Ottawa, Ontario, January 12, 2007
PRESENT: The Honourable Mr. Justice O'Reilly
BETWEEN:
PFIZER CANADA INC. and PFIZER INC.
and
THE MINISTER OF HEALTH
REASONS FOR JUDGMENT AND JUDGMENT
[1]
Apotex seeks to market tablets containing sildenafil, a
compound for which Pfizer owns a patent. Sildenafil is the active ingredient in
Pfizer’s medicine called Viagra (used in the treatment of erectile
dysfunction), as well as in another called Revatio (for pulmonary hypertension),
which are the subject of other patents.
[2]
Pfizer seeks an order prohibiting the Minister of Health
from issuing Apotex a Notice of Compliance under the Patented Medicines
(Notice of Compliance) Regulations, SOR/93-133, as amended. The Notice of
Compliance would permit Apotex to put its sildenafil tablets on the market.
Apotex alleges that Pfizer’s patent is invalid and, therefore, that Pfizer is
not entitled to the prohibition order it seeks. To obtain a prohibition order,
Pfizer must prove that Apotex’s allegations are unjustified. I find that Pfizer
has failed to do so and, therefore, I must dismiss Pfizer’s application.
I. Issue
[3]
Has Pfizer established that Apotex’s allegations challenging
the validity of Canadian Patent No. 2,044,748 patent are unjustified?
II.
Analysis
(a) Proceedings under the Notice of Compliance (NOC)
Regulations
[4] Proceedings under these Regulations serve a limited purpose. They provide an expeditious means of determining of issues relating to the validity and scope of drug patents within the regulatory scheme governing manufacturers' rights to market their products in Canada. They are not equivalent to a civil action for patent infringement: Hoffmann-La Roche Ltd. v. Canada (Minister of National Health & Welfare), [1996] F.C.J. No. 1333 (C.A.) (QL), at para. 12. The Court's ruling under the Regulations is not binding in any subsequent action between the parties: Fournier Pharma Inc. v. Canada (Minister of Health), 2004 FC 1718, [2004] F.C.J. No. 2149 (T.D.) (QL).
(b) The Legal Burden of Proof on Pfizer
[5] In proceedings under the Regulations, the respondent commonly alleges that it will not infringe the applicant’s patent, or that the applicant’s patent is invalid, or both. Here, Apotex suggests that Pfizer’s ‘748 patent is invalid. As the applicant, Pfizer bears the legal burden of persuading me, on a balance of probabilities, that Apotex’s allegation of invalidity is unjustified: Pfizer Canada Inc. v. Novopharm Ltd., 2005 FCA 270, [2005] F.C.J. No. 1318 (C.A.) (QL). If it fails to do so, I cannot issue an order of prohibition.
[6] While the case law is clear about the legal burden on applicants, it is less so with respect to the burden that falls on respondents, especially where the presumption of validity applies (Patent Act, R.S.C. 1985, c. P-4, s. 43(2)) (relevant enactment are set out in an Annex). Some decisions suggest that respondents must prove invalidity on a balance of probabilities: Aventis Pharma Inc. v. Apotex Inc., 2005 FC 1283, [2005] F.C.J. No. 1559 (T.D.) (QL), aff’d 2006 FCA 64, [2006] F.C.J. No. 208 (C.A.) (QL); Aventis Pharma Inc. v. Apotex Inc., 2005 FC 1504, [2005] F.C.J. No. 1843 (T.D.) (QL). Others state that respondents must merely put their allegations “into play” and adduce evidence sufficient to rebut the presumption of validity: Bristol-Myers Squibb Canada Co. v. Novopharm Ltd., 2005 FC 1458, [2005] F.C.J. No. 1791 (T.D.) (QL); SmithKline Beecham Pharma Inc. v. Apotex Inc., 2001 FCT 770, [2001] F.C.J. No. 1118), aff’d 2002 FCA 216, [2002] F.C.J. No. 801 (C.A.) (QL); Pfizer Canada Inc. v. Canada (Minister of Health), 2005 FC 1205, [2005] F.C.J. No. 1607 (T.D.) (QL).
[7] The proposition that a respondent must prove invalidity on a balance of probabilities is traceable to the discussion of the presumption of validity of a patent in Bayer Inc. v. Canada (Minister of National Health and Welfare), [2000] F.C.J. No. 464 (C.A.) (QL). There, Justice Karen Sharlow of the Federal Court of Appeal stated that the presumption of validity is rebutted and no longer relevant where the respondent has proved invalidity on a balance of probabilities (para. 9). However, I do not take Justice Sharlow’s statement to be a definitive statement of the burden of proof on respondents. It is clear, as she stated, that a patent cannot be presumed to be valid in the face of proof to the contrary. This does not necessarily mean, however, that there is a legal burden on respondents to prove invalidity on the balance of probabilities.
