Ms. Jennifer Wilkie
Mr. Harry RadomskiFOR RESPONDENT APOTEX INC.
SOLICITORS OF RECORD:
Gowlings Strathy & Henderson FOR APPLICANT Ottawa, Ontario
Goodman, Phillips & Vineberg
Toronto, Ontario FOR RESPONDENT APOTEX INC.
Mr. Morris Rosenberg FOR RESPONDENT MINISTER OF Deputy Attorney General of Canada HEALTH Ottawa, Ontario
[i]. Applicants'Application Record, at 0607.
[ii]. Ibid. at 0622.
[iii]. Ibid. at 0046.
[iv]. Ibid. at 0064 and 0066.
[v]. Ibid. at 0931.
[vi]. Ibid. at 0932.
[vii]. Ibid. at 0686.
[viii]. Ibid. at 0686.
[ix]. Ibid. at 1232.
[x]. Ibid. at 1235.
[xi]. Ibid. at 1333.
[xii]. Ibid. at 0127-29.
[xiii]. See cross-examination of Dr. Stütz, ibid. at 0130 and 0139._
[xiv]. Ibid. at 0164-65.
[xv]. Ibid. at 0302 and 0491.
[xvi]. Ibid. at 0088 and 0301.
[xvii]. Ibid. at 0142-43.
[xviii]. Ibid. at 0477-83.
[xix]. Ibid. at 1468.
[xx]. Ibid. at 1468.
[xxi]. Ibid. at 0089.
[xxii]. Ibid. at 0093.
[xxiii]. Ibid. at 0170.
[xxiv]. Ibid. at 1077.
[xxv]. Ibid. at 1079.
[xxvi]. Ibid. at 0807.
[xxvii]. Ibid. at 0977.
[xxviii]. Ibid. at 1052.
[xxix]. Ibid. at 1053.
[xxx]. Ibid. at 1068-69.
[xxxii]. Ibid. at 0930-32.
[xxxiii]. Ibid. at 0930-32.
[xxxiv]. Ibid. at 0931.
[xxxv]. Ibid. at 0681-90.
[xxxvi]. Ibid. at 0680.
[xxxvii]. Ibid. at 0687.
[xxxviii]. Ibid. at 0687.
[xxxix]. Ibid. at 1332 and 1504-06.
[xl]. Ibid. at 098-99.
[xli]. Ibid. at 1085-86.
[xlii]. Ibid. at 1077.
[xliii]. Ibid. at 1086-87.
[xliv]. Ibid. at 1087-89.
[xlv]. Ibid. at 0811-14.
[xlvi]. Ibid. at 0815.
[xlvii]. Ibid. at 0815.
[xlviii]. Ibid. at 1085.
[xlix]. Ibid. at 0560.
[l]. Ibid. at 0561.
[li]. Ibid. at 0561.
[lii]. Ibid. at 0561.