Date: 20030620
Docket: T-1914-01
Citation: 2003 FCT 771
PRESENT: The Honourable Mr. Justice Campbell
BETWEEN:
AB HASSLE and ASTRAZENECA CANADA INC.
Applicants
- and -
APOTEX INC. and THE MINISTER OF HEALTH
Respondents
REASONS FOR ORDER AND ORDER
CAMPBELL J.
[1] Since 1990, the Applicants ("Astra") have held the Canadian Patent 1,264,751 ("the Patent" or "the 751 Patent") to a form of omeprazole, namely certain base addition salts of omeprazole which are compounds effective in treating gastric acid disorders. Now, some three years from the expiry of the Patent, the Respondent, Apotex Inc. ("Apotex") attacks the Patent's validity pursuant to the provisions of the Patented Medicines (Notice of Compliance) Regulations ("NOC " and "the Regulations").
[2] Of particular importance in the present case is the magnesium base addition salt of omeprazole, which is claim 4 of the 751 Patent, and in respect of which, Apotex wishes to obtain a NOC from the Minister of Health in order to sell and advertise the drug. In order to accomplish this, pursuant to the Regulations, a determination is required in the present summary proceeding that the Patent is invalid.
[3] The legal considerations with respect to the NOC process are well established (see: Hoffmann-LaRoche Ltd. v. Canada (Minister of National Health and Welfare), 70 C.P.R. (3d) 206 at pp.210-212) and are not in contest in the present application, with the important exception of the evidentiary and persuasive burden of proof in an application such as the one in the present case where patent validity is the only issue for determination.
[4] In its Notice of Allegation ("the NOA"), Apotex alleges that the Patent is invalid on the ground of anticipation; Apotex argues that the 751 Patent is invalid because Astra's European Patent Application 5129 published in 1979 ("the 5129 Application") teaches an uninventive person skilled in the art how to produce Astra's salt form of omeprazole.
[5] The filing date of the 5129 Application is important because, by s.27(1)(b) of the Patent Act, for Astra to obtain the 751 Patent, the invention it claims must not have been described in any publication printed more than two years before the date of filing the application for the Patent, which was March 2, 1984.
[6] Apotex also alleges that the Patent is invalid on the ground of obviousness; the primary allegation is that the prior art to the Patent, including the 5129 Application, shows that Astra's salt form of omeprazole was known by persons skilled in the art and would have been produced accordingly.
[7] The Canadian equivalent to the 5129 Patent Application resulted in the now expired Patent 1127158 ("the 158 Patent"). The only importance of the 158 Patent in the present case is with respect to the allegation of double patenting which is addressed below in Section F.
[8] It is common ground that the science underlying the 751 Patent was no mystery when the Patent was granted. Omeprazole is but one of thousands of compounds claimed in the 5129 Patent Application and patented in Canada by the 158 Patent. There is no disagreement that, from looking at its formula, a person skilled in the art would know that "salts", being either "base addition salts" or "acid addition salts" of the compound omeprazole, could be formed without difficulty. An introduction to the science is needed to understand the difference between the two. The following is a helpful precis:
Acids, Bases and Salts
Once a chemical entity such as omeprazole is synthesized, it is common for salts of the parent chemical entity to be prepared in order to alter certain physical and chemical properties of the compound for the purposes of drug development, for example, solubility, storage stability, etc.
Salts can be viewed generally as the product of a reaction between an "acid" and a "base". An acid is a chemical entity whose molecules tend to lose a hydrogen (H), i.e. hydrogen donor, and a "base" is a chemical entity whose molecules tend to receive a hydrogen, i.e. hydrogen acceptor. A base addition salt is formed when a chemical entity reacts with a base and loses a hydrogen. An acid addition salt is formed when a chemical entity reacts with an acid and gains a hydrogen.
Some chemical entities have a number of functional groups within them, some of which are hydrogen acceptors and some of which are hydrogen donors, thus permitting them to become either base addition salts or acid addition salts. Omeprazole is such a chemical entity.
A base addition salt of omeprazole may be obtained by removing the hydrogen attached at the N1 nitrogen position of the benzimidazole. For example, a base addition salt of omeprazole would be obtained by reacting omeprazole with the base sodium hydroxide (NaOH) resulting in sodium omeprazole (the Na displacing the hydrogen at the N1 nitrogen position of the benzimidazole). The hydrogen would join the OH to become H2O, water.
Omeprazole may also be reacted to form an acid addition salt. Omeprazole has, in principle, two potential sites that could act as the proton acceptor necessary to create the acid addition salt, namely, the N3 nitrogen position of the benzimidazole and the N1 nitrogen position of the pyridine. An acid addition salt of omeprazole could be created by reacting omeprazole with hydrochloric acid (HCl) to create omeprazole hydrogen chloride in which the donated hydrogen would bind at either the N3 position of the benzimidazole or the N1 position of the pyridine, together with the addition of the chlorine to the molecule.
The strength or weakness of an acid or of a base is the measure of its strength in donating a hydrogen in the case of an acid and its strength in accepting a hydrogen in the case of a base. The stronger the acid, the greater the propensity to donate a hydrogen and hence the more readily it will react with a base to form a base addition salt.
The strength of an acid or of a base is measured by, among other things, a value known as the pK value, pKa in the case of acids and pKb in the case of bases. The stronger the acid or base is, the lower the pKa or pKb value will be.
When an acid and base react to form a salt, whether the resultant solution formed is neutral, acidic or basic will depend upon the strength of the acid and base used in the reaction. Hence, reacting equal parts of a strong acid and a strong base or a weak acid and a weak base will result in a solution that is essentially neutral as evidenced by the resulting pH (the measure of basicity/acidicity) of that solution being essentially 7. In contrast, the reaction of equal parts of a strong acid and a weak base would result in a solution that is acidic, meaning that the pH of the solution would be less than 7 whereas the reaction of equal parts of a weak acid and strong base would result in a solution that would be basic, meaning that the pH of that solution would be greater than 7.
(Respondent's Record (RR), pp. 4-6, excluding footnotes)
[9] The 751 Patent claims rights to certain "base addition salts" of omeprazole. If there could be no difficulty in understanding how to produce the base addition salt of omeprazole, the important question naturally arises: How is Astra entitled to patent protection? Astra argues that, while the science was well understood that a person skilled in the art could produce base addition salts of omeprazole, that same skilled person operating in a therapeutic environment would not because it would not have been expected that a base addition salt of omeprazole would have therapeutic value.
[10] As it turns out, base addition salts of omeprazole certainly do have therapeutic value, and Astra argues that the creative spark of its invention is this discovery.
[11] Thus, the present case revolves around the difference between "could" and "would". That is, while an uninventive person skilled in the art could have come to the 751 Patent from the teachings of the 5129 Patent Application, would he or she?
[12] A word is required concerning the credibility of the expert witnesses on both sides of the present application who swore affidavits and who went through cross-examination thereupon.
[13] On behalf of Astra, the following experts gave evidence by way of affidavit:
1. Dr. Peder Berntsson, PhD in Organic Chemistry, was employed as the Senior Scientific Advisor, Scientific Patent Support, at Astra until 2001.
2. Dr. James D. Wuest, PhD in Organic Chemistry, is a Professor of Chemistry at the University of Montreal.
3. Dr. Gordon Amidon, PhD in Pharmaceutical Chemistry, is a Professor of Pharmacy at the University of Michigan.
4. Dr. Christopher T. Rhodes, PhD in Pharmaceutics, is a Professor of Applied Pharmaceutical Sciences at the University of Rhode Island and President of PharmaCon Inc., a pharmaceutical consulting firm.
[14] On behalf of Apotex, the following experts gave evidence by way of affidavit:
1. Dr. Zak T. Chowhan, PhD in Pharmaceutical Chemistry, is an independent consultant in the field of Pharmaceutical Development.
2. Dr. Eli Shefter, PhD in Pharmaceutics, is an independent consultant.
3. Dr. Hendricksson, PhD in Organic Chemistry, is a Professor of Chemistry at Brandeis University in Massachusetts.
4. Dr. Edward Lee-Ruff, PhD in Organic Chemistry, is a Professor of Chemistry at York University in Toronto.
5. Dr. Robert McClelland, PhD in Chemistry, is a Professor of Chemistry at the University of Toronto.
6. Dr. Robert S. Brown, PhD in Chemistry, is a Professor of Chemistry at Queens University.
7. Dr. Michael V. Sefton, ScD in Chemical Engineering, is a Professor in and Director of the Institute of Biomaterials and Biomedical Engineering at the University of Toronto and a Professor in the Department of Chemical Engineering and Applied Chemistry at the University of Toronto.
[15] Each side to the present case cast aspersions of partisanship on the experts of the other in an attempt to impact negatively upon their credibility. As will be seen below, I have assigned weight to the evidence provided by the experts, but this is done according to what each says in the full context of the evidence on the record, and not according to who they are and whatever possible connection they have with the party for whom they are testifying.
