Date: 070200
Docket: T-1970-94
BETWEEN:
JANSSEN PHARMACEUTICA INC. and
JANSSEN PHARMACEUTICA naamloze vennootschap
Applicants
- and -
APOTEX INC. and
THE MINISTER OF NATIONAL HEALTH & WELFARE
Respondents
REASONS FOR ORDER
NADON J.
[1] By originating notice of motion filed on August 22, 1994, the Applicants seek an Order prohibiting the Minister of Health (the "Minister") from issuing a Notice of Compliance ("NOC") to the Respondent Apotex Inc. ("Apotex") in respect of the drug cisapride. On July 13, 1995, and on January 18, 1996, the Applicants filed an amended originating notice of motion and a further amended originating notice of motion1.
[2] The Applicants" application is brought pursuant to the Patented Medicines (Notice of Compliance) Regulations2 (the "Regulations"). In accordance with subsection 6(2) of the Regulations, I must prohibit the Minister from issuing a NOC to Apotex if I conclude that the allegations made by Apotex pursuant to section 5 of the Regulations are not justified. On July 11, 1994, Apotex served the following Notice of Allegation on the Applicants:
| This is a Notice of Allegation pursuant to Section 5(3)(b) of the Patented Medicines (Notice of Compliance) Regulations. |
| With respect to patent 1183847, we allege that no claim for the medicine itself and no claim for the use of the medicine would be infringed by the making, constructing, using or selling by us of tablets containing cisapride monohydrate. |
| The legal and factual basis for this allegation is as follows: |
| The patent has no claim for the use of the medicine. It has a claim for the medicine itself, but such claim is limited to the medicine itself when produced by processes described and claimed or by their obvious chemical equivalents. The process that will be used for the production of our cisapride monohydrate does not fall within the scope of patent 1183847. |
| In accordance with the relevant jurisprudence, we will provide a more detailed statement when a protective order or agreement is in place. |
[3] In November of 1994, subject to a protective order dated November 1, 1994, Apotex filed a detailed Statement of Fact and Law. Paragraphs 4, 5 and 6 of the Statement simply repeat the Notice of Allegation served on the Applicants on July 11, 1994. In paragraphs 10 and 11, Apotex sets out the facts upon which it relies in support of its Notice of Allegation:
| 10. The process used by Torcan, Apotex Inc."s supplier, is appended as Schedule "1" to this detailed statement |
| 11. Appended as Schedule "2" is the Affidavit of Dr. McClelland sworn on September 2, 1994 which justifies why the Torcan"s process is not within the scope of the "847 Patent. |
[4] In paragraph 12 of its detailed Statement of Fact and Law, Apotex submits that the process3 used by its supplier, Torcan, does not infringe the Applicants" "847 Patent and that the Torcan process is not an obvious chemical equivalent of the processes claimed in the "847 Patent.
[5] The Applicant, Janssen Pharmaceutica naamloze vennootschap ("Janssen Belgium"), is the owner of Canadian Patent 1,183,847 (the " "847 Patent "). The other Applicant, Janssen Pharmaceutica Inc. ("Janssen Canada"), is an exclusive licencee under the "847 Patent, which was included in the patent lists it submitted to the Minister pursuant to subsection 4(1) of the Regulations. The Minister has issued NOCs to Janssen Canada in respect of 5 mg, 10 mg and 20 mg tablets, and 1 mg/ml oral suspension of cisapride. The chemical name of cisapride is cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxy-benzamide. The structural formula for cisapride is the following:
[6] Cisapride has utility as a peristaltic stimulant used to treat gastrointestinal disorders. It has become the medicine of choice for treatment of gastrointestinal motility disorders in humans. Sales of cisapride have, so far, exceeded $600 million per year. It cannot be disputed that cisapride is a commercial success.
[7] The "847 Patent relates to a number of novel compounds that have utility as new pharmaceuticals. The particular compounds which constitute the subject matter of the "847 Patent are N-(4-piperidinyl) benzamides having the general formula I:
Cisapride is one of the important compounds within formula I.
[8] When the "847 Patent was filed, cisapride was a novel compound. The patent contains process and product by process claims to cisapride. Because of limitations contained in the Patent Act , R.S., c. P-4, at the time of filing, and more particularly, in subsection 41(1) thereof4, cisapride was not claimed in product per se format. But for these limitations, the patent would have covered cisapride regardless of the process by which it was made.
[9] The "847 Patent sets forth different ways of making cisapride and related compounds. There are 8 claims in the "847 Patent. For the present purposes, only claims 1 and 5 need be considered.
[10] In claim 1, three alternative processes for preparing the compounds of formula I are claimed, followed by a number of optional subsequent steps. One of the processes, the first one, is the most relevant for the determination of the issue before me. Pursuant to this process, an amide bond is formed through a nucleophilic substitution or an acylation reaction between the nitrogen of the piperidine of formula II and the carbonyl group on the carboxylic acid of formula III or a functional derivative of the carboxylic acid of formula III.
[11] One of the optional steps set out in claim 1 is the replacement of the hydrogen at R1 with a methyl group (-CH3). This step is known as 0-methylation. Another optional step set out in claim 1 is the preparation of stereochemical isomers of the relevant compounds, i.e. making the cis- or trans-isomers of the compound.
[12] Using the specific language of claim 1 of the "847 Patent, the first process can be formulated as follows: a process for preparing the compounds of formula I, characterized by:
1) reacting a piperidine of formula II
with a carboxylic acid of formula III
or an appropriate functional derivative thereof, in a suitable medium; and if desired; where R1 is hydrogen, converting a compound of formula
into a compound of formula
by reacting (I-a-1) with an appropriate alkylating agent of formula of R1-a-W(VI) in a suitable medium, said R1-a having a meaning of R1 provided that hydrogen is excluded; ...
And/or preparing stereochemically isomeric forms thereof.
[13] Claim 5 claims a number of compounds, including cisapride, when prepared or produced by the processes of claim 1 or by any obvious chemical equivalents thereof. Thus, claim 5 covers the processes claimed in claim 1 and all processes pursuant to which cisapride is prepared or produced which constitute obvious chemical equivalents of the processes claimed in claim 1. It goes without saying that processes which constitute obvious chemical equivalents are not identical to the claimed processes.