[8] Section 43 of the Act states that patents are presumed to be valid in the absence of evidence to the contrary. As Justice Binnie has observed, this statutory presumption is “rather weakly worded” (Apotex Inc. v. Wellcome Foundation Ltd., [2002] 4 S.C.R. 153, at para. 43). If a respondent presents some reliable evidence of invalidity, the presumption falls away. The applicant must then do more than merely rely on the statutory presumption in order to obtain the relief it seeks. It must prove on a balance of probabilities that the respondent’s allegations are unsupportable. On the other hand, if the respondent’s allegations of invalidity are unsupported by reliable evidence, then the applicant can simply point to the presumption of validity and obtain its prohibition order without the need to disprove the respondent’s allegations.
[9] In my view, the burden on a respondent under the Regulations is an “evidential burden” – a burden merely to adduce evidence of invalidity. Once it has discharged this burden, the presumption of validity dissolves and the Court must then determine whether the applicant has discharged its legal burden of proof. I believe this is what is meant in those cases where the Court has stated that the respondent must put its allegations “into play”. It must present sufficient evidence to give its allegations of invalidity an air of reality.
[10] Of course, respondents will usually try to prove invalidity on a balance of probabilities in an effort to ensure that applicants fail to obtain the relief they seek. But it would be wrong to describe this as a legal burden. Only applicants shoulder a legal burden. Respondents merely bear an evidential burden, as described above. It is also fair to say that they carry a “tactical burden” - a burden of providing enough evidence to persuade the Court that an applicant should be denied the relief it seeks. If it fails to provide that evidence, the respondent runs the risk of losing its case.
[11] I have discussed the burdens falling on applicants and respondents in cases of alleged invalidity under the Regulations. I believe that the same principles apply where respondents allege that they will not infringe the applicants’ patents. However, it is unnecessary for me to say more on the subject, given that that the case before me relates solely to invalidity.
[12] To summarize, Pfizer bears the legal burden of proving on a balance of probabilities that Apotex’s allegations of invalidity are unjustified. Apotex merely has an evidentiary burden to put its case “into play” by presenting sufficient evidence to give its allegations of invalidity an air of reality. If it meets that burden, then it has rebutted the presumption of validity. I must then determine whether Pfizer has established that Apotex’s allegations of invalidity are unjustified. If Apotex does not meet its evidential burden, then Pfizer can simply rely on the presumption of validity to obtain its prohibition order.
[13] Apotex has clearly put its case “into play” through the reports and cross-examination of its experts. Its allegations of invalidity have an air of reality. I cannot presume, therefore, that Pfizer’s ‘748 patent is valid. I must determine whether Pfizer has proved that Apotex’s grounds for challenging the patent are unjustified based on the whole of the evidence.
(c) The ‘748 Patent
(i) The compounds
[14]
The ‘748 covers a very broad range of compounds - Apotex
says the number is 260 quintillion. However, Pfizer seeks to protect only one
compound: sildenafil. Accordingly, Pfizer argues that Apotex’s allegations are
unjustified in respect of two of the claims under the ‘748 patent – Claims 6
and 17. Claim 6 relates to sildenafil alone. Claim 17 refers to all of the
compounds covered by the patent (including, therefore, sildenafil) for use in
the treatment of four particular conditions: angina, hypertension, heart
failure and atherosclerosis.
[15] Pfizer says that the compounds identified in the ‘748 patent have certain biochemical properties that suggest they may be useful in the treatment of a wide range of conditions. To appreciate what these properties are, one must understand some basic features of the human involuntary nervous system and intracellular dynamics.
[16]
Our involuntary nervous system operates by
sending signals to parts of the body that need to react to certain stimuli.
Those signals are sent by chemical couriers – so-called “first messengers”.
Those messengers communicate with certain chemicals on or within human cells –
so-called “second messengers”. These second messengers stimulate the production
of other chemicals within the cell, and it is those substances that dictate the
response to the initial stimulus.
[17] Human cells also have a built-in control mechanism. At some point, the reaction to the initial stimulus must abate. That reaction is slowed by another process. Substances within the cell gradually neutralize the second messengers, so their signals and the corresponding physiological response gradually diminish and stop.
[18] An important first messenger in our body is nitrous oxide (NO). There are two main second messengers. They are both cyclic nucleotides (cyclic adenosine 3’5’-monophosphate and cyclic guanosine 3’5’-monophosphate), abbreviated as cAMP and cGMP respectively. The second messengers are neutralized by enzymes called phosphodiesterases, abbreviated as PDEs. Some PDEs react primarily to cAMP, some to cGMP, and some to both. Accordingly, some PDEs can be described as being predominantly cAMP PDEs or cGMP PDEs. Different areas of the body have different kinds of PDEs in their cells.
[19] Sometimes it is desirable to extend the duration of the physiological reaction stimulated by a first messenger. This can be done in two different ways, or by a combination of both. One way would be to increase the supply of a first messenger, for example, by administering NO. This would ultimately stimulate the production of the chemicals responsible for a particular physiological reaction, through the process described above. This is referred to as a “front-end” approach. Alternatively, one could curtail the effect of the PDE responsible for neutralizing the operative second messenger. Certain compounds, known as PDE inhibitors, limit the effectiveness of PDEs. They do so by interfering with the PDE’s ability to interact with cAMP or cGMP, the second messengers. Once a PDE is prevented from doing its job, the second messenger keeps sending its signal, and the corresponding physiological response continues. Use of PDE inhibitors is described as a “back-end” approach.