[16] Each of the expert witnesses to the present case have sworn that the evidence they have provided is true. On this basis, an evaluator of the evidence must start from the proposition that the witnesses are credible unless good cause is shown, and can be articulated, to the contrary (for an example of this general principle see: Maldonado v. Canada (Minister of Employment and Immigration), [1980] 2 F.C. 302 (C.A.). That is, while they might hold differing views on a given topic, it must be assumed that they are not just saying things to bestow a benefit on the party who is relying on their evidence. In my opinion, it is unfair to the witnesses and, accordingly, to each of the parties, to make negative credibility findings in the guise of findings of weight without seeing and hearing each witness testify.
[17] I have absolutely no reason to question the credibility of each of the experts in the present case.
A. The preliminary objection
[18] In 1998, Apotex made its first attempt to attack the validity of the 751 Patent under the Regulations. This attempt was aborted after its expert witnesses were cross examined on their affidavits. It appears that two of the experts held opinions that were contrary to Apotex's interests as alleged in the NOA; it appears that Apotex concluded that it just did not have the evidence it required to succeed in proving its allegations. The 1998 attempt was discontinued by Court order on an agreement between Apotex and Astra.
[19] Thus, the NOA in the present case is Apotex's second attempt. It is important to note that counsel for Astra in the present case confirmed during the course of oral argument that the discontinuance of the 1998 NOA did not result in any cost or inconvenience to Astra. However, as a preliminary objection in the present case, Astra makes the argument that this second attempt by Apotex constitutes an abuse of the Court's process. When pressed for the exact reason for taking this position, counsel for Astra confirmed that it has to do with the evidence of the two witnesses who supplied evidence against the allegations in the 1998 NOA. Indeed, in the present application, without any notice provided in the written submission, during the course of oral argument Astra attempted to get the evidence of these witnesses into the record of the present case on an argument that this could be done through hearsay evidence contained in the affidavit of a lawyer and patent agent who is a member of Astra's legal team. Understandably, counsel for Apotex objected. As a result, on the basis of lack of notice, I disallowed Astra's evidentiary attempt.
[20] Apotex's first NOA attempt ended by an agreement without apparent detriment to Astra before the Court was involved directly in the NOC process. I see no basis for an abuse of process argument simply because Apotex has made a second attempt.
[21] During the course of the hearing, counsel for Astra admitted that the abuse of process argument really centres on the fact that Astra would like to have used the evidence of Apotex's two unhelpful witnesses in the present case, but could not. In answer to the question "why not?", counsel for Astra responded that it could be assumed that they would not be available simply because they had given evidence on behalf of Apotex.
[22] There is no evidence that Apotex has acted unfairly in using the NOC process allowed under the Regulations, and, specifically, there is no evidence that Apotex has done anything to inhibit Astra's ability to produce the evidence it believes would be helpful in the present application. As a result, in my opinion, there is no conduct by Apotex that gives rise to an abuse of process concern. Thus, during the course of oral argument, I rejected Astra's abuse argument.
B. The burden of proof with respect to patent validity
[23] Apotex argues that, in part, the purpose of the Regulations is to permit a patent owner to proceed summarily to protect its patent rights where the generic's allegations of non-infringement or invalidity have "no merit". I find that, certainly with respect to an attack of invalidity, Apotex's argument does not reflect the present state of the law.
[24] Justice Stone at 210 to 211 of Hoffman-La Roche, supra, provides the following analysis specifically with respect the NOC process with respect to allegation of infringement:
The initiator of a section 6 proceeding, being the person having the carriage of the litigation, bears "the initial burden of proof" which is a difficult burden because "it must be to disprove some or all of the allegations in the notice of allegation which, if left unchallenged, would have allowed the Minister to issue a notice of compliance".
This burden, known in a civil case as either the "persuasive burden" or the "legal burden", is the burden of establishing a case to the civil standard of proof. By contrast, the "evidential burden" consists of the burden of putting an issue in play and means that a party has the responsibility to ensure that there is sufficient evidence of the existence or non-existence of a fact or an issue on the record to pass the threshold for that particular fact or issue.
Where the notice of compliance of a second person alleges non-infringement, the court should start from the proposition that "the allegations of fact in the notice of allegation are true except to the extent that the contrary has been shown by the applicant".
In determining whether or not the allegations are "justified" "the court must then decide whether, on the basis of such facts as have been assumed or proven, the allegations would give rise in law to the conclusion that the patent would not be infringed by the respondent".
The Minister's decision of whether to issue a notice of compliance must turn on whether the allegations of the second person are "sufficiently substantiated to support a conclusion for administrative purposes ... that the applicant's patent would not be infringed if the generic's product is put on the market". [footnotes omitted] [Emphasis added]
[25] However, specifically with respect to allegations of patent invalidity, in Bayer Inc. v. Canada (Minister of National Health and Welfare) [2000] F.C.J. No. 464, the Appeal Division of this Court has clarified the evidential burden on Apotex in the present case. At paragraph 5, Justice Sharlow says as follows:
An application for a prohibition order under the Patent Medicines (Notice of Compliance) Regulations is like any other application for judicial review in the sense that the applicant has the burden of establishing its entitlement to the order sought. Bayer, in other words, had the burden of proving that the allegation of invalidity made by Apotex was not justified. The Motions Judge said as much in paragraph 15 of his reasons:
The substantive issue in this application is whether Bayer has discharged its burden in establishing that the Apotex allegation of invalidity is not justified.
In seeking to discharge its burden of proving the allegation to be unjustified, Bayer relied on the statutory presumption of the validity of its patent. Because that presumption exists, it may be said that Apotex, as the party responding to the application for a prohibition order, has a burden of proof in this sense: if Apotex had adduced no evidence that was capable of establishing the invalidity of the patent, Bayer could have succeeded on the basis of the statutory presumption alone. As the Motions Judge correctly said at paragraph 15:
A statutory presumption, for example, may assist Bayer and "have the effect of displacing the burden of proof".
The quotation is from Merck Frosst Canada Inc. v. Canada (Minister of National Health and Welfare) (1994), 55 C.P.R. (3d) 302 (F.C.A.), where Hugessen J.A. said at 319:
As I understand the scheme of the [Patent Medicines (Notice of Compliance) Regulations], it is the party moving under s. 6, in this case Merck, which, as the initiator of the proceedings, has the carriage of the litigation and bears the initial burden of proof. That burden, as it seems to me, is a difficult one since it must be to disprove some or all of the allegations in the notice of allegation which, if left unchallenged, would allow the Minister to issue a notice of compliance. There may, of course, be some presumptions (such as for example the statutory presumption of validity of a patent ) [...] which may help the moving party and have the effect of displacing the burden of proof.
However, in this case Apotex did adduce evidence, in the form of an affidavit, that the Motions Judge correctly accepted as going to the question of validity.
The operation of the statutory presumption in the face of evidence of invalidity depends upon the strength of the evidence. If the evidence proves on a balance of probabilities that the patent is invalid, the presumption is rebutted and is no longer relevant: Diversified Products Corp. v. Tye-Sil Corp. (1991), 35 C.P.R. (3d) 350 (F.C.A.) at 359. [Emphasis added]
[26] Bayer, supra was cited with approval by Justice MacDonald in Hoffmann-La Roche v. Canada (Minister of National Health and Welfare) [2000] F.C.J. No. 1356, where he said:
Nu-Pharm challenges the motions judge's approach to the presumption of validity under the Patent Act. In Bayer v. Canada (Minister of National Health and Welfare) [2000] F.C.J. No. 464 (QL) at para. 9, Sharlow J.A. stated:
The operation of the statutory presumption in the face of evidence of invalidity depends upon the strength of the evidence. If the evidence proves on a balance of probabilities that the patent is invalid, the presumption is rebutted and is no longer relevant: Diversified Products Corp. v. Tye-Sil Corp. (1991), 35 C.P.R. (3d) 350 (F.C.A.) at 359.
Muldoon J.'s finding that Nu-Pharm's evidence was insufficient to displace the statutory presumption is a finding that, on a balance of probabilities, Nu-Pharm did not prove that the patent was invalid. We see no legal error in the approach of the learned judge.
[27] Therefore, the question is not whether Apotex's invalidity allegations have "no merit"; the question to be answered in the present case is: Has Apotex proved, on a balance of probabilities by the evidence supporting its allegations in the NOA, that the 751 Patent is invalid?
C. Features of the 751 Patent
[28] The opening passages of the 751 Patent, as abridged, are as follows:
Novel compounds
Field of the invention
The invention relates to novel salts of the known compound omeprazole
Background of the invention
The compound known under the generic name omeprazole ... which is described i.a. in European patent specification [the 5129 Application] is being extensively investigated clinically as a gastric acid secretion inhibiting agent.