[14] The Applicants" position is that the Torcan Process uses the processes of claim 1 and/or obvious chemical equivalents thereof of the "847 Patent and consequently infringes claim 5. It therefore follows, according to the Applicants, that any sale of cisapride by Apotex, fabricated or produced by the Torcan Process, will infringe the "847 Patent. The Applicants thus submit that Apotex" allegation of non-infringement is not justified.
[15] There is no disagreement between the parties that the claims of a patent and in the present matter, the claims of the "847 Patent, should be given a purposive construction. In Catnic Components Limited and Another v. Hill and Smith Limited [1982] R.P.C. 183 at 243 (H.L.), Lord Diplock puts the matter as follows:
| ... A patent specification should be given a purposive construction rather than a purely literal one derived from applying it to the kind of meticulous verbal analysis in which lawyers are too often tempted by their training to indulge. The question in each case is: whether persons with practical knowledge and experience of the kind of work in which the invention was intended to be used, would understand that strict compliance with a particular descriptive word or phrase appearing in a claim was intended by the patentee to be an essential requirement of the invention so that any variant would fall outside the monopoly claimed, even though it could have no material effect upon the way the invention worked. |
[16] I agree entirely with the comments made by Mr. Creber, counsel for the Applicants, at paragraph 57 of his Memorandum, where he states:
| The construction of a patent must be neither benevolent nor harsh, but rather should be reasonable and fair to both patentee and public. The patent must be construed by a mind willing to understand, not a mind desirous of misunderstanding. The court should not apply an overly technical or astute approach when construing the patent and should endeavour to give effect to the construction which will give the inventor protection for that which he has in good faith invented. This is particularly so for a truly meritorious or "pioneering invention" such as that claimed in the Janssen patent. The compound cisapride is an important pharmaceutical compound used to treat gastrointestinal disorders. Cisapride was a new substance and a new product as of the filing date of the application for this patent. |
[17] As I indicated earlier, an order prohibiting the Minister from issuing a NOC until after the expiration of the patent must be made by this Court if it is found that none of the allegations made by Apotex is justified. In its Notice of Allegation, Apotex stated that the cisapride to be manufactured by its supplier would be made by a non-infringing process, the Torcan Process.
[18] As I also indicated earlier, were it not for sub-section 41(1) of the Patent Act, the patentee would have been entitled to a product per se claim to the compound cisapride, regardless of how it was made. In Pfizer Canada Inc. v. Apotex Inc. (1997), 77 C.P.R. (3d) 547 at 560-561, Richard J. (as he then was) made the following remarks:
| But for section 41(1), the patentee would have been entitled to a product per se claim to the compound fluconazole when made by any process. The types of reactions included in the claims were general reactions known at the time of the Pfizer Patent and there was nothing inventive in the idea of using these reactions. These were only included to comply with section 41(1) in order that the claims of the patent include process limitations. Therefore, these features are not essential features. This conclusion is supported by the fact that the underlying invention is fluconazole and not the claimed process. |
| In addition to the specific wording of claim 10 of the Pfizer Patent to "obvious chemical equivalents", and similar wording in section 41(1), the Patent Regulations provide that the process put forward by Apotex must not infringe product by process claims for fluconazole or the obvious chemical equivalents of those processes. |
Although the compound at issue before Richard J. in Pfizer was fluconazole, his above remarks are, in my view, relevant to the present matter and I agree entirely with them. The types of reactions included in the "847 Patent claim were also general reactions known at the time of the "847 Patent and there was nothing inventive in the idea of using these reactions. Consequently, it is clear that the patentee did not intend to be limited to the specific processes set forth in claim 1 since the process limitations were only included so as to comply with subsection 41(1) of the Patent Act . Claim 5 of the "847 Patent includes the processes of claim 1 and all other obvious chemical equivalent processes. In that light, it cannot, in my view, be said that the process limitations are essential features. At page 571 in Pfizer , Richard J. (as he then was) also said:
| The patentee did not intend to exclude variants from the scope of the invention claimed. The process requirements were prescribed by law and not intended by the patentee to be essential limitations in the invention. The processes claimed are not limited in the text of the Pfizer Patent... |
[19] Both sides adduced the evidence of expert witnesses. Dr. Victor Snieckus, who obtained his PhD in chemistry from the University of Oregon in 1965, is a chemist and professor of chemistry at the University of Waterloo. He testified as an expert on behalf of the Applicants. In his affidavit, sworn on May 23, 1996, Dr. Snieckus explains at paragraph 9, the patent"s teaching with respect to the making of cisapride:
| 9. In addition, the patent teaches how to make the various starting compounds and how to transform these starting compounds to make, inter alia, cisapride. One method described in the patent is a nine step process to make cisapride starting from a 4-piperidinone (XIX)5. |
| a. The first reaction is the halogenation of a 4-piperidinone with a halogenating agent to form compound (XX) (page 18, lines 7 - 12); |
| b. The second step is reacting compound (XX) with an appropriate alcohol and water to form a piperidine of formula (XXI) (page, 18, lines 12 - 14, page 19); |
| c. The piperidine (XXI) can then be converted into compound (XIII), a substituted piperidinone, by stirring in acidic aqueous medium (page 18, lines 15 - 17, page 19); |
| d. The patent also teaches at page 17, lines 11-16 that the piperidinone of formula (XIII) can be transformed into substituted piperidinone of formula (VII) (see page 8 for (VII)) by a two step process of removal of the protective group (P) to form intermediate (VII-a), to which is then added the (3-fluorophenoxy)propyl group (L); |
| e. The resulting piperidinone is then transformed to piperidine of formula (II) using reductive amination, a two step process (page 15, lines 31 - 35, page 16); |
| f. The piperidine (II) then undergoes a condensation reaction with, inter alia, an ester (III) to form the nitrogen-carbonyl bond to give formula (I) (pages 5 - 6); and |
| g. Cisapride is then made by replacing the hydrogen at R1 attached to the oxygen at the 3 position of the piperidine ring with a methyl group (pages 8 and 13). |
| A diagramatic representation of the Janssen synthetic pathway is now shown to me and marked as Exhibit "F" to this my affidavit. I have drawn a box around the steps (f and g) claimed in the Janssen process.6 |
[20] As Dr. Snieckus indicates in paragraph 9 of his affidavit, only steps (f) and (g) are claimed in the "847 Patent. These steps are the acylation reaction7 and 0-methylation, which Dr. Snieckus explains as follows: the acylation reaction is "a nucleophilic acyl substitution reaction involving the nonbonding electrons of the nitrogen attacking the carbonyl carbon, which results in the displacement of an appropriate leaving group Y, to form the nitrogen-carbonyl carbon bond". He explains 0-methylation as "substituting the hydrogen of the hydroxy group with a methyl group (-CH3 )".