[20] The ‘748 patent describes the compounds contained in it as “potent and selective cGMP PDE inhibitors”. This means that the compounds are purported to be effective PDE inhibitors and more effective at inhibiting cGMP PDEs than cAMP PDEs. This makes them potentially suitable for certain “back-end” treatments, or for use in combination with “front-end” approaches. They function by interfering with the role that cGMP PDEs would normally play – that is, neutralizing the second messenger, cGMP – and allowing the physical response that the second messenger is calling for to continue.
[21] As mentioned, the ‘748 covers of a broad range of compounds. However, the patent categorizes certain compounds as “preferred”, “particularly preferred” and “especially preferred”. Sildenafil is one of seven compounds in the “especially preferred” class.
(ii) The invention
[22] The ‘748 patent states that the compounds “exhibit selectivity for inhibition of cGMP PDEs rather than” cAMP PDEs. It goes on to state that this property “can give rise to beneficial platelet anti-aggregatory, anti-vasospastic and vasodilatory activity”. By virtue of these characteristics, the patent states that the compounds have “utility” in the “treatment of a number of disorders, including
Stable, unstable and variant . . . angina, hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency . . ., peripheral vascular disease, stroke, bronchitis, chronic asthma, allergic rhinitis, glaucoma, and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS).”
[23] Later, the ‘748 patent mentions that “also included in the invention are radiolabelled derivatives” of the compounds, which are “suitable for biological studies”.
(iii) Creating the compounds
[24] The ‘748 patent describes how the compounds can be prepared. It goes on to say that the necessary chemical reactions are “entirely conventional” and can be carried out with reference to standard text books and the examples set out in the patent. The patent contains 58 examples of how various compounds coming with the patent’s scope (including sildenafil) can be prepared.
(iv) Determining the properties of the compounds
[25] The patent says that a compound’s ability to inhibit cGMP PDEs is evaluated by determining its so-called “IC50 value”. This is a reference to a well-known measurement of the potency of PDE inhibitors. The IC50 value refers to the concentration of the compound required to inhibit 50% of a PDE’s activity.
[26] The patent refers to a test for determining the properties of the compounds. It states that PDE enzymes were taken from rabbit platelets and rat kidneys. This yielded three different PDEs. The compounds were tested for their capacity to inhibit these PDEs and the results showed that “the compounds of the present invention are potent and selective inhibitors of both cGMP PDEs”. This test is discussed in greater detail below.
(d) Apotex’s allegations of invalidity
[27] Apotex alleges in its Notice of Allegation (NOA) that many of the claims in the ‘748 patent are invalid. As mentioned, Pfizer is only concerned about Claims 6 and 17 in respect of sildenafil.
[28] Apotex alleges that the ‘748 patent provides a very sketchy picture of the chemical attributes of the compounds, particularly their capacity to inhibit cGMP PDEs. The patent contains no specific IC50 values for any particular compounds. The patent merely states that tests show that the compounds (i.e. all of them) are potent and selective inhibitors of “both cGMP PDEs”. Apotex states that it is unclear which cGMP PDEs were inhibited, or to what degree. The patent also mentions some testing of compounds for their ability to inhibit platelet aggregation (useful for the treatment of some cardiac conditions) and to reduce hypertension in rats but, again, no particular compounds are mentioned and no results are given.
[29] Apotex also submits that Pfizer did not have an adequate factual basis to suggest, or a sound line of reasoning from which to infer, that the compounds set out in the ‘748 patent would be useful for their stated purposes. Further, Apotex alleges that the ‘748 patent fails to set out the basis on which a skilled reader could determine how the purported invention would work. Apotex relies on the description of the required elements of the doctrine of sound prediction established by the Supreme Court of Canada in Apotex Inc. v. Wellcome Foundation Ltd., above.
[30]
Apotex
also suggests that the effectiveness of PDE inhibitors for particular purposes
can only be predicted if one knows the type of PDE in the target tissue. So, an
inhibitor of PDE5 might be effective in treating erectile dysfunction (because
there is PDE5 in the corpus cavernosum, an area of the penis) but be useless,
or even harmful, for treating certain heart conditions. Given the limited state
of knowledge about the distribution of PDEs at the priority date of the patent
(June 20, 1990), Apotex alleges that Pfizer did not have a sound basis for
predicting the compounds’ value in treating particular conditions. This is
particularly so, Apotex argues, when the patent does not disclose the degree to
which the compounds target particular PDEs.