Omeprazole is useful for inhibiting gastric acid secretion as well as for providing gastrointestinal cytoprotective effects in mammals and man. In a more general sense, omeprazole may be used for prevention and treatment of gastrointestinal inflammatory diseases in mammals and man, including e.g. gastritis, gastric ulcer, and duodenal ulcer. Furthermore, omeprazole may be used for prevention and treatment of other gastrointestinal disorders where cytoprotective and/or gastric antisecretory effect is desirable, e.g. in patients with gastrinomas, in patients with acute upper gastrointestinal bleeding, and in patients with a history of chronic and excessive alcohol consumption
The term "omeprazole" as used in this specification designates the neutral form of the compound of the formula (I), that is the form as given in the formula (I) without salt forming components present.
A problem with omeprazole is its stability characteristics. Upon storage without any special precautions being taken, it is degraded at a rate which is higher than desired. At storage during accelerated conditions, that is a +37oC and at a relative humidity of 80% for a period of 6 months, about 6% of the substance is converted to degradation products. While the rate of decomposition of omeprazole at normal storage conditions is lower, it is nevertheless desirable to obtain physical forms of omeprazole which exhibit improved stability. This need for more stable forms of omeprazole is apparent when considering the often considerable time periods involved from synthesis of the active substance through its incorporation in pharmaceutical preparations, distribution of the finished product to pharmacies etc. up to the consumption of the preparation by the patient. The present invention provides such forms of omeprazole which exhibit improved storage stability.
The invention
It has been found that the novel alkaline salts of omeprazole ... are more stable during storage than the corresponding neutral form of omeprazole. The salts...are also easier to handle than the neutral form in the manufacture of pharmaceutical dosage units. ...The Mg 2+ salt is particularly preferred. (Applicant's Record (AR), pp.47-50)
[29] The relevant claims of the 751 Patent, wherein formula I represents specific base addition salts of omeprazole, are as follows:
1. A compound of the formula I
(I)
wherein n is 1, 2, or 4; and An+ is Li+, Na+, K+, Mg2+, Ca2+, Ti4+, N+(R1)4 or H2N-C+NH2-NH2
wherein R1 is an alkyl group containing 1-4 carbon atoms.
...
4. A compound according to claim 1 wherein An+ is Mg2+
...
8. A pharmaceutical composition comprising as active ingredient an effective amount of a compound according to claim 1, 2 or 3 in admixture with pharmaceutically acceptable diluent or carrier.
9. A pharmaceutical composition comprising as active ingredient an effective amount of a compound according to claim 4 in admixture with pharmaceutically acceptable diluent or carrier.
(AR, p.62, p.64)
[30] Claim 4 protects the magnesium base addition salt of omeprazole which is of particular practical interest to Apotex.
[31] The key feature of the Patent is that a base addition salt of omeprazole is a solid. As will be discussed below, Astra's NOA alleges that, from the prior art, solution studies of omeprazole would inevitably lead to the formation of the base addition salt in solution. With respect to its allegation, Apotex tenders evidence that, in the course of doing the solution studies as part of standard pre-formulation procedure in the study of omeprazole, the stability of the base addition salt of omeprazole would be determined and this quality would be appreciated; consequently, Apotex argues, Astra cannot claim an invention.
[32] With respect to the relevance of the solution studies, it is important to make a finding with respect to Apotex's "salt in solution" argument. There is no dispute that the compound of base addition salt of omeprazole is a solid. The dispute is with respect to whether the compound exists when in solution.
[33] I find that the determination of the question is a matter of chemistry theory. Astra has produced cogent evidence to prove that, in aqueous solution, the base addition salt of omeprazole is no longer present. Under cross-examination, Apotex's experts have agreed that this is a correct statement in theory.
[34] In order to support its argument, Astra relies on the affidavit of Dr. Amidon, which states as follows:
A "salt" is a solid substance consisting of distinct ions with opposite charges. In the context of an omeprazole salt, each omeprazole anion (negatively charged omeprazole ion) is associated with cations (positively charged species). Once such a salt is dissolved, the salt itself is no longer present. Rather, one has a solution containing the omeprazole anions and salt cations plus any other additives to the solution. While a salt might be isolated from the solution, the solution containing ions is not the salt per se.
My conclusion in this regard is reinforced by the disclosure to the '751 patent. In each of examples 1 to 9 the end product of the preparation is a solid material described as a salt. At page 4, the inventors describe the synthetic process, including the fact that the "salt is thereafter isolated". (AR, pp. 177-178)
[35] Dr. Wuest also referred to the solid state of salts, as follows:
A salt is a substance that consists of distinct ions of opposite charges. Salts are normally understood to be solid substances. In general, salts result from the reactions of acids and bases. The most common example of a salt is sodium chloride (NaCl), which is comprised of a sodium cation (Na+) and a chloride anion (Cl-). It is formed under appropriate conditions when the base NaOH reacts with the acid Hcl. (AR, p. 1716)
[36] Astra also supports its argument that salt compounds are solids by relying on the testimony of many of Apotex's witnesses, obtained through cross-examination. Dr. Sefton answered as follows:
Q. Do you understand the word "compound" to be referring to- and let's go back to my hypothetical with the sodium chloride dissolved in the aqueous solution. When we had the sodium chloride, the solid substance, in our hand, that could be referred to as a compound?
A. Yes.
Q. Then, when it was completely dissociated and solvated in dilute aqueous solution, could we still say we have a compound, sodium chloride, in solution?
A. No, I would be hard-pressed to call that a compound now.
Q. That is because the sodium chloride, when it is completely dissociated in the manner I described, would not be understood by people in your field to be a compound because you don't have the molecules per se anymore.
A. Yes. I would be inclined to think of it- I would not be using the word "compound" in that solution of sodium chloride so easily.
Q. But you are comfortable that the solid material sodium chloride can be described as a compound?
A. Yes. (AR, pp. 5045-5046)
[37] In addition, Astra questioned Dr. Lee-Ruff as follows:
Q. I want to ask you next about the word "compound". Are you familiar with that word as a word that is a term of art in chemistry?
A. Yes.
Q. If I read out something to you, can you tell me whether you agree or disagree with this being a definition acceptable to you for "compound":
"A substance composed of atoms or ions of two or more elements in chemical combination. The constituents are united by bonds or valent forces. A compound is a homogenous entity where the elements have definite proportions by weight and are represented by a chemical formula".
A. I would agree.
....
Q. In accordance with this definition I have read out, does that definition include a situation where in aqueous solution you have anions and cations which are each completely solvated? For example, if you took sodium chloride and put it into a dilute aqueous solution and you had water molecules surrounding the anions and the cations, would the definition of "compound" that I read out include anions that were solvated in the way that I have described?
A. It would include both the anions and the cations which are solvated. What you have is a solution of the compound.
Q. Would you include in the compound the water which is solvating the anions and the cations?
A. I would not simply because the solvation forces are a lot weaker than the forces that are associated with the binding of the anion and cation in the compound itself.
Q. What do you mean by "the compound itself" in that context that you have just been describing?
A. In the sense that the compound is the sodium chloride and the fact the water is associated would not be part of the compound simply because these interactions are relatively weak compared to the interactions between the anions and cations, sodium chloride.
...
Q. That attraction force in the solid state is overcome in the aqueous solution by the combined or total forces exerted by the water in respect of the cation and the anion.
A. That is correct.
Q. Given that and, in particular, given that there is a greater attraction in the aqueous solution between the individual cations and anions and the water molecules as compared to the attraction between the sodium and the chlorine in the solid state, when we go back to this definition of "compound" that I read out to you and, in particular, the part that talks about the constituents being united by bonds or valence forces, would you not have to describe what we have in solution in a way that would include the water molecules since they are now the constituents that are involved in the greatest attraction forces with the anions and cations?
A. The solvation shell interaction of the anions and cations with the water molecules is not co-valent bonds, they are not ionic bonds. They are weaker electrostatic interactions. I would refer to the aqueous solution of sodium chloride as a solution of the original salt.
Q. The original salt being what you had in the solid-
A. The solid sodium chloride.
Q. In this definition that we looked at it talks about constituents united by bonds or valence forces. On the right-hand side of the diagram you are looking at [AR, p.4439] there are no bonds, are there?
A. No, those are weak electrostatic interactions between water molecules and the anions and cations. I would not call this a formal bond in the sense of an ionic bond or a co-valent bond.
...
Q. According to the definition, you would not have a compound. If we go back to my example of sodium chloride being what is illustrated in the diagram before you, you would not have in solution the compound sodium chloride. It does not exist, per se, in the solution.
A. According to the definition, you are correct.
Q. Is it your view that the compound, sodium chloride, does exist in solution, that the compound, per se, exists in solution if it is totally dissolved and completely dissociated?
A. Yes, it exists as a solution of sodium chloride, just like any solid when dissolved exists as a solution of that particular solid.