[21] Dr. Snieckus then goes on to explain the above two claimed steps in greater detail and the two reactions which immediately precede the acylation, i.e. the formation of an imine of the piperidinone, followed by a reduction of the carbon-nitrogen double bond to form a piperidine of formula (II).
[22] Dr. Snieckus concludes his analysis of the "847 Patent by restating, at paragraph 29 of his affidavit, that the patent teaches a nine step process, namely:
| (1) Halogenation |
| (2) Hydroxy substitution |
| (3) Formation of piperidinone |
| (4) Deprotection |
| (5) Addition of L |
| (6) Formation of imine |
| (7) Formation of amine |
| (8) Condensation reaction |
| (9) 0-Methylation |
.
[23] Exhibit "F" of Dr. Snieckus" affidavit clearly shows the above nine steps. However, as I have already indicated, of the nine steps described in the "847 Patent, only steps 8 and 9 (referred to as steps (f) and (g) in paragraph 9 of Dr. Snieckus" affidavit) are claimed in claim 1. In Dr. Snieckus" opinion, the substance of the invention covered by the "847 Patent is the formation of cisapride and the formation of the carbon-nitrogen-carbonyl bond is the most important aspect of the claimed process.
[24] With respect to claim 5 of the "847 Patent, Dr. Snieckus simply states, what in my view is fairly obvious from a reading of the claim, that it covers not only the specific processes described in claim 1 but all other processes which "consist of obvious variants to the specific processes set out" in claim 1.
[25] Two other experts testified on behalf of the Applicants, namely Dr. G. Van Lommen and Dr. Alain P. Raoult. Both witnesses hold degrees of doctor of philosophy in chemistry. Dr. Van Lommen is employed by the Applicant, Janssen Belgium, and Dr. Raoult is employed by the Applicant, Janssen Canada. Both witnesses agree with the opinion given by Dr. Snieckus regarding the processes claimed in claims 1 and 5 of the "847 Patent. Dr. Van Lommen and Dr. Raoult agree with Dr. Snieckus that the essence of claim 1 is the formation of the nitrogen-carbon bond through a nucleophilic substitution reaction between a piperidine of formula II with a carboxylic acid or a functional derivative of a carboxylic acid of formula III.
[26] After their discussion of the "847 Patent and more particularly, their discussion of claims 1 and 5 thereof, the Applicants" experts turned their attention to the Torcan Process. At paragraph 31 of his affidavit, Dr. Snieckus sets out the question which he has been asked to address:
| The issue that I have been asked to address is whether the Torcan Process for making cisapride is within the claims of the Janssen patent. As part of this question I have been asked to consider whether the Torcan Process is an obvious chemical equivalent of the Janssen patent and therefore is within the claims of the patent. |
[27] In Exhibit I to his affidavit, Dr. Snieckus sets out an expanded synthetic pathway which provides the general details of the Torcan Process8. In Dr. Snieckus" opinion, there are twelve compounds and thus, eleven steps in the Torcan Process. The relevant reactions, according to Dr. Snieckus, are those which follow the formation of compound 7, namely, the formation of imine (addition of nitrogen at the 4 position on the piperidine ring), the formation of amine (addition of methoxy(-0CH3 ), also at the 4 position on the piperidine ring), and intramolecular acylation to form the amide bond.
[28] At paragraph 54 of his affidavit, Dr. Snieckus states that "There is a very close concordance between the Janssen and the Torcan Process" in that the Torcan Process uses "...all nine of the steps described in the Janssen patent, to which they have included some additional steps". The following comparison then follows:
JANSSEN PROCESS TORCAN PROCESS COMPOUND #
| 1) halogenation 1) halogenation 1 " > 2 |
| 2) hydroxy substitution 2) hydroxy substitution 2 " > 3 |
| 3) formation of piperidinone (XIII) 3) deprotection 3 " > 4 |
| 4) deprotection 4) addition of L 4 " > 5 |
| * formation of ester 5 " > 6 |
| 5) addition of L 5) formation of piperidinone (XIII)6 " > 7 |
| 6) formation of imine 6) formation of imine 7 " > 7a |
| 7) formation of amine 7) formation of amine 7a " > 7b |
| 8) condensation reaction (acylation) 8) condensation reaction (acylation) 7b " > 8 |
| * elimination of methanol 8 " > 10 |
| * removal of Cbz protecting group 10 " > 11 |
| 9) O-methylation 9) 0-methylation 11 " > 12 |
[29] Dr. Snieckus then states that the reordering of steps 3, 4 and 5 and the additional (*) steps of the Torcan Process result from Torcan"s decision to form the amide bond through a nucleophilic substitution or an acylation as an intramolecular reaction and not as an intermolecular reaction.