[31] Accordingly, Apotex suggests that Pfizer had no factual basis, at the relevant date, for its assertion that the compounds could do what the patent said they could do. Nor, therefore, could they articulate a coherent line of reasoning from facts to a conclusion that the compounds had the therapeutic utility described in the patent. Finally, Apotex argues that even if Pfizer did have both a factual basis and a sound line of reasoning supporting the patent’s assertions, it failed to provide proper disclosure.
(e) Pfizer’s
response
[32] Pfizer submits that Apotex has misconstrued the ‘748 patent. It argues that its Claim 6 does not mention any specific use for sildenafil and, therefore, that it qualifies as an invention, so long as there is some useful purpose for it mentioned in the patent. According to Pfizer’s view of the essential ingredients of a patent, the ‘748 patent should be considered valid if sildenafil could be used simply as a research tool. Pfizer also suggests that it does not have to show that sildenafil is useful in the treatment of the many conditions mentioned in the patent. Those conditions, it says, are simply examples of the areas where cGMP PDE inhibitors were known or expected to be effective. Further, sildenafil is clearly a potent and selective PDE inhibitor, just as the patent states. In any case, Pfizer also argues that it was also soundly predictable that sildenafil would be useful in the treatment of the various conditions identified in the patent.
[33] With respect to Claim 17 of the patent, Pfizer argues that it was soundly predictable that sildenafil would be useful in the treatment of the four conditions named in it: angina, hypertension, heart failure and atherosclerosis.
[34] Pfizer also argues that it satisfied its obligation to disclose the characteristics of the compounds in the patent and the means by which the compounds were tested for their capacity to inhibit cGMP PDEs.
[35] Accordingly, Pfizer argues that Apotex’s allegations are unjustified, at least in respect of Claims 6 and 17, as they relate to sildenafil.
(f) The concept of utility and the doctrine of sound prediction
[36] The Supreme Court of Canada identified the conditions for a valid patent relating to compounds in Apotex Inc. v. Wellcome Foundation Ltd., above. While the patent there related to a new use (treatment of HIV/AIDS) for an old chemical compound (AZT), there is nothing in the judgment that leads me to conclude that the principles set out in it do not apply equally to new compounds.
[37] Justice Binnie, speaking for the full Court, noted that “[u]tility is an essential part of the definition of an ‘invention’” (citing s. 2 of the Patent Act). Accordingly, “unless the inventor is in a position to establish utility as of the time the patent is applied for, on the basis of either demonstration or sound prediction, the Commissioner ‘by law’ is required to refuse the patent” (para. 46). A similar approach has been taken in this Court: see, e.g., Aventis Pharma Inc. v. Apotex Inc., 2005 FC 1283, [2005] F.C.J. No. 1559 (T.D.) (QL), aff’d 2006 FCA 64, [2006] F.C.J. No. 208 (C.A.) (QL).
[38] Justice Binnie set out three requirements of the doctrine of sound prediction:
Firstly, . . . there must be a factual
basis for the prediction. . . .Secondly, the inventor must have at the date of
the patent application an articulable and “sound” line of reasoning from which
the desired result can be inferred from the factual basis. . . . Thirdly, there
must be proper disclosure. Normally, it is sufficient if the specification
provides a full, clear and exact description of the nature of the invention and
the manner in which it can be practised. It is generally not necessary for an
inventor to provide a theory of why the invention works. Practical
readers merely want to know that it does work and how to work it. (At para. 70.)
[39]
The
doctrine of sound prediction allows inventors to patent new and useful products
even before their utility has been established through tests, so long as they
can show a factual basis for predicting utility, a sound basis for
extrapolating from those facts to the desired result, and provide an adequate
description of the invention and how it works. Only if these requirements are
met does the public get a fair exchange on the monopoly benefits that patentees
enjoy.
[40]
Therefore,
in order for Pfizer to succeed, it must prove that Apotex’s allegations - that Pfizer
has failed to demonstrate the utility of the compounds or satisfy the
requirements of the sound prediction doctrine - are unjustified.
(g) Construing the claims of the ‘748 patent
[41] As I read the patent, having considered the expert evidence tendered by both parties, there are really two levels of utility referred to in the patent. The first level relates to the properties of the compounds themselves as “potent and selective” cGMP PDE inhibitors. Compounds that manifest those qualities might be useful, for example, for their ability to cause smooth muscles to relax, for their anti-aggregatory or anti-hypertensive effects, or for use in the laboratory. At the second level, because of those inherent properties, the compounds might be useful in the treatment of a wide variety of conditions.
[42] Much of Apotex’s argument relates to the lack of demonstrated utility or sound prediction in relation to the compounds’ use in treating the conditions named in the patent. However, I agree with Pfizer that, at least for its Claim 6 (which is a claim for the compound sildenafil alone) it is enough if Pfizer can prove that sildenafil had a useful property (i.e. potent and selective cGMP PDE inhibition) that may make it suitable for use in the treatment of certain diseases or conditions, or for use in the laboratory. In doing so, Pfizer would show that its product met the definition of an “invention” set out in the Act. I am satisfied from the evidence that, at the priority date of the patent, it was expected that PDE inhibitors could be useful in the treatment of certain conditions. Scientists were looking for compounds that were more potent and selective cGMP inhibitors than were currently available. Accordingly, for Claim 6, Pfizer merely has to show that sildenafil had been demonstrated, or soundly predicted, to be useful simply by virtue of its capacity to act as a potent and selective cGMP PDE inhibitor.