Q. That term denotes what you started with in the solid state. Correct?
A. Yes. (AR, pp. 4453-4458)
[38] Finally, during his cross-examination, Dr. Chowhan said the following:
Q. Just focussing on the word "compound", do you understand the word "compound" in the context of pharmaceuticals or chemicals generally to signify a solid material?
A. Not necessarily.
Q. Let me give you a further example. If I take sodium chloride, table salt, if I have it in my hand, it is a white crystalline material. Do you agree?
A. Yes.
Q. If I put it into my glass of water and mix around the water, it will disappear. Correct?
A. Right.
Q. It disappears because the sodium chloride dissolves in the water.
A. Yes.
Q. As part of the dissolution process, the sodium part of the sodium chloride and the chloride part of the sodium chloride move apart. Yes?
A. Yes.
Q. And they are solvated by the water molecules. Right?
A. Right.
Q. When I had the sodium chloride in my hand, the crystalline material, and it was a solid, I could refer to that as a compound, could I not?
A. Of course.
Q. And you would understand what I am referring to?
A. If you had it in your hand, yes.
Q. After I have dissolved it in the water, in your view, do I have the compound?
A. You have the compound in solution.
Q. What does that mean?
A. That means it is a solution. It is dissolved.
Q. It has been dissolved.
A. Yes.
Q. But the solid material no longer exists.
A. Yes. (AR, pp. 3846-3848)
[39] On the basis of the evidence quoted, I find that the compound of base addition salt of omeprazole does not exist in solution.
[40] The question now is whether the Patent can withstand Apotex's attacks of invalidity. I accept Astra's argument that Apotex is bound by the legal and factual basis for the allegations set out in the NOA, and that the issues set out in the NOA may not be expanded or amended by Apotex during the proceeding(AB Hassle v. Canada (Minister of National Health and Welfare (2000) 7, C.P.R. (4th) 272 at 288, 289 (C.A.).
[41] In the analysis which follows, I have adopted the written argument strategy put forward by Astra which is to first cite directly from the NOA as it is framed by Apotex under various topic headings, and then to decide with respect to the content of each.
D. The attack of anticipation
[42] Section 27(1) of the Patent Act stipulates that a patent will only be valid where it describes a novel invention that has not previously been anticipated by a prior invention. An invention is said to be anticipated if its essential features are disclosed in a single piece of prior art as stated by Justice Hugessen in Beloit Canada Ltd. et al. v. Valmet ((1986), 8 C.P.R. (3d) 289 (F.C.A.)) at 297 as follows:
One must, in effect, be able to look at a prior single publication and find in it all the information which, for practical purposes, is needed to produce the claimed invention without the exercise of any inventive skill. The prior publication must contain so clear a direction that a skilled person reading and following it would in every case without possibility of error be led to the claimed invention. Where, as here, the invention consists of a combination of several known elements, any publication which does not teach the combination of all the elements claimed cannot possibly be anticipatory.
[43] The test for anticipation was also clearly set out by Wetston J. in Almecon Industries Ltd. v. Nutron Manufacturing Ltd. (1996) 65 C.P.R. (3d) 417 at 428-429, affirmed (1997) 72 C.P.R. (3d) 397 (F.C.A.), leave to appeal denied [1997] S.C.C. No. 374) as follows:
In Proctor & Gamble Co. v. Kimberly-Clark of Canada Ltd. (1991), 40 C.P.R. (3d) 1 (F.C.T.D.), Teitelbaum J. noted than an analysis of anticipation involves a two-fold test. Firstly, the court must consider whether the prior disclosure gives clear and unmistakable directions which would, in every case and without possibility of error, lead a skilled person to arrive at what is covered by the claims of the patent-in-suit. In other words, in light of the prior patent, was it inevitable that a skilled person would be led to discover the patent-in-suit?
If the first question is answered in the affirmative, the court must then ask if the prior patent conveys enough information which, for practical purposes, would be sufficient for the skilled person to know how to make the claimed invention without the exercise of any inventive skill. This is the enabling disclosure test. Thus, in order to satisfy the tests of anticipation, one has to show that the prior patent has enough description to enable the skilled person to construct the invention and put it to its proper use.
[44] Anticipation also precludes the grant of a patent where the invention claimed has been in prior use.
1. Is the 5129 Application a prior single publication?
[45] The 5129 Application makes claim to many compounds, and, with respect to each, the "therapeutically acceptable salt thereof". Claim 23 of the 5129 Application refers precisely to omeprazole.
[46] Apotex argues that the 751 Patent is invalid primarily because the 5129 Application is a "prior single publication" which meets the test for anticipation as quoted. Elements of this document important to the argument are as follows:
AB HÄSSLE
Mölndal/SWEDEN
Inventors: U`Junggren and S E Sjöstrand
KM 575-1
79-03-07
UI/LB/EMH
Gastric acid secretion agents
The present invention relates to new compounds having valuable properties in affecting gastric acid secretion in mammals, including man, as well as the process for their preparation, method of affecting gastric acid secretion and pharmaceutical preparations containing said novel compounds.
The object of the present invention is to obtain compounds which affect gastric acid secretion, and which inhibit exogenously or endogenously stimulated gastric acid secretion. These compounds can be used in the treatment of peptic ulcer disease.
It is previously known that compounds of the formula I and II wherein R1 and R2 are each selected from the group consisting of hydrogen, alkyl, halogen, cyano, carboxy, caboxyalkyl, carboalkoxy, carboalkoxyalkyl, carbemoyl, carbemoyloxy, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl and acyl in any position, R3 is selected from the group consisting of hydrogen, alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, and alkylsulphonyl, and R4 is selected from the group consisting of straight and branched alkylene groups having 1 to 4 carbon atoms, whereby at most one methylene group is present between S and the pyridyl group, and whereby the pyridyl group may be further substituted with alkyl or halogen, possess inhibiting effect of gastric acid secretion.
It has now, however, surprisingly been found that the compounds defined below possess a still greater inhibiting effect than those given above.
Compounds of the invention are those of the general formula III in which R1 and R2 are the same or different and are selected from the group consisting of hydrogen, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy and alkanoyl in any position, R6 is selected from the group consisting of hydrogen, methyl, and ethyl, R3, R4 and R5 re the same or different and are each selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, methoxyethoxy, and ethoxyethoxy, with the proviso that R3, R4 and R5 are not all hydrogen, and the further proviso that when two of R3, R4 and R5 are hydrogen, the third of R3, R4 and R5 is not methyl.
The invention also extends to therapeutically acceptable salts of compounds of formula III [as claimed in Claims 1 to 6].
...
Depending on the process conditions and the starting materials, the end product is obtained either as the free base or in the acid addition salt, both of which are included within the scope of the invention. Thus, basic, neutral or mixed salts may be obtained as well as hemi, mono, sesqui or polyhydrates.
The acid addition salts of the new compounds may in a manner known per se, be transformed into free base using basic agents such as alkali or by ion exchange. On the other hand, the free bases obtained may form salts with organic or inorganic acids. In the preparation of acid addition salts preferably such acids are used which form suitable therapeutically acceptable salts.
....
These or other salts of the new compounds, as e.g. picrates, may serve as purifying agents of the free bases obtained. Salts of the bases may be formed, separated from solution, and then the free base can be recovered from a new salt solution in a purer state. Because of the relationship between the new compounds in free base form and their salts, it will be understood that the corresponding salts are included within the scope of the invention.
...
The starting materials are known or may, if they should be new, be obtained according to processes known as per se.
In clinical use the compounds of the invention are administrated orally, rectally or by injection in the form of a pharmaceutical preparation which contains an active component either as a free base or as a pharmaceutically acceptable, non-toxic acid addition salt, such as hydrochloride, lactate, acetate, sulfamate, in combination with a pharmaceutically acceptable carrier.
[Emphasis added] (Applicants' Record (AR, pp. 1821-1829)
[47] With respect to the 5129 Application, Astra is correct in its submission that the disclosure explicitly advises that: the free base of omeprazole, also called the neutral form, and the acid addition salt are included within the scope of the applied for invention; no reference is made to base addition salts; and there are repeated references to acid addition salts throughout the disclosure, including examples and disclosure of acids for use in making the acid addition salts.
[48] Apotex's allegation of anticipation with respect to the 5129 Application, and in particular with respect to the passages emphasised in the quote just provided, is that the drafter of the document intended that the skilled reader should read in words that do not appear. That is, even though no mention is made of base addition salts, a skilled reader would know they are included. This argument is based on a suggested interpretation of key passages in the document, in particular, the key phrase "therapeutically acceptable salt thereof". Allegation A.(i) of the NOA provides the content for this argument, the acceptance or rejection of which affects the relevance of the allegations which follow:
ANTICIPATION
A. European Patent Application No. [EP 5129] described and claimed base addition salts of omeprazole and pharmaceutical compositions which contained base addition salts of omeprazole. More particularly:
(i) Claims 1 to 6 of [EP 5129] disclose a class of compounds and a "therapeutically acceptable salt thereof". The phrase "a therapeutically acceptable salt thereof" is a term of art which describes and encompasses both the acid addition and base addition salts of the members of this class of compounds. Included within this class of compounds is a disclosure of the compound omeprazole and each of the base addition salts of omeprazole [Emphasis added];(AR, p.12)
[49] Apotex's argument depends on a finding that base addition salts of omeprazole are included within the key phrase "therapeutically acceptable salt thereof" as alleged in paragraph (I) quoted and emphasised above. To deal appropriately with this argument, it is first necessary to interpret the contents of the 5129 Application.