[30] However, according to Dr. Snieckus, the essential step in both the Janssen Process and the Torcan Process is the formation of the carbon-nitrogen-carbonyl linkage by way of an acylation. Dr. Snieckus then states that both the Janssen and Torcan processes use the same 8th and 9th steps, i.e. acylation and 0-methylation, which are claimed in claim 1 of the "847 Patent. At paragraph 56 of his affidavit, Dr. Snieckus puts his point of view as follows:
| 56. As discussed above under the heading "Claim 1", the common goal of the processes described in claim 1 is the formation of the carbon-nitrogen-carbonyl linkage between the piperidine ring and the substituted benzoyl group. The Torcan Process uses the reaction of Process 1 of claim 1, to generate the same nitrogen linkage. Specifically, in both reactions: |
| (1) the reactions are nucleophilic acyl substitution reactions, namely the reaction of a piperidine and a functional derivative of a carboxylic acid; |
| (2) the types of compounds involved are the same, namely a 4-amino piperidine and a functional derivative of a carboxylic acid (an ester); |
| (3) the functional groups involved in the two reactions are the same, namely an amine and an ester; |
| (4) the attacking group is the same, namely a nitrogen with a pair of nonbonding electrons; |
| (5) the leaving group is the same, namely an alkoxy; |
| (6) the pair of nonbonding electrons of the nitrogen attacks the carbonyl carbon of the ester group; and |
| (7) the same bonds are broken and formed by the same mechanism (in the same manner). |
[31] At paragraphs 57 to 68 of his affidavit, Dr. Snieckus discusses the nature of intramolecular reactions and intermolecular reactions. He explains that the reaction that compound 7b of the Torcan Process undergoes is known as an intramolecular nucleophilic acyl substitution reaction, which he defines as "any reactions where the groups involved in the reaction start off as part of the same molecule, as opposed to an intermolecular reaction, where the groups involved in the reaction start off as part of separate molecules". In his opinion, the only difference between the intermolecular and intramolecular reactions is that the two reactive groups are part of the same molecule, rather than being part of different molecules. The nature of the reactions, according to Dr. Snieckus, is the same, i.e. it is determined by the nature of the reactive groups.
[32] Dr. Snieckus states that in considering a synthetic pathway, a synthetic organic chemist "should consider intramolecular versions of an intermolecular reaction". In support of his assertion, Dr. Snieckus relies on a lecture delivered in November 1969 by A. Eschenmoser, entitled "Roads to Corrins", where Eschenmoser makes the following remarks:
| Whenever in the synthesis of complex organic molecules one is confronted with a situation where the success of an intermolecular synthetic process is thwarted by any type of kinetically controlled lack of reactivity, one should look out for opportunities of altering the structural stage in such a way that the critical synthetic step can proceed intramolecularly rather than intermolecularly. |
[33] Dr. Snieckus then opines that the attack of amine on an ester, i.e. the type of intramolecular reaction found in the Torcan Process, is a well known reaction and has been known to be used since at least 1937. In support of that proposition, he refers to an article entitled "The Action of Ammonia on Benzoin" by David Davidson, Marvin Weiss and Murray Jelling, published in J. Org. Chem., 1937, 2, 328. He also refers to an article written by G.E. McCastland and Donald Arthur Smith entitled "Stereochemistry of Aminocyclanols. Synthesis of cis Epimers via Oxazolines. The 2-Aminocyclopentanols", Am. Chem. J., 1950, 72, 2190 at 2192.
[34] According to Dr. Snieckus, there is nothing in the "847 Patent that limits the reaction of the piperidine of formula II and the functional derivative of a carbolic acid of formula III to an intermolecular reaction. Consequently, in Dr. Snieckus" opinion, the Torcan intramolecular reaction is not excluded from claim 1 since both reactions are identical, i.e., nucleophilic acyl substitution reactions "where the non-bonding electron pair on the nitrogen attack the carbon of the carbonyl group".
[35] Thus, in Dr. Snieckus" opinion, one should consider an intramolecular reaction as an alternative to an intermolecular reaction. The intramolecular reaction which is found in the Torcan Process is the attack of an amine on an ester, and this reaction is "well-known and has been done on similar systems since at least 1937".
[36] Dr. Snieckus then concludes that on a purposive reading of the "847 Patent, the Torcan Process is literally within claim 1 of the "847 Patent. He then goes on to state that in any event, the Torcan Process is within claim 5 in that "The use of an intramolecular variant for an intermolecular reaction would be obvious to consider, especially in light of the teachings of Eschenmoser who tells us to consider the intramolecular alternative".
[37] Dr. Snieckus then goes on to discuss the "minor differences" which he sees between claim 1 of the "847 Patent and the Torcan Process. In his view, after the formation of the nitrogen-carbonyl bond, the molecule is within formula I, save for the presence of a methoxy group at the 4 position of the piperidine ring, and the presence of a protecting group on the benzene ring. Furthermore, it is not clear whether the correct stereo-chemistry has been established in compound 8. Consequently, to take compound 8 to compound 10, the methoxy must be removed and the proper cis stereo-chemistry must be established, and that is accomplished in the following way, namely, the removal of the methoxy group to form the ketone, followed by stereo-selective reduction of the ketone to establish the correct stereo-chemistry.
[38] To take compound 10 to compound 11 requires the removal of a protecting group (Cbz) on the nitrogen of the benzene group. At paragraph 50 of his affidavit, Dr. Snieckus makes the following comments regarding protecting groups:
| A protecting group is a group which temporarily masks a reactive site to avoid unwanted side reactions, and which once its purpose is served, is removed at any appropriate subsequent step. In selecting a synthetic pathway, the choice of protecting group is a secondary concern. Only once the pathway has been selected does one choose a protecting group by which the chosen pathway will best proceed... |
[39] With respect to the Cbz protecting group, Dr. Snieckus states that it is a well-known protecting group for amines. He then goes on to state that based on his review of the Torcan Process, the prime purpose of the Cbz is to avoid unwanted side reactions when the ester, compound (6), is formed. He then states at paragraph 51 of his affidavit::
| ...Therefore, in order to make cisapride, this protecting group must be removed. This is accomplished in the catalytic reduction of compound (10) with H2 and palladium on carbon to form compound (11). This is the standard textbook method for removing a Cbz protecting group. |
[40] The last step of the Torcan Process, i.e., the one necessary to take compound (11) to cisapride, is 0-methylation. That step is explained as follows by Dr. Snieckus at paragraph 53 of his affidavit:
| It should be pointed out that at lines 97 to 103 of claim 1 the reaction from compound (11) to compound (12) is specifically claimed. In compound (11), R1 is hydrogen and the compound of formula (I-a-1) is equal to compound (11) and is transformed into a compound of (I-a-2), namely, compound (12). The reaction is carried out using an appropriate alkylating agent, such as dimethyl sulphate and is carried out in a suitable medium, such as tetrohydrofuran. This portion of the claim is literally used in the Torcan Process - see Schedule I to the Detailed Statement (Exhibit "B"). |
[41] In the Torcan Process, according to Dr. Snieckus, the hydrogen at R1 attached to the oxygen at the 3 position of the piperidine is replaced with a methyl group from dimethyl sulphate to result in cisapride, compound (12).