[43] However, where the patent is more specific and claims that a compound is actually useful for the treatment of particular diseases and conditions, the patentee must show the compound’s utility in those areas. Accordingly, for Pfizer’s Claim 17 (which is a claim for the compounds’ use in particular treatments), it must demonstrate actual utility, or establish that utility was soundly predictable, in those areas. But Pfizer can only be successful in defending Claim 17 if it succeeds in defending Claim 6. Proof of sildenafil’s utility in the treatment of the conditions named in Claim 17 (i.e. angina, hypertension, heart failure or athersclerosis), or a sound prediction that it would be useful for that purpose, is obviously dependent on proof that sildenafil was known (or soundly predicted) to be a potent and selective cGMP PDE inhibitor in 1990.
[44] Therefore, unless Pfizer can prove that sildenafil had been shown, or that it was soundly predicted, to be a potent and selective cGMP PDE inhibitor at the priority date of the patent, it will fail to meet its burden of proof on both Claims 6 and 17. It will not have proved that Apotex’s most basic allegation – that there is no evidence that sildenafil or, in fact, any of the compounds of the patent were actually known or expected to be potent and selective PDE inhibitors – is unjustified.
(h) The Evidence
[45] The experts for both parties agree on the basic science of PDE inhibition as described above. As mentioned, much of the dispute between the parties relates to the utility of PDE inhibitors in the treatment of the conditions mentioned in the patent. Accordingly, the bulk of the expert evidence tendered by the parties addressed the question whether the compounds of the patent would be useful for that purpose – Apotex’s experts stated that the compounds would not be useful, and Pfizer’s experts stated that they could be.
[46] In addition, the parties’ experts disagreed on the most fundamental of Apotex’s allegations - that neither sildenafil nor any of the other compounds of the patent had actually been shown, or soundly predicted, to be potent and selective PDE inhibitors at the priority date of the patent, June 20, 1990. The following is a summary of the main evidence on this point.
(i) Apotex’s expert evidence
[47] Dr. Joseph Beavo is a professor of Pharmacology at the University of Washington and is acknowledged to be one of the world’s foremost experts on PDEs. He stated that, in order to determine a compound’s capacity to selectively inhibit cGMP PDEs, it would first be necessary to isolate a pure sample of a cGMP PDE because the risk of contamination and ambiguous results is great. No clear method for obtaining a pure sample is cited in the patent. The patent refers to a common method used by W.J. Thompson, in which PDEs are obtained from rabbit platelets and rat kidney, but that test would only yield partial separation of PDEs. Other more effective methods were known and used in 1990, including by Thompson himself. Dr. Beavo does not believe the patent informs a skilled user how the PDEs were isolated or how the compounds were tested for their potency and selectivity. Further, the patent gives no data about any of the compounds. While the patent groups the compounds into categories, no criteria are given for those groupings. The patent does not describe how to reproduce the results of the tests mentioned.
[48] Dr. Jonathan Dordick is a professor of Biology and Chemical and Biological Engineering at the Rensseler Polytechnic Institute. His opinion echoed Dr. Beavo’s on this point. He stated that tests for potency and selectivity must be conducted under rigorous conditions, and within the same sample, in order for the results to be reliable. The patent does not give sufficient information on the test conditions or sampling methodology. The patent mentions a process by which the PDE samples were tested, a test developed by W.J. Thompson and M.M. Appleman, but then states that the test was modified. The patent does not disclose the manner in which the test was modified. A skilled person would not be able to reproduce the test results. Even if the patent had given the IC50 values for particular compounds (which it does not), that would not be enough information on its own – one would have to know the circumstances under which those values had been obtained. In fact, the patent gives no information about which compounds were tested, what IC50 values were obtained in relation to the three PDEs that had allegedly been isolated, or what the conditions of the tests were.
[49] Dr. Dordick made similar comments about the patent’s description of the testing of the compounds’ capacity to inhibit platelet aggregation or reduce hypertension. No precise methodology is given for the tests, nor are any results given for any particular compounds.
[50] Dr. Akio Yamazaki is a professor of Opthamalogy at Wayne State University. He concurred with Dr. Dordick’s opinion on the patent’s lack of detailed testing methodologies and results. In his view, the Thompson test would not yield a pure sample of PDEs. In fact, that test had been abandoned for that purpose before 1990. In essence, he concluded that there appears to have been no factual basis for soundly predicting that the compounds of the patent were actually potent and selective cGMP PDE inhibitors.