[50] The question is: Would a person skilled in the art be given such clear direction that, by reading and following the 5129 Application, in every case without possibility of error, be lead to the invention in Patent 751, being the base addition salt of omeprazole? In my opinion, the answer is "no", unless Apotex's "term of art" interpretation argument succeeds.
a. "therapeutically acceptable salt thereof" as a term of art
[51] The plain meaning interpretation of the key phrase "therapeutically acceptable salt thereof" would lead a reader to ask the question: "What salts?", to which the response would come: "Well, only those considered to be therapeutically acceptable." The responder might then go on to say: "It appears from the fact that only acid addition salts are mentioned in the document, that only acid addition salts are considered therapeutically acceptable". The following emphasised sentence from the 5129 Application appears to confirm this conclusion:
Depending on the process conditions and the starting materials, the end product is obtained either as the free base or in the acid addition salt, both of which are included within the scope of the invention. Thus, basic, neutral or mixed salts may be obtained [Emphasis added]
[52] However, Apotex makes the argument that a person skilled in the art would read the key phrase "therapeutically acceptable salt thereof" quite differently, and in such a way as to know that both acid and base addition salts are included. This argument is based on the statement that "therapeutically acceptable salt thereof" is a term of art; as cited above, in the NOA, Apotex chose to allege that:
"therapeutically acceptable salt thereof" is a term of art which describes and encompasses both the acid addition and the base addition salts of the members of this class of compounds. Included within this class of compounds is a disclosure of the compound omeprazole and each of the base addition salts of omeprazole.
[Emphasis added]
[53] The New Shorter Oxford English Dictionary (1993 ed.) defines " term of art" as:
a word or phrase used in a definite or precise sense in some particular subject or discipline; a technical expression.
[54] Apotex relies on the affidavit evidence of Dr. McClelland to prove the point in issue as follows:
16. These claims do not limit the nature of the salt form. A person skilled-in-the-art examining structure III at the time of this patent would immediately recognize that structure III would form both base addition salts and acid addition salts. The formation of base addition salts would be apparent because of the presence of the benzimidazole with the acidic hydrogen at position 1. By the time of the '129 patent, benzimidazoles were well established to readily form base addition salts. A number of patents have appeared disclosing and/or claiming base addition salts of benzimidazoles (see my discussion in paragraphs 64-68 in this Affidavit). Moreover, compound III was of such a structure that one would immediately and inevitably deduce that these compounds were significantly more acidic than the parent benzimidazole itself, so that stable base addition salts would be easily and readily formed with a number of bases (see my discussion in paragraphs 38-63 of this my Affidavit).
17. Apotex document 100 is an article from 1977 published in the Journal of Pharmaceutical Sciences entitled "Pharmaceutical Salts". Table 1 of this article contains a list of FDA-approved commercially marketed salts. This table contains a listing with the heading "Anion", which a person skilled-in-the-art would interpret as applying to acid addition salts. The listing with the heading "Cation" would be recognized by persons skilled in the art as referring to base addition salts. It can be seen that the latter list contains lithium (Li+), sodium (Na+), potassium (K+), magnesium (Mg+2) and calcium (Ca+2), cations that appear in claim 1 of the '751 patent. My conclusion is that, by 1977, the term "therapeutically acceptable salt" was recognized as including both acid addition salts and base addition salts; under the latter category were included salts of Li+, Na+, K+, Mg+2 and Ca+2. (AR, p.5962)
[55] In my opinion, Dr. McClelland's evidence does not offer proof of the allegation that "therapeutically acceptable salt thereof" is a term of art. From his evidence we know that, from the 5129 Application formula, both base addition and acid addition salts can be formed. This is not a contested fact in the present case. We also know that by 1977, some base addition salts were FDA approved. However, in my opinion, these facts do not give any credence to the opinion that the phrase "therapeutically acceptable salt thereof" is a term of art.
[56] One might expect that if it were a term of art some history and context for the use of the term would be provided, and perhaps examples would be given to prove the point in issue. That is, the issue is not whether base addition salts could be produced, or whether some were considered safe, the issue is whether the four words used in the phrase to be interpreted, as a result of usage and acceptance, have a meaning not evident; that is, they are a pointer to an understanding which is unexpressed.
[57] The phrase "judicial notice" comes to mind as an example of a term of art. All lawyers know what it means, but who else could? The phrase gives no clue as to its meaning, but for those skilled in the art of law, it points to an understanding which is unexpressed: notorious facts can be accepted as evidence without the necessity of formal proof.
[58] In my opinion, the evidence supplied by Dr. McClelland, and the like evidence of Drs. Chowhan, Hendrickson, and Rhodes (see RR, footnotes 55 and 56 for references), does not prove on any standard that "therapeutically acceptable salt thereof" is a term of art. Therefore, I find that it has no special meaning beyond that communicated by the context in which it is used in the present case being the 5129 Application.
[59] A great deal of effort has been spent by both sides of the present case to give meaning to the words of Application 5129. As decided above, the burden rests with Apotex to provide evidence strong enough to prove, on a balance of probabilities, that the Patent is invalid. With respect to the point under discussion, Apotex chose to prove that the key phrase "therapeutically acceptable salt thereof" has special meaning; it has failed to do so. Thus the skilled person Dr. McClelland speaks of is not really applying the science of chemistry when he or she tries to interpret the 5129 Application, but instead is grappling with language problems, which in my opinion, does not render as probable the interpretation argued by Apotex.
[60] As a result of the analysis, I do not accept Apotex's "term of art" argument.
b. the effect of other phrases
[61] Apotex alleges as follows:
(ii) Specific reference is made in [EP 5129] at page 7, line 38, to the inclusion of "basic, neutral or or [sic] mixed salts as well as hemi, mono, sesqui or polyhydrates" as being within the scope of the invention. The use of the term "basic" is a term of art which describes and encompasses a base addition salt, and within the meaning of [EP 5129] means base addition salts [Emphasis added]; (AR, p.2)
[62] Apotex argues that the emphasised portion of the phrase from the 5129 Application, already quoted above, provides some evidence that base addition salts are intended to be included in it:
Depending on the process conditions and the starting materials, the end product is obtained either as the free base or in the acid addition salt, both of which are included within the scope of the invention. Thus, basic, neutral or mixed salts may be obtained
[63] As the argument goes, in the context of the 5192 Patent, the reference to "basic" salts is necessarily a reference to base addition salts and would be so understood by a person skilled in the art. This argument is based on the allegation that "basic" is a term of art. As was the case with respect to the finding that "therapeutically acceptable salt thereof" is not a term of art, I find no evidentiary basis for the allegation that the term "basic" is a term of art. Thus, I find this allegation is not proved on a balance of probabilities.
[64] On a second approach to the interpretation of the phrase, Apotex argues that it would be clear to a person skilled in the art that the only salts of the compounds of Formula III which are capable of producing a basic solution are base addition salts; thus, the term "basic salt" as applied to omeprazole would necessarily mean a base addition salt of omeprazole.
[65] I cannot find that Apotex has met its burden of proof with respect to this argument. First, as an evidentiary matter on the record, whether an acid addition salt can produce a basic solution is a seriously contested point of fact in the present case, and second, there is no evidence to say what the opinion of the drafters might have been on this point at the time the document was drawn. In addition, I agree with Astra that the use of the word "thus" points away from an intention to mean base addition salts and towards the acid addition salts mentioned in the proceeding sentence. Thus, I find that Apotex has not proved this allegation on a balance of probabilities.
[66] In its written fact and law statement, Apotex makes a further argument with respect to the interpretation of the 5129 Application.
[67] Claim 1 in the 5129 Application claims "a compound of formula III or a therapeutically acceptable salt thereof in which R1 and R2 are...". Each of claims 5 and 6 claim " a compound according to claim 1 or a therapeutically acceptable salt thereof in which R1 and R2 and R6 have...". However, claim 8 claims "a pharmaceutical preparation for inhibiting gastric acid secretion, characterized in that it contains as active agent a compound of formula III or a pharmaceutically acceptable non-toxic acid addition salt thereof in a therapeutically effective amount in which R1 and R2 are...". Claim 9 claims a pharmaceutical preparation according to claim 8 "or a pharmaceutically acceptable non-toxic addition salt thereof". It is agreed that the fact that "acid" is not mentioned in claim 9 is a typographic error.