[42] At paragraph 86 of his affidavit, speaking of the above differences between the processes of claim 1 and the Torcan Process, Dr. Snieckus says the following:
| 86. A comparison of these two sheets9 that the only differences are the minor variation in R1, the addition of a protecting group and the presence of the methoxy group at the 4 position of the piperidine ring. As stated above, the difference to R1 does not affect the relevant reactions. Furthermore, it is due to Torcan"s choice of starting compounds prior to the relevant steps, e.g. condensation and 0-methylation, that extra steps are required to remove the methoxy and protecting groups without these functional groups having served any purpose throughout the reactions of interest. |
[43] In Dr. Snieckus" opinion, the above will have no effect on the substance of the reaction claimed in the "847 Patent, that is, a condensation reaction of an amine and an ester. In his view, the Torcan Process "is a minor variant on the entire synthetic process set out in the Janssen Patent". The differences between the "847 Patent and the Torcan Process result, in his view, from the necessity of additional steps because of the intramolecular reaction. In Exhibit Q 10 to his affidavit, Dr. Snieckus has summarized the relevant parts of the Torcan Process. According to Dr. Snieckus, this exhibit shows quite clearly that the Torcan Process, beginning with compound (1) includes all nine steps of the "847 Patent. At paragraph 87 of his affidavit, Dr. Snieckus concludes on this as follows:
| The Torcan Process does carry out both of the claimed steps, in substantially the same manner, using substantially the same reactants, namely, condensation (step 8) and methylation (step 9) and does so in the same order with only additional, unessential, steps interposed. |
[44] Dr. Van Lommen agrees with the opinion given by Dr. Snieckus regarding the Torcan Process. In addressing the differences between the processes of claim 1 of the "847 Patent and the Torcan Process, Dr. Van Lommen, at paragraphs 21, 22 and 24 of his affidavit, sworn on May 23, 1996, makes the following remarks:
| 21. While there are some differences in the fine details of the different reactions, these differences do not affect the substance of the claimed reaction, namely, the condensation reaction. In addition, if one considers the entire synthetic pathway, it is clear that the Torcan Process is but a variant of the synthetic process set out in the Janssen patent. All nine steps are used in both Torcan Processes. The differences are the interposition of additional steps necessitated by doing the condensation reactions as an intramolecular reaction. No advantages flow from the use of the Torcan variant. Indeed, the Torcan process appear to be less efficient and there is no chemical reason to use an intramolecular reaction. Overall the same pathway is employed in essentially the same order. |
| 22. Torcan has added complexity to their process in an apparent attempt to differentiate their process from the patented process. In doing so, however, they still employ essentially the same reactions, using essentially the same reactants, in the same manner to achieve the same result in essentially the same order. Thus, the two Torcan Processes, in my opinion, are obvious chemical equivalents to the Janssen patent claimed process. |
| [...] |
| 24. I am convinced that the differences in the order of reactions, and the addition of extra steps are not significant, and that the Torcan processes follow essentially the same strategy of synthesis as that set out, for a synthetic organic chemist skilled in the art. |
[45] Dr. Van Lommen also states that nothing in the "847 Patent limits the reaction of the piperidine and the functional derivative of a carboxylic acid to an intermolecular reaction. Dr. Van Lommen also refers to the lecture delivered by Eschenmoser in November 1969, entitled "Roads to Corrins" and makes the following comments, at paragraph 16 of his affidavit, in regard thereto:
| 16. While Eschenmoser suggests using an intramolecular reaction when the intermolecular variant does not work, there is no reason to not use his teachings where the intermolecular reaction does work. Generally, however, one would not use an intramolecular variant when the intermolecular does work as the preparation of the intramolecular reactant will involve additional steps, generally resulting in a less efficient synthesis. |
[46] I now turn to the evidence of Dr. McClelland, Apotex" expert witness, whose affidavit was sworn on September 21, 1994, and upon which Apotex relies in support of its allegation that the Torcan Process does not infringe the "847 Patent. It will be recalled that Dr. McClelland"s affidavit was attached as Schedule "2" to Apotex" detailed Statement of Fact and Law filed in November of 1994.
[47] Dr. McClelland also holds a PhD. in chemistry, a degree which he obtained from the University of Toronto in 1969. He is presently a professor in the Department of Chemistry at the University of Toronto. Dr. McClelland"s conclusion, after his analysis of the claims of the "847 Patent and the Torcan Process, is that the Torcan Process is not within the scope of the claims of the "847 Patent, nor is it an obvious chemical equivalent of any process claimed in the "847 Patent.
[48] After examining the three processes of claim 1 of the "847 Patent and the Apotex process, Dr. McClelland states "that there are significant differences in the way these processes form the linkage described in paragraph 8 of this affidavit". The linkage described in paragraph 8 of Dr. McClelland"s affidavit is the joining of the 4-amino-5-chloro-2-methoxybenzoyl with the 4-position of the piperidine ring. In paragraphs 16(i) to 16(v) of his affidavit, he explains the "significant differences" as follows:
| 16. A comparison of the three steps of the Apotex process outlined in paragraphs 14 and 15 hereinabove with the reactions claimed in Claim 1 of the "847 Patent show that there are significant differences in the way these processes form the linkage described in paragraph 8 of this Affidavit: |
| (i) The three processes of the "847 Patent each join the 4-amino-5-chloro-2-methoxybenzoyl unit (Box A) directly to the 4-position of the piperidine ring. In the Apotex process this linkage is initially through the 3-position of the piperidine ring; |
| (ii) the three reactions of the "847 Patent that join the 4-amino-5-chloro-2-methoxybenzoyl unit (Box A) to the piperidine ring proceed via an amide linkage. In the Apotex process this linkage is initially through an oxygen, so that the initial product is an ester not an amide; |
| (iii) the three processes of the "847 Patent that join the 4-amino-5-chloro-2-methoxybenzoyl unit (Box A) to the piperidine ring require a previous reaction stage in which the nitrogen is introduced onto one of the units, in process 1 onto the piperidine ring and in processes 2 and 3 onto the benzoyl group. In the Apotex process the amino group is introduced after the 4-amino-5-chloro-2-methoxybenzoyl unit and piperidine have been linked; |
| (iv) the three processes of the "847 Patent are all inter molecular processes in which two different molecules are reacted together. The step in the Apotex process in which the amide bond is formed is an intramolecular reaction in which the elements reacting are already part of the same molecule; |
| (v) the three processes of the "847 Patent, each result in 4-aminopiperidine derivative in which there is no other substituent at position 4. In the step in the Apotex process in which the amide bond is formed and the benzoyl group is transferred to position 4, a second substituent, a methoxy group is also present at position 4 in the product. |
[49] Dr. McClelland then goes on to state that the cis stereochemistry is an important element in preparing cisapride. According to him, the Apotex process "differs considerably" from the "847 Patent processes in regard to the cis stereochemistry. In paragraphs 18, 19 and 20 of his affidavit, he explains in greater detail the "significant differences in the manner in the which the cis stereochemistry is introduced". He explains these differences as follows.