[51] Dr. Jackie Corbin is a professor of Molecular Physiology and Biophysics at theVanderbilt School of Medicine. He confirmed the view that the patent does not provide sufficient information to permit a person skilled in the art to practise the alleged invention. He noted that to describe the compounds as “potent” would be meaningless without some frame of reference. Similarly, “selectivity” cannot be understood without reference to relative potencies. Further, the patent gives no information about the compounds’ effects on particular tissues. It would be impossible, without that information, to know what the properties of particular compounds would be or to what purpose they might be put.
[52] In addition to these points, Dr. Alexander Klibanov, a professor of Chemistry and Bioengineering at MIT, noted that the patent refers to a prior European patent application for a similar family of compounds, but describes those compounds as being neither potent nor selective PDE inhibitors. Yet, the ‘748 patent discloses no basis for believing that the compounds described in it are superior.
[53] Many of Apotex’s experts stated that the patent is ambiguous when it states that the compounds are potent and selective inhibitors of “both cGMP PDEs”. They point out that the compounds were ostensibly tested for their inhibitory capacity against three PDEs, what are now known as PDE1, PDE3 and PDE5. PDE3 is primarily a cAMP PDE so, presumably, the compounds were not potent or selective in relation to it. PDE5 is a cGMP PDE, so the patent was presumably referring to it as one of the PDEs for which the compounds were believed to be potent and selective inhibitors. The ambiguity lies in the reference to PDE1, which is capable of operating against both cAMP and cGMP. A compound that is a potent and selective PDE1 inhibitor might, therefore, elevate cAMP rather than cGMP. Apotex’s experts, therefore, suggest that it is anomalous to describe the compounds as potent and selective inhibitors of “both cGMP PDEs” because PDE1 cannot be accurately described as a cGMP PDE.
[54] In my view, however, in the context in which the phrase appears, it is clear that where the patent refered to “both cGMP PDEs”, it meant PDE1 (to the extent that it can operate against cGMP) and PDE5 (clearly a cGMP PDE), as distinguished from PDE3 (referred to in the patent as a cAMP PDE).
(ii) Pfizer’s
expert evidence
[55] Dr. Christopher Triggle is a professor of Pharmacology and Therapeutics at the University of Calgary. He noted that the patent discloses new chemical compounds, including sildenafil, “that have been found to be potent and selective inhibitors of cGMP PDEs” (emphasis added). This wording suggests that the compounds, including sildenafil, have subsequently been determined to have the property that the patent says they have. Nowhere does he state that the compounds were actually known to have that property in 1990. He says that the IC50 values for the compounds could be determined by a skilled user after conducting the tests described in the patent, if one wanted to know how potent and selective a particular compound was. Similarly, a skilled user could determine the degree to which a given compound exhibited anti-aggregatory or anti-hypertensive effects.
[56] Dr. Rodolphe Fischmeister is the Director of Research at the Institut de la Santé et de la Recherche Médicale and Head of the Cellular and Molecular Cardiology Laboratory at the University of Paris. He assumed that that the patentee had not actually tested all of the millions of compounds of the patent. He suggested that a skilled reader of the patent would expect that a representative sample of the compounds would have been tested, including those in the “especially preferred” category and those whose preparation is described in detail in the patent. In his affidavit, he states “[w]hy anyone would want to assay millions of compounds to determine their potency is beyond me”. Yet he does not suggest any other means by which the compounds might have been classified as “preferred”, “particularly preferred” and “especially preferred”, or on what basis all of the compounds could be accurately described as potent and selective cGMP PDE inhibitors.
[57] Dr. Fischmeister also assumed that the IC50 values for the compounds of the patent (again, presumably not all of them) were determined, although the patent does not actually state that those values were ascertained. It merely states that “compound affinities for cGMP and cAMP PDEs are assessed by determination of their IC50 values”. Further, he assumed that the compounds, once tested, probably yielded IC50 values in the nanomolar range (indicating potency) and had lower values for PDE1 and PDE5 than they had for PDE3 (indicating selectivity).
[58] With regard to the methods of isolating and testing PDEs (i.e. the Thompson methodologies), Dr. Fischmeister stated in cross-examination that the tests must have been conducted correctly or else the patentee could not have arrived at the conclusion that sildenafil, and the other compounds of the patent, were potent and selective cGMP PDE inhibitors. This suggests to me that Dr. Fischmeister was reading the patent with the knowledge that sildenafil had subsequently been determined to be a potent and selective cGMP PDE inhibitor, rather than evaluating what the patentees knew or could have soundly predicted in 1990. With regard to the Thompson method itself, he agreed with Apotex’s experts that it was an inadequate test for determining potency and selectivity.
[59] Regarding the compounds’ platelet anti-aggregatory effects, Dr. Fischmeister stated that a skilled reader would conclude from reading the patent that the compounds had such an effect and, therefore, that the compounds would potentially be useful in the treatment of certain cardiovascular conditions. The same would be true with respect to the compounds’ anti-hypertensive effects.
[60] Pfizer’s experts conceded that they did not know whether tests had actually been conducted or by what methodology, before the priority date of the patent. None had seen or been provided with any test results.