[68] Apotex asks that significance be placed on the difference between the wording in claims 1, 5, and 6 and claim 8. Apotex argues that its interpretation of "therapeutically acceptable salt thereof" includes both base and acid addition salts is reinforced by the fact that claim 8 contains a limitation to acid addition salt which does not appear in the general phrase. Dr. McClelland's affidavit evidence on this point is as follows:
18. Recognizing that compounds of formula III of EP 5129 patent can form both types of salts, a person-skilled-in-the-art would read the term "therapeutically acceptable salts" that appears in claims 1, 5 and 6 as including both acid addition salts and base addition salts. Claim 8, on the other hand, contains the phrase "a compound of formula III or a pharmaceutically acceptable non-toxic acid addition salt thereof." This claim 8 does limit the nature of the salt form to acid addition salts. That a similar limitation does not appear in claims 1, 5 and 6 would be understood by persons skilled in the art as meaning that there is no limitation to the nature of the salt in these claims, i.e. that base addition salts are also included. (AR, p.5962)
[69] Again, in my opinion, the person skilled in the art is trying to find a solution to a language not a chemistry problem. As a result, I give no weight to the opinion as expert evidence. The language of the 5129 document is what it is: difficult. I am not prepared to put weight on the difference between the claims to add words which are not there.
[70] From the plain meaning of the words in the 5129 Application read in full context, I find that acid addition salts are clearly claimed within the scope of the claimed invention. For the reasons just provided, I cannot find that, on a balance of probabilities, a person skilled in the art would read the words so as to conclude that base addition salts are also claimed.
3. The "inevitability" of producing base addition salts
[71] Apotex alleges as follows:
(iii) [EP 5129] discloses the compound omeprazole and its therapeutically acceptable salts and pharmaceutical compositions which contain such compounds. The practice of this teaching to prepare a pharmaceutical preparation of the disclosed compound omeprazole by a person skilled in the art would have inevitably resulted in the preparation and use of the base addition salts of omeprazole. As part of routine pre-formulation studies that are conducted in order to prepare a pharmaceutical preparation for omeprazole, a study of stability of omeprazole at various pH levels and the solubility of omeprazole would be required. Studies of the stability and solubility of omeprazole in a basic solution would have occurred. The result of dissolving omeprazole in a basic solution would have been the formation of a base addition salt of omeprazole. Furthermore, the physical and chemical characteristics of omeprazole are such that the stability and solubility of omeprazole are maximized at a basic pH level. The inevitable result of these studies would have been the use of a base addition salt of omeprazole for an omeprazole pharmaceutical composition as would be understood by persons skilled in the art from [EP 5129];
(iv) [EP 5129], at page 8, describes the treatment of acid addition salts of the class of compounds described by formula III with a basic agent such as alkali in order to convert the compound to its corresponding free base. The practice of this teaching by persons skilled in the art, with respect to the acid addition salts of omeprazole, a member of this class of compounds, would have inevitably resulted in the production of a base addition salt of omeprazole;
(v) [EP 5129], at page 10, describes and teaches aqueous preparations of the compounds of formula III intended for use as pharmaceuticals. Omeprazole is a member of the class of compounds within formula III. The physical and chemical characteristics of omeprazole are such that it is only soluble at a basic pH level and also only stable at a basic pH level. As such, a person skilled in the art practising these teachings would have inevitably made a solution of omeprazole with a basic pH level, thus forming a base addition salt of omeprazole;
(vi) [EP 5129], at page 5, describes a process for making the general class of compounds of formula III by a process of reacting a compound of formula V with a compound of formula VI. The formula V compound is a potassium, sodium or lithium base addition salt. A person skilled in the art using this process to make omeprazole would have inevitably made a potassium, sodium or lithium base addition salt of omeprazole since the use of sufficient base required in order to allow the reaction to proceed would result in the production of such base addition salts of omeprazole;
(vii) Included within the scope of the claims of the '751 Patent, are hydrated forms of the base addition salts of omeprazole and compositions that contain such hydrates. (AR, pp.11-31)
[72] At issue in the present case is the validity of the 751 Patent which makes claim to base addition salts of omeprazole. Apotex argues that the 5129 Patent Application is a prior single publication from which a person skilled in the art would, without the exercise of inventive skill, find all the information which, for practical purposes, is needed to produce base addition salts . To achieve this, the 5129 Application must contain so clear a direction that a skilled person reading and following it would, in every case and without possibility of error, be led to the claimed invention.
[73] Apotex has failed to prove on a balance of probabilities that base addition salts are included in the claims of the 5129 Application. As a consequence, persons skilled in the art would not receive clear direction that would lead to the formulation of base addition salts. Thus, in my opinion, allegations (iii) to (vii) just quoted, which allege that solution studies of omeprazole would result in the formation of base addition salts, are irrelevant to the issue of whether the 5129 Application is a prior publication within the meaning of the test for anticipation.
[74] As a result, I am unable to find on a balance of probabilities that the 5219 Application is a prior single publication required by the test for anticipation.
2. Was the invention in the Patent in prior use?
[75] Apotex's secondary anticipation argument is that the invention that the Patent claims was in use prior to its filing, which, by s.27(1)(a) of the Patent Act, would make the Patent invalid. In this respect, Apotex's allegation is as follows:
B. Base addition salts of omeprazole were known and used prior to the alleged invention by the named inventor of the '751 patent Arne Brändström. I.v. and oral dosages of omeprazole were used in the treatment of patients with Zollinger-Ellison Syndrome prior to on or about June of 1982. The details of this prior use are disclosed in the article entitled "Control of Acute Zollinger-Ellison Syndrome with Intravenous Omeprazole", The Lancet, November 27, 1982, [Apotex Document #3] The i.v. and oral dosages used at this time contained base addition salts of omeprazole.
C. Base addition salts of omeprazole were known and used prior to the alleged invention by the named inventor of the '751 patent Arne Brändström. Oral dosages of omeprazole were used in the treatment of patients with Zollinger-Ellison Syndrome. The details of this prior use were disclosed at a World Congress of Gastroenterology (Stockholm, June 1982). The oral dosages used at this time contained base additional salts of omeprazole.
D. Base addition salts of omeprazole were known and used prior to the alleged invention by the named inventor of the '751 patent Arne Brändström. During public human studies conducted in June 1980 by Astra a suspension of omeprazole and an alkaline aqueous phase was used.
E. Base addition salts of omeprazole were known and used prior to the alleged invention by the named inventor of the '751 patent Arne Brändström. During public Phase II bioavailability studies conducted in 1981 by Astra base addition salts of omeprazole were used. (AR, pp.15-16)
[76] The disclosure mentioned in paragraph (B) is a letter to the editor of the November 17, 1982 issue of the medical journal The Lancet. The article refers to a case description of a man who received an oral dose of omeprazole for treatment of a perforated jejunal (duodenal) ulcer. Apotex argues that omeprazole must have been administered as a solution containing a base addition salt. As the argument goes, it would be apparent to any skilled formulator that: because acid addition salts of omeprazole are relatively unstable in aqueous solutions, neutral omeprazole is very slightly soluble in water, the compound has acceptable stability in alkaline solutions, and the dose injected was 60mg three times per day, therefore, the choice would have been to formulate the injection with a soluble base addition salt.
[77] However, because only neutral omeprazole is mentioned in the letter, Astra argues that there is nothing to support the view that base addition salts were made and then administered. I agree. I find that Apotex's argument relies on what amounts to expert speculation, and, as a result, I give it no weight. Therefore, I find that Apotex's evidence does not prove prior use on a balance of probabilities.
[78] While Apotex makes allegations that public human studies and bioavailability studies prove prior use, no such evidence was produced. Therefore, I find there is no proof of these allegations.
E. The attack of obviousness
[79] The major difference between anticipation and obviousness is that anticipation requires an exact prior description in a single source (Creations 2000 Inc. v. Canper Industrial Products Ltd. (1990), 34 C.P.R. (3d) 178, per Hugessen J.A. at 182 (F.C.A.), while obviousness can be based on everything from a single disclosure to a "mosaic" of the prior art (Beloit v. Valmet, supra at 294). Both are questions of fact. (Rothmans, Benson & Hedges Inc. v. Imperial Tobacco Ltd. (1993), 47 C.P.R. (3d) 188 per Desjardins J.A. at 198 (F.C.A.).
[80] The test for obviousness is stated in Beecham Can. Ltd. v. Proctor & Gamble Co. (1982), 61 C.P.R. (2d) 1 at 27 (Fed. C.A.) per Urie J., leave to appeal to S.C.C. refused (1982), 63 C.P.R. (2d) 260n (S.C.C.) as follows:
The question to be answered is whether at the date of the invention....an unimaginative skilled technician, in light of his general knowledge and the literature and information on the subject available to him on that date, would have been led directly and without difficulty to [the] invention.