| 20. [...] |
| (a) The Apotex reaction that accomplishes this stereochemistry is the reduction of a ketone to an alcohol. In the "847 Patent reductive aminations of ketones are claimed in which the products are amines or amides; |
| (b) in the Apotex process the stereochemistry is introduced through a reaction that occurs at position 3 of the piperidine ring. In the "847 Patent, the reaction occurs at position 4 of the piperidine; |
| (c) in the Apotex process the group that directs the reduction in such a way that the product has a cis stereochemistry is the amide group already substituted at position 4. This is a bulky group and ensures that there is a significant preference for the cis product. In the "847 Patent the group that directs the reduction to give the cis product is te hydroxy or alkoxy group at position 3. This not only a different group, but is smaller, and there is less of a preference for cis addition, as attested by some of the examples where mixtures of cis and trans products result, for example in Examples XVIII and XXVIII. |
[50] In cross-examination, Dr. McClelland agreed that the essence of the first process of claim 1 was the acylation of an amine and that the essence of the bonds that were being made was the nitrogen carbonyl bond. He also agreed that "the most important thing" of the condensation reaction was the formation of the bond between the nitrogen and the carbon of the carbonyl.
[51] It is interesting to note that in his affidavit, Dr. McClelland does not give any opinion with respect to intermediate compounds 7a and 7b. All he states is that nitrogen is "introduced" at the 4 position of the piperidine ring. During his cross-examination, Dr. McClelland suggested four mechanisms pursuant to which compound 7 is taken to compound 8. He added that he could think of many other possibilities in taking compound 7 and transforming it into compound 8. He did not, however, give an opinion with respect to how these reactions would proceed.
[52] With respect to compound 7b of the Torcan Process, Dr. McClelland stated, during cross-examination, that the compound is an ester and that an ester is a functional derivative of a carbolic acid.
[53] I should point out that Dr. McClelland does not, in effect, give an opinion regarding claim 5 of the "857 Patent, which claims cisapride when made by the processes of claim 1 and all other processes which constitute chemical equivalents thereof. Dr. McClelland, at paragraph 23 of his affidavit, makes a bald statement that the Torcan Process is not an obvious chemical equivalent, but he offers no explanation nor reasons in support of that assertion.
[54] In his Memorandum of Fact and Law, Mr. Radomski, counsel for Apotex, summarizes the differences between the "847 Patent and the Torcan Process as follows:
| 1. The broad general strategy to create cisapride employed in each of the processes is fundamentally different; |
| 2. The specific strategies, chemistry, reactants and mechanisms employed in each of the processes is fundamentally different; |
| 3. The main substituents of cisapride are assembled in the formation of the ester, compound A [intermediate 7] , in which the C-3O substituent is joined to the benzoyl block. Such joinder is not part of the Janssen process; |
| 4. The amide bond is formed by a condensation reaction in the Janssen process whereas the Torcan process does not employ a condensation reaction; |
| 5. The essential reaction in the Janssen process is an intermolecular reaction whereas the Torcan process employs an intramolecular reaction; |
| 6. The manipulation of oxidation states in the Torcan process is different from that in the Janssen process providing for different chemical compounds with different physical and chemical characteristics; and |
| 7. The formation of the cis stereochemistry in the Torcan process is different from that of the Janssen process. |
[55] Counsel then goes on to make the following statement at paragraph 43 of his Memorandum:
| 43. By reason of the foregoing, and particularly, the nature of the various transformations involved in the Torcan process, it is plain that the Torcan process involves new and unobvious chemistry employed to make cisapride. Nowhere in the "847 Patent is such chemistry disclosed or even suggested. Furthermore, as noted above, even without such novel and unobvious chemistry, the strategy, chemistry, reactants and mechanisms employed in the Torcan process are fundamentally different from those utilized in the Janssen process. As a result, the Torcan process is not an obvious chemical equivalent to the Janssen process. |
[56] Finally, in paragraphs 116 through 121, Mr. Radomski sets forth his submissions as to why the Torcan Process does not infringe the "847 Patent:
| 116. In considering the question of infringement of claims to a process which claims the manufacture of a medicine, it is appropriate to consider not only the final step but also the steps preceding the final steps as well as the intermediates used in the final step and in the steps preceding the final step and the processes to make those intermediates. This is particularly apt in a case such as the case at bar where the intermediates of the Torcan pathway and the process for their manufacture are fundamental to the carrying out of the process and were not expected to be suitable to be used to make the medicine cisapride. |
| 117. In the case at bar, as noted above, the Torcan process is different from and not infringing of the Janssen process to make cisapride. The Janssen process is limited to the very specific processes contemplated within the "847 Patent and no others. |
| 118. As appears from the "847 Patent at page 5, lines 5 - 10, page 6, lines 18 - end of page and page 7, line 27 - page 8, line 2, the compounds of Formula I including cisapride can be made by these processes. These processes are transplanted to claim 1. The Torcan process is not within the ambit of the processes set out in claim 1 to the "847 Patent, and particularly, within the ambit of process claim 1(1). |
| 119. Fundamental to the Janssen process is the use of an intermolecular reaction of two molecules to make cisapride. The Torcan process does not employ an intermolecular reaction for the production of cisapride. Torcan"s process employs an intramolecular reaction. Moreover, none of the intermediates or process steps employed in the Torcan process are explicitly or implicitly disclosed in the "847 Patent either in the disclosure or the claims. The compounds, the methodologies, the sequencing and the steps are all distinct in the Torcan process. Despite the assertions by Janssen that individual steps in the Torcan process are known generically, none of the references disclose Torcan"s process, strategy or precise chemistry. |
| 120. As a result, the components of the cisapride molecule are assembled in the Torcan process in a manner that is functionally, mechanically and strategically distinct, and not equivalent to, what occurs in the Janssen process. |
| 121. Claim 5 of the "847 Patent claims "an obvious chemical equivalent thereof" with reference to the previously claimed Janssen process. For the reasons stated above, the Torcan process is not an obvious chemical equivalent of the Janssen process. While functionally both processes produce cisapride, they are neither chemical equivalents nor obvious chemical equivalents of one another. |
[57] For the reasons that follow, I am of the view that the Torcan Process falls within the scope of the "847 Patent or is an obvious chemical equivalent of the processes of claim 1 of the "847 Patent.