IV. Conclusion
(a) The bargain
of patent law
[61] It is important to recall that the requirement to prove utility rests on the fundamental bargain of patent law – that patentees exchange a monopoly on their inventions in exchange for disclosing to the public the nature of those inventions and sufficient information to allow skilled persons to understand and reproduce them:
The consideration for the grant is twofold: “first, there must be a new and useful invention, and secondly, the inventor must, in return for the grant of a patent, give to the public an adequate description of the invention with sufficiently complete and accurate details as will enable a workman, skilled in the art to which the invention relates, to construct or use that invention when the period of the monopoly has expired. (Consolboard Inc. v. MacMillan Bloedel (Saskatchewan) Ltd., [1981] 1 S.C.R. 504 at 517, quoting Fox, Canadian Patent Law and Practice (4th ed.), at p. 163).
[62]
In
addition, Justice Binnie has pointed out:
The patent system is designed to advance research and development and to encourage broader economic activity. Achievement of these objectives is undermined however if competitors fear to tread in the vicinity of the patent because its scope lacks a reasonable measure of precision and certainty….The patent owner, competitors, potential infringers and the public generally are thus entitled to clear and definite rules as to the extent of the monopoly conferred (Free World Trust v. Électro Santé Inc., [2002] 2 S.C.R. 1024 at paras. 42-3).
[63] In Apotex Inc. v. Wellcome Foundation Ltd., above, Justice Binnie gave an example of what a patent relating to a new and useful produce should contain. He described the essential elements of the hypothetical patent for the Wright brothers’ airplane:
The patent….would have to teach precisely how the machine could be made to fly. Section 34(1)(b) of the Patent Act requires the applicant to set out in the specification “the method of constructing, making … or using a machine … in such full, clear, concise and exact terms as to enable any person skilled in the art … to make, construct or use it”. This means the Wright brothers’ hypothetical patent would have to describe, amongst other things how to design an air foil that creates “lift” by reducing the air pressure on the upper surface of the wing as the air rushes over it as well as a suitable method of forward locomotion. If the essentials of the heavier-than-air flying machine were set out with sufficient precision to allow the reader actually to make a flying machine that flies, it is hard to accept the “hypothetical” that experts would continue to insist, after it had flown, that the prediction was unsound….
On the other hand, if the patent failed
to disclose the essentials of heavier-than-air flying machine, such that no one
would “soundly predict” whether or not the ill-defined thing could get off the
ground, then the patent would be rightly invalidated, even though the inventors
had flown some sort of machine in the meantime. It goes back to the same point.
The public is entitled to accurate and meaningful teaching in exchange for
suffering the patent monopoly. The patent claims must be supported by the
disclosure. Speculation, even if it afterwards proves justified, does not
provide valid consideration (at paras. 82-3).
[64] After referring to the analogy of the Wright brothers’ airplane, counsel for Pfizer frequently referred to sildenafil as an “F-16” – in other words, it is currently one of the most potent and selective PDE inhibitors known to science. The question, though, is whether, Pfizer has proved that, in 1990, anyone had demonstrated, or soundly predicted, that this compound could fly.
(b) Are Apotex’s allegations of invalidity unjustified?
[65] In my view, Pfizer has failed to prove that Apotex’s allegations are unjustified. In particular, Pfizer has failed to prove that the compounds of the ‘748 patent generally, or sildenafil in particular, had been shown, or soundly predicted, to be potent and selective cGMP PDE inhibitors in 1990. Given that Pfizer has failed to meet its burden of proof in relation to that fundamental allegation, it cannot show that the compounds had utility in the treatment of the particular conditions.
[66] Looking first to the language of the patent itself, there are numerous instances where vague language stands in the way of comprehending what the patent purports to teach skilled readers:
· The patent covers millions of compounds (at least), all of which are said to be potent and selective PDE inhibitors, and some of which are preferred, particularly preferred or especially preferred, but the patent contains no criteria to distinguish one group from another and no basis for concluding that they actually possess those properties.
· The terms “potent” and “selective” are relative, but the patent provides no information about how potent or selective any compounds are, or which cGMP PDE they inhibit.
· The patent states that potency and selectivity are measured by determining a compound’s IC50 value, but does not actually state that any such values were obtained or, if they were, what they were.
· The patent states that the compounds were isolated and tested by modifying well-known methodologies but does not clearly identify which methodologies were actually used or what the modification was.
· The patent states that platelet anti-aggregatory activity is measured by determining a compound’s ability to inhibit platelet aggregation in vitro, but does not state that any such tests were actually carried out or, if they were, what the results were. This test is described as being based “essentially” on the method devised by J.F. Mustard, et al., but no information is given about how the test was modified.
· The patent states that anti-hypertensive activity is determined by administering a compound to hypertensive rats and then measuring blood pressure, but does not state that such tests were actually carried out or, if they were, what the results were. The patent says that the compound can be administered to the rats either intravenously or orally, but does not specify which means were employed if, indeed, any such tests were actually carried out.