[81] The test was also more recently stated in Beloit v. Valmet, supra by Justice
Hugessen where at 294 he says:
...The classical touchstone for obviousness is the technician skilled in the art but having no scintilla of inventiveness or imagination; a paragon of deduction and dexterity, wholly devoid of intuition; a triumph of the left hemisphere over the right. The question to be asked is whether this mythical creature (the man in the Clapham omnibus of patent law) would, in light of the state of the art and of common general knowledge as at the claimed date of invention, have come directly and without difficulty to the solution taught by the patent. It is a very difficult test to satisfy.
[82] Apotex's allegation on obviousness is as follows:
OBVIOUSNESS
The '751 Patent claims a priority filing date of March 4, 1983 from Swedish Patent Application no. 8301182.5. Taking this date as the latest date for determining obviousness, Apotex alleges that the '751 Patent and each of the claims of the '751 Patent is invalid on the basis that the subject matter of the '751 Patent and each of these claims is obvious and non-inventive having regard to the state of the art. Apotex relies on the factual basis set out above which establish the anticipation of the claims of the '751 Patent in support of its allegation that the claims of the '751 Patent are also obvious. In addition to the factual bases set out above, Apotex relies on the following in further support of its allegation of obviousness.
(i) [EP 5129] disclosed the compound omeprazole. Omeprazole contains two heterocyclic ring systems, a substituted benzimidazole and a pyridine ring. The conversion of omeprazole into its base addition salt is effected by the removal of a proton from the benzimidazole ring portion of omeprazole. The following were well known to persons skilled in the art:
(a) acid-base type chemical reactions;
(b) the removal of a proton from a benzimidazole moiety to form the corresponding base addition salt;
(c) the pKa of unsubstituted benzimidazole is approximately 13 and that unsubstituted benzimidazole readily forms a base addition salt;
(d) the effect of various substituent groups on the pKa of a molecule, in particular, in the case of omeprazole, the S-O group (sulfoxide) in omeprazole would have the effect of lowering, relative to unsubstituted benzimidazole, the pKa of the proton on the benzimidazole moiety; and
(e) the omeprazole would readily react with an alkaline reagent to give a base addition salt.
Support for the above allegations are found in the following documents: [Apotex Documents 4 through 12 omitted].
Therefore, having known of the compound omeprazole and the prior art teachings discussed above, there would have been no invention in making base addition salt of omeprazole.
In support of the allegations of anticipation and obviousness, Apotex relies on the further following documents which teach the pre-formulation studies were a routine part of the preparation of a pharmaceutical composition: [Apotex Documents 121 through 128 omitted] (AR, pp.16-20)
1. State of the art
[83] One of the central issues in the present application is an evaluation of the state of the art in medicinal chemistry at the time of filing of the patent application.
[84] The invention claimed in the 751 Patent is the discovery of the therapeutic value of base addition salts of omeprazole, and, in particular, the magnesium salt. As the Patent states: "the present invention provides such new forms of omeprazole which exhibit improved storage stability" (AR, p.49).
[85] Apotex alleges that the formulation of base addition salts of omeprazole was known in the art at the time of the filing of the 751 Patent. In order to prove this allegation, Apotex relies on the affidavit of Dr. Hendrickson, in which he makes the following comments:
10. The acid addition salts of Omeprazole are somewhat more frequently mentioned in the body of the EP 5129 patent application. The basic pyridine nitrogen is well known to form acid addition salts. The benzimidazole part requires a strong base to form its salt. This is because the simple benzimidazole has a pKa of 12.78.
11. However, the substitution of an electron-withdrawing group onto the 2-position of benzimidazole was well known to chemists before 1980 to dramatically lower the pKa. Common electron-withdrawing groups include carbonyls (C=O) as in ketones and esters, and sulfonyls (S=O) as in sulfoxides and sulfones. In particular their effect on acidity of benzimidzoles was most clearly described by Butchel et al in 1970 (Doc. 63), who showed that the pKa of benzimidazole itself dropped to 10.95 with an ester in the 2-position and further to 8.55 with a methylsulfone. ...
12. Omeprazole is a benzimidazole-2-sulfoxide, and the actual pKa of omeprazole was measured as 8.8 (doc 129, 1985) in good agreement with the earlier prediction from the interpolation above. As its pKa is below 10, this clearly means that omeprazole will dissolve easily in a weak NaOH solution to fully form its base addition salt. However, as remarked above, even without this particular literature documentation, the enhanced solubility of omeprazole in weak NaOH solution would have been observed in the earliest synthetic work, and the chemists would have certainly recognized formation of the base addition salt in this observation alone.
13. All of the acid-base chemistry was well-known to any practising synthetic chemist, who would directly recognize the formation of a base addition salt on adding alkaline reagents to Omeprazole. This is of course implicit in the statement in the patent application that "Basic, neutral or mixed salts may be obtained". (AR pp. 1745-1746)
[86] In response, Astra submits that the formulation of base addition salts, while known in chemistry, was not part of the prior art with respect to the production of pharmaceutical compounds. In support of its position, Astra relies on the affidavit of Dr. Amidon, which states as follows:
112. In my view, the salts of the 751 patent and their advantages would not have been obvious to the average skilled person in the art in 1983 for the following reasons:
(i) A skilled person would have had no motivation to prepare base addition salts of omeprazole and such salts would not have been prepared;
(ii) Assuming a skilled person decided to prepare base addition salts of omeprazole then the enhanced stability could not be predicted.
(iii) No Motivation to Prepare Base Addition Salts of Omeprazole
113. While Apotex asserts in the September 4 letter certain facts regarding benzomidazoles and their ability to form base addition salts, nowhere does Apotex address why someone would be motivated to try and make base addition salts of omeprazole in the first place.
114. In my opinion, for the reasons I will set out, there would have been no motivation to synthesize and test such salts. In particular, a skilled person seeking to formulate omeprazole would have found that the compound had adequate characteristics to be developed as a neutral compound.
115. In particular, the free base omeprazole met the minimum standards for development:
sufficient activity
acceptable stability for purposes of synthesis and handling by the medicinal chemist
adequate solubility
acceptable toxicity profile
acceptable melting point
116. Support for this view can be seen from the following facts regarding omeprazole.
117. First, neutral omeprazole is marketed in the United States (under the trade name Prilosec) confirming that the neutral free base was adequate for development purposes.
118. Second, EP 5129 discloses that neutral omeprazole has a melting point of 156 C which is more than high enough for pharmaceutical processing. As a result a salt would be unnecessary as the melting point is sufficiently high to permit pharmaceutical formulation and processing.
119. Third, in Apotex Document #129 entitled "Development of an oral formulation of omeprazole" the solubility is reported by 0.1mg/ml. While low, the solubility is adequate for development purposes, given the relatively low dose used for omeprazole (Numerous pharmaceutical products are administered orally with solubilities of 0.001 to 0.03 mg/ml, e.g piroxicam, glyburide, digoxin, solubilities as much as 10 to 100 fold lower than that of omeprazole). Further, it is apparent from the article that omeprazole has adequate dissolution properties. As a result, the skilled person would not make a salt in order to improve solubility or dissolution properties.
120. Fourth, there are references in the art as of 1982 that show the administration of omeprazole free base. Both EP5129 and The Lancet article (Apotex Document #3) teach administration of the free base. In EP5129 a suspension of omeprazole was administered to dogs; in The Lancet publication the suspension was administered orally to humans.
121. Even if the skilled person considered whether to try and prepare a base addition salt, such person would have dismissed the idea as unnecessary and resulting in needless delay in the development of the drug for human use.
122. First, since the 158 patent disclosed only the preparation of acid addition salts, the implication to a skilled person would be that base addition salts of formula III could not be readily prepared.
123. Second, the skilled person would have been concerned about the basicity of any base addition salts of omeprazole that might be prepared. The skilled person would expect that omeprazole would be only weakly acidic. Any resulting base addition salts would be quite basic in solution. Indeed I understand from counsel that a post-1983
publication discloses that the pKa for the benzomidazole portion of omeprazole is 8.7.
124. Based on a pKa of 8.7, a skilled person would have thought a base addition salt was too basic to be useful in formulating parenteral formulations. For example, omeprazole sodium salt would be expected to have a solution pH of around about 11. A skilled formulator would appreciate that this was not desirable for an intravenous formulation and would recognize that steps would need to be taken to reduce the pH of the solution. However, as the pH of the solution was buffered down towards a more neutral pH, the predominate form of omeprazole in solution would have been the free base and there would be the same difficulties with the solubility of the formulation. The solubility of the salts and free base of omeprazole is essentially the same at any given solution pH, resulting in no advantage in making the salt for an i.v. solution.
125. Similarly, the skilled person would be discouraged from using a very basic compound in an oral formulation as such salts can have unwanted biological effects. For example, the potassium salt of indomethacin was removed from the market when it was found that it induced lesions in the intestine.