[58] In my view, on a purposive construction of the "847 Patent "and construing the claims with a mind willing to understand the true essentials of the invention"11, the true purpose of the first process of claim 1 is to make cisapride by the formation of the amide bond, and optionally, 0-methylation and/or preparing the cis isomer. With respect to claim 5 of the "847 Patent, it is my view that the claim claims cisapride when made or prepared by the first process of claim 1, i.e. formation of the amide bond, and optionally, 0-methylation and/or preparing the cis isomer, and by all other obvious chemical equivalents of the claim 1 process.
[59] I now turn to the specific issue before me in these proceedings, i.e. whether the Torcan Process infringes the "847 Patent. I have already referred to the House of Lords decision in Catnic where Lord Diplock, at page 243, opined that courts should give patents a purposive construction rather than a purely literally construction. In Improver Corporation v. Remington Consumer Products Ltd. (1989), 17 F.S.R. 181 at 189 (Pat.Ct.), Hofman J. (as he then was) sets out, as follows, the three-part test put forward by Lord Diplock in Catnic:
| 1. Does the variant have a material effect upon the way the invention works? If yes, the variant is outside the claim. If no, - |
| 2. Would this (i.e. that the variant had no material effect) have been obvious at the date of publication of the patent to a reader skilled in the art? If no, the variant is outside the claim. If yes, - |
| 3. Would the reader skilled in the art nevertheless have understood from the language of the claim that the patentee intended that strict compliance with the primary meaning was an essential requirement of the invention? If yes, the variant is outside the claim. |
[60] In Novocol Chemical Manufacturing Company of Canada Limited v. W.R. MacFarlane, et al [1939] Ex. C.R. 151 at p. 161, Maclean J. made the following statement:
| ... It is usually fairly safe to define an equivalent as a thing which performs a function in substantially the same manner as the thing of which it is alleged to be an equivalent. |
Thus, in my view, where the variant performs the same function in substantially the same manner, it will constitute an equivalent. After having reviewed the case law, Mr. Creber, for the Applicants, makes the following statement in his Memorandum at page 36, paragraph 82, with which I am in entire agreement:
| Based on the above jurisprudence, it would appear that the phrase "obvious chemical equivalent" means that the detailed chemistry, the functional groups involved in the reaction, the detailed reaction conditions and the starting compounds can be different, yet still be considered equivalent if the two processes achieve the same purpose in an analgous [sic] manner. |
[61] In paragraph 117 of his Memorandum, counsel for Apotex argued that the "847 Patent process was limited to those processes "contemplated within the "847 Patent". This is obviously not correct in view of the clear wording of claim 5, which claims all obvious processes which are chemical equivalents of the claim 1 process. The approach taken by Apotex in paragraph 117 of its Memorandum is not surprising, since Dr. McClelland, as I indicated earlier, did not give an opinion regarding claim 5 of the "847 Patent. He did not consider whether the Torcan Process could be viewed as an obvious chemical equivalent to the claim 1 processes. Rather, he concentrated, as Mr. Creber pointed out, on highlighting the differences between the Torcan Process and the "847 Patent claim. That is why, in my view, he failed to discuss, in his affidavit, intermediate compounds 7a and 7b. I agree with the comment made by Dr. Snieckus at paragraph 94 of his Affidavit, where he says:
| All the comments on the comparison set out in paragraph 16 of Dr. McClelland"s affidavit, ignore intermediates (7a) and (7b). A comparison of the intermediates (7a) and (7b) with the claims, however, would show that the comparison Dr. McClelland is making is of a precursor compound and not the critical compound that should be considered with respect to the claims of the patent. |
[62] It is undeniable, in my view, that the Torcan amide bond is made in a manner analogous to the "847 Patent amide bond, i.e. by way of a nucleophilic acyl substitution reaction involving the non-bonded electrons of the nitrogen attacking the carbonyl carbon, which results in the displacement of an appropriate leaving group Y, to form the nitrogen-carbonyl carbon bond. There are a number of variants between the "847 Patent and the Torcan Process, of which the principal is the use of an intramolecular acylation in lieu of an intermolecular acylation. The issue, therefore, is whether, by reason of these variants, the Torcan Process falls outside the scope of the "847 Patent.
[63] I accept, as credible, the evidence given by the Applicants" experts and in particular, that of Dr. Snieckus. Dr. McClelland did not, in my view, attempt to construe the "847 Patent with a mind willing to understand the true essentials of the invention. To do so would have required him, as Dr. Snieckus did, to examine the synthetic pathway of the "847 Patent so as to discover what the patentee really wanted to achieve and the means thereto. Rather, Dr. McClelland appears to have examined the "847 Patent and the Torcan Process for the specific purpose of emphasizing the differences between the processes. Whether or not there were similarities between the processes was something which did not appear to be of interest to Dr. McClelland.
[64] Nowhere in his affidavit does Dr. McClelland refer to or discuss the similarities between the processes claimed in the "847 Patent and the Torcan Process. I agree with the Applicants that the correct approach was to compare the functional similarities and not to compare differences. That is what Dr. McClelland ought to have done, but did not do.
[65] In paragraph 30 hereinabove, I referred to paragraph 56 of Dr. Snieckus" affidavit, where he points out the similarities between the essential reactions of both the Torcan Process and the processes of claim 1 of the "847 Patent.
[66] As I have already indicated, the principal variant at issue here is the use by Torcan of an intramolecular reaction to make the amide bond. The only difference between Torcan"s intramolecular reaction and the intermolecular reaction of the "847 Patent is that in the former reaction, the two reactive groups, an amine and an ester, are part of the same molecule, whereas in the latter reaction, the reactive groups are part of different molecules.
[67] The nature of the reactions, however, is the same, i.e. it is determined by the nature of the reactive groups.
[68] Bearing in mind that it has been know for quite some time that a synthetic organic chemist should consider intramolecular versions of an intermolecular reaction when planning a synthetic pathway and that the Torcan intramolecular reaction, the attack of amine on an ester, is well known and has been done since 1937, it is clear, in my view, that if the Torcan Process does not fall within the scope of claim 1, it constitutes an obvious chemically equivalent process. The use of an intramolecular variant would, in the light of Eschenmoser"s teachings, be obvious to consider.
[69] There is nothing in the "847 Patent which limits the main reaction, i.e. the piperidine and the functional derivative of a carboxylic acid, to an intermolecular reaction.
[70] Consequently, the intramolecular reaction is either within the scope of the "847 Patent or it is an obvious chemical equivalent of the acylation reaction claimed in claim 1 of the patent, since it would be obvious that it would work in a manner similar to the intermolecular reaction and would achieve the same purpose, i.e. the formation of the amide bond.
[71] At paragraph 59 of these Reasons, I reproduced the Catnic test, as set out by Hofman J. (as he then was) in Improver. The three questions, in my view, must be answered as follows:
| 1. No. Both the intramolecular and intermolecular acylations make the amide bond using the same type of reaction. |
| 2. Yes. Considering the teachings of Eschenmoser, it would have been obvious that the amide bond could be made by way of an intramolecular acylation. |
| 3. No. It is clear that the patentee did not intend strict compliance with the processes described in claim 1, since claim 5 covers all obvious chemical equivalents. |
[1] With respect to the other variants, namely the differences in R1, the presence of the methoxy and the presence of a protecting group, I accept Dr. Snieckus" opinion, for the reasons that he gives, that these variants do not affect the substance of the main reaction.
[2] The key step in the making of cisapride, whether under the Torcan Process or the "847 Patent, is the formation of the amide bond. I agree with the following statement which Dr. Snieckus makes at paragraph 70 of his affidavit:
| ... it is clear that the Torcan process is a minor variant in the entire synthetic process set out in the Janssen patent. All nine steps set out in Exhibit "F" are used by the Torcan process. The differences are the interposition of additional steps necessitated by doing the condensation reaction as an intramolecular reaction. |
I also agree with and accept Dr. Snieckus" comment, found at paragraph 99 of his affidavit, that what Torcan has done is to add "complexity to its process in an apparent attempt to differentiate its process from the patented process".
[3] As a result, I must conclude that any sale of cisapride by Apotex, made by the Torcan Process, will infringe the "847 Patent. Thus, Apotex" allegation of non-infringement is not justified.
[4] I will therefore make an Order prohibiting the Minister from issuing a NOC to Apotex in respect of tablets of cisapride monohydrate, made by the Torcan Process and/or the NDS process, until the expiration of the "847 Patent.
[5] I will also order that costs be payable to the Applicants.
Marc Nadon
_________________________
JUDGE
CALGARY, Alberta
February 7, 2000.
APPENDIX A
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APPENDIX A
Page 2 of 2
APPENDIX B
Page 1 of 2
APPENDIX B
Page 2 of 2
APPENDIX C
Page 1 of 1
Date: 070200
Docket: T-1970-94
CALGARY, ALBERTA, THIS 7TH DAY OF FEBRUARY 2000
PRESENT: THE HONOURABLE MR. JUSTICE NADON
BETWEEN:
JANSSEN PHARMACEUTICA INC. and
JANSSEN PHARMACEUTICA naamloze vennootschap
Applicants
- and -
APOTEX INC. and
THE MINISTER OF NATIONAL HEALTH & WELFARE
Respondents
ORDER
The Minister of National Health and Welfare is prohibited from issuing a Notice of Compliance to the Respondent Apotex Inc. in respect of tablets of cisapride monohydrate made by the Torcan Process and/or the New Drug Submission process until the expiration of the 1,183,847 Patent.
The Applicants shall be entitled to their costs.
Marc Nadon
________________________
JUDGE
__________________1 The amendments and the reasons which led the Applicants to make them are not relevant for the present purposes.
2 [S.O.R. 93-133] See Campbell J."s review of the relevant provisions of the Regulations in Merck Frosst Canada Inc. et al v. Canada (Minister of National Health and Welfare) et al , 160 F.T.R. 161 at pp. 162-164, paragraphs 2 to 11.
3 The process Apotex submits that it will use, if it is issued a NOC by the Minister, has been referred to in these proceedings as the Revised Torcan Process in the Applicants" Memorandum of Fact and Law, and as the Torcan Process in Apotex" Memorandum of Fact and Law. Thus, for the present purposes, the Torcan Process and the Revised Torcan Process are the same. Another process referred to in these proceedings is the process set out by Apotex in its new drug submission (the "NDS process"). It was not disputed before me that the NDS process literally infringes the "847 Patent. Consequently, the only issue for determination in these proceedings is whether the Torcan Process or the Revised Torcan Process infringes the "847 Patent.
4 41(1) In the case of inventions 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 .
5 The Roman numeral references used by Dr. Snieckus are the figures which are set out in the "847 Patent.
6 Exhibit "F" to Dr. Snieckus" affidavit is reproduced as Appendix A to these Reasons.
7 The acylation reaction was referred to by the various experts as a nucleophilic substitution, a condensation, N-acylation and nucleophilic acyl substitution reaction.
8 Exhibit I to Dr. Snieckus" affidavit is reproduced as Appendix B to these Reasons.
9 These two sheets are his Exhibits "Q" and "R".
10 Exhibit Q to Dr. Snieckus" affidavit is reproduced as Appendix C to these Reasons.
11 The words in quote are those of Richard J. in Pfizer at page 215, paragraph 96.