126. Indeed, a skilled person looking ahead to both an oral and i.v. formulation utilizing the same active ingredient might conclude that a more appropriate method of dealing with the acid sensitivity and insolubility of neutral omeprazole in the i.v. formulation would be to prepare a solubilized formulation of omeprazole using a suitable co-stabilizing agent a method well known in the art. This would suggest to a skilled person that they ought to avoid preparation of a salt altogether. (AR pp. 184-187)
[87] Astra also relies on the transcripts of the cross-examination of Dr. Chowhan with respect to the 5129 Application as prior art as follows:
Q. You may recall that the European Application gives a number of examples of acid addition salts. That would be part of the prior art. Right?
A. Right.
Q. The person assigned the task of formulating omeprazole could have that European Application. Right?
A. Right.
Q. They would see in there acid addition salts. Right?
A. Right.
Q. They would not see in there examples of base addition salts?
A. No.
Q. Sorry, are you agreeing with me?
A. Yes, I do.
Q. Am I correct that one of the first things the person would do would be to proceed to make acid addition salts because they are looking at a document where acid addition salts have been made, and they would then start to investigate acid addition salts? Right?
A. Yes, correct. They would investigate both the neutral compound and the acid addition salt.
Q. From the fact that the literature shows that acid addition salts were made and there is no reference to base addition salts, it would be natural for the skilled person to focus on acid addition salts?
A. Yes. (AR, pp. 4006-4007)
[88] In support of its argument that the invention claimed in the Patent was not obvious, Astra argues that, in the production of pharmaceutical compounds, while a skilled formulator could have produced a base addition salt of omeprazole, he or she would not have done so. This is so because, at the time of the filing of the 751 Patent, the prevailing knowledge was that the base addition salt of omeprazole is a compound that is too basic, and thus too reactive, to be useful for pharmaceutical administration. In this respect, I put weight on the evidence of Dr. Amidon. Also as evidence that this was the understanding of the state of the art in the actual development of pharmaceutical compounds, I put weight on the confidential evidence of Dr. Berntsson (AR, pp.5876-5877, paragraphs 43 to 49).
[89] I am satisfied on the evidence that there was sufficient teaching away from the use of base addition salts so as to discourage a formulator from exploring beyond normal pH values (i.e. 7-8). This fact is clearly demonstrated by the following passage from the cross examination of Dr. Lee-Ruff:
Q. You would appreciate that, if things are very acidic or very basic, they can be caustic to human tissues?
A. Yes.
Q. For example, you, as a chemist, would not want someone to pour a very acidic solution on your hands. Am I correct?
A. You are correct.
Q. Equally, if I put before you a bottle of water and I said the pH in that bottle of water was 12, would you be a little apprehensive about drinking that?
A. I certainly would.
Q. If that pH in that bottle of water was 11, would you also be apprehensive?
A. Yes.
Q. That would be because you would be concerned that the level of basicity could irritate the tissue in the esophagus or somewhere from the mouth down to your stomach.
A. Yes. (AR, p.4475-4476)
[90] Apotex relies on its solution studies evidence as proof that the invention claimed in the 751 Patent, being the discovery of the stability characteristics of the base addition salts of omeprazole, would be obvious to a person skilled in the art conducting solution studies of omeprazole. In response, Astra argues that the solution studies evidence does not assist Apotex to discharge its burden of proof because, since the base addition salts of omeprazole are solid compounds which do not exist in solution, solution studies cannot provide an accurate prediction of the stability of the solid compound. I accept Astra's argument. In particular, the following passage from the cross-examination of Dr. Lee-Ruff is on point:
Q. A compound that is unstable in solution could be stable in the solid state. Correct?
A. Conceivably, yes.
Q. That is because there are properties that affect solid state stability that are really divorced from what one would see in a solution environment.
A. Yes-can I qualify?
Q. Yes.
A. Not always because compounds which are very hygroscopic will tend to form what are called micro solutions at the surface which behave similarly to the solution phase.
.....
Q. We are just talking as a general matter. I know you are saying that in some cases- let's keep it at a general level. While you did qualify and you indicated that in some cases you would see certain things, you do accept as a general matter that one cannot predict accurately solid state stability from solution stability studies.
A. In general, that is true, yes. (AR, pp. 4495-4496)
[91] In conclusion, I find that upon considering the evidence and argument advanced by both Apotex and Astra, Apotex has not proved its allegation of obviousness on a balance of probabilities.
F. Other grounds of attack
1. Double patenting and obviousness type double patenting
[92] Apotex's allegation is as follows:
DOUBLE PATENTING
Base addition salts of omeprazole, including magnesium omeprazole, and pharmaceutical compositions containing such salts of the '751 Patent are specifically covered by the claims of Canadian Letters Patent No. 1,127,158, now expired. In the alternative, if claims of Canadian Letters Patent 1,127,158 only cover the compound omeprazole and its acid addition salts, Apotex alleges that there is nothing further inventive in preparing the base addition salts of omeprazole or compositions containing such salts. Therefore, the claims of the '751 Patent are invalid on the basis of same invention double patenting and/or obviousness type double patenting.
[93] Given the findings above rejecting the allegations of anticipation and obviousness, I find that Apotex has failed to provide any proof of this allegation.
2. Inutility
[94] Apotex's allegation is as follows:
INUTILITY
Apotex further alleges that claims 8 to 11 of the '751 patent are invalid on the basis that these claims contain within their scope embodiments which lack utility as pharmaceutical composition. Claims 8 to 11 relate to pharmaceutical compositions which comprise as the active ingredient one of the specified base addition salts of omeprazole. Included within the scope of these claims are parenteral solutions for intravenous use which contain one of the base addition salts of omeprazole as the active ingredient. Included within the scope of each claim is a parenteral solution for intravenous use which contains either magnesium or calcium omeprazole as the active ingredient. However, the chemical and physical properties of magnesium or calcium omeprazole are such that they are essentially insoluble in water. Such property renders them unsuitable for the preparation of a therapeutically acceptable parenteral solution for intravenous use.
[95] Since Apotex did not maintain this allegation in argument, I am unable to conclude that it has been proved.
G. Conclusion
[96] With respect to the presumption that the 751 Patent is valid, it important to recall Justice Sharlow's finding in Bayer, supra:
The operation of the statutory presumption in the face of evidence of invalidity depends upon the strength of the evidence. If the evidence proves on a balance of probabilities that the patent is invalid, the presumption is rebutted and is no longer relevant: Diversified Products Corp. v. Tye-Sil Corp. (1991), 35 C.P.R. (3d) 350 (F.C.A.) at 359.
[97] Given the findings made with respect to the allegations in the NOA, I find that, on the whole of the evidence produced by Apotex, Apotex has failed to prove, on a balance of probabilities, that the 751 Patent is invalid. Thus, I find that the presumption that the Patent is valid is not rebutted.
O R D E R
Accordingly, for the reasons provided, I hereby make an order prohibiting the Minister of Health from issuing a Notice of Compliance to the Respondent, Apotex Inc., until after the expiration of Canadian Patent 1,264,751.
I award costs to the Applicant.
(Sgd.) "Douglas R. Campbell"
Judge
VANCOUVER
TRIAL DIVISION
Date: 20030620
Docket: T-1914-01
BETWEEN:
AB HASSLE & ASTRAZENECA CANADA INC.
_ Applicants
- and -
APOTEX INC. & THE MINISTER OF HEALTH
Respondents
REASONS FOR ORDER AND ORDER
FEDERAL COURT OF CANADA
TRIAL DIVISION
NAMES OF COUNSEL AND SOLICITORS OF RECORD
DOCKET: T-1914-01
STYLE OF CAUSE: AB HASSLE & ASTRAZENECA CANADA INC.
Applicants
- and -
APOTEX INC. & THE MINISTER OF HEALTH
Respondents
PLACE OF HEARING: TORONTO, ONTARIO
DATE OF HEARING: JUNE 3, 4, 5, 2003
REASONS FOR ORDER
AND ORDER BY: HON. JUSTICE CAMPBELL
DATED: FRIDAY, JUNE 20, 2003
APPEARANCES: Mr. Gunar Gaikis
Mr. Sheldon Hamilton
Ms. Sally Hemming
FOR THE APPLICANTS
Mr. H. Radomski
Mr. A. Brodkin
Mr. R. Tuzi
FOR THE RESPONDENT
APOTEX INC.
Morris Rosenberg
Deputy Attorney General of Canada
FOR THE RESPONDENT
THE MINISTER OF HEALTH
SOLICITORS OF RECORD: Smart & Biggar
Toronto, Ontario
FOR THE APPLICANTS
Goodmans
Toronto, Ontario
FOR THE RESPONDENT
APOTEX INC.
Morris Rosenberg
Deputy Attorney General of Canada
FOR THE RESPONDENT
THE MINISTER OF HEALTH