· The patent implies that the compounds are potent and selective cGMP PDE inhibitors when compared to a similar family of compounds contained in a European patent application, but provides no basis for that favourable comparison.
[67] None of Pfizer’s evidence helped resolve the ambiguities in the patent. Pfizer’s experts took the patent at face value. Because the patent said that the compounds were potent and selective cGMP PDE inhibitors, the experts assumed that they had been tested and found to be so. They assumed that IC50 values had been taken for some group of compounds, which enabled them to be classified in the manner set out in the patent. They assumed that tests of platelet anti-aggregatory and anti-hypertensive activities had been carried out and yielded positive results. As one of Pfizer’s experts stated candidly on cross-examination, if what the patentees “claimed was not true, we would not be sitting here” (Dr. Tony Durst, Professor Emeritus of Chemistry, University of Ottawa).
[68] It is clear, however, that after-the-fact confirmation of the utility of a purported invention is not enough to uphold a patent. Justice Binnie made that clear in his Wright brothers analogy set out above. He also emphasizes the importance of this principle in the area of pharmaceutical patents:
Were the law to be otherwise, major pharmaceutical corporations could (subject to cost considerations) patent whole stables of chemical compounds for all sorts of desirable but unrealized purposes is a shot-gun approach hoping that, as in a lottery, a certain percentage of compounds will serendipitously turn out to be useful for the purposes claimed. Such a system would reward deep pockets and the ingenuity of patents rather than the ingenuity of true inventors. (Apotex Inc. v. Wellcome Foundation Ltd., above at para. 80.)
[69] The assumptions made by Pfizer’s experts do not amount to evidence that would help Pfizer satisfy its burden of proof. Apotex’s most basic allegation is that the patent does not assist a skilled reader to appreciate the properties that the compounds contained in the patent exhibit. It does not describe how the allegedly useful properties of potency and selectivity were established or give any indication of how potent or selective any of the compounds are, either in respect of particular PDEs or in relation to specific tissues. Without that, the patent does not describe an invention that meets the requirement of utility. Certainly, there is nothing in the record before me that would suggest that anyone knew, or could have soundly predicted, that sildenafil was an extremely potent and selective cGMP PDE inhibitor, most particularly in relation to PDE5.
[70] It is interesting to compare the evidence before me with the evidence submitted in the Apotex Inc. v. Wellcome Foundation Ltd. case, above. In that case, there was evidence before the Court relating to what the patentee’s scientists knew at critical points in time before the patent for AZT was registered, and what the results of numerous tests had revealed. Here, I have no evidence whatsoever on that score. Utility and sound prediction are questions of fact and must obviously be supported by evidence. I note that in the other sound prediction cases cited to me, evidence of what was known or not known at the relevant date was before the Court: Pfizer Canada Inc. v. Canada (Minister of Health), 2005 FC 1205, [2005] F.C.J. No. 1607 (F.C.) (QL); Aventis Pharma Inc. v. Apotex Inc., above.
[71] Therefore, I must conclude that Pfizer has failed to meet its burden of proving that Apotex’s allegations were unjustified. In particular, it has not proved that the compounds of the patent, or sildenafil in particular, had been demonstrated to be potent and selective cGMP PDE inhibitors. Nor has it proved that there was a factual basis to support a sound prediction that the compounds had those properties. Further, the patent fails to provide skilled readers enough information to be able to understand what the properties of the compounds were or how to use them.
[72]
Accordingly,
Pfizer’s application for an order of prohibition is denied, with costs.
JUDGMENT
THIS COURT’S
JUDGMENT IS THAT:
1. The application for an order of prohibition is denied, with costs.
Annex
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Patent Act, R.S.C. 1985, c. P-4
Definitions
2. In this Act, except as otherwise provided,
means any new and useful art, process, machine, manufacture or composition of matter, or any new and useful improvement in any art, process, machine, manufacture or composition of matter; Specification 27. (3) The specification of an invention must … (b) set out clearly the various steps in a process, or the method of constructing, making, compounding or using a machine, manufacture or composition of matter, in such full, clear, concise and exact terms as to enable any person skilled in the art or science to which it pertains, or with which it is most closely connected, to make, construct, compound or use it;
Form and duration of patent 43. (1) Subject to section 46, every patent granted under this Act shall be issued under the seal of the Patent Office, and shall bear on its face the filing date of the application for the patent, the date on which the application became open to public inspection under section 10, the date on which the patent is granted and issued and any prescribed information.
Validity of patent
(2) After the patent is issued, it shall, in the absence of any evidence to the contrary, be valid and avail the patentee and the legal representatives of the patentee for the term mentioned in section 44 or 45, whichever is applicable.
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Loi sur les brevets, L.R.C. 1985, Ch. P-4
Définitions
2. Sauf disposition contraire, les définitions qui suivent s’appliquent à la présente loi.
«invention » Toute réalisation, tout procédé, toute machine, fabrication ou composition de matières, ainsi que tout perfectionnement de l’un d’eux, présentant le caractère de la nouveauté et de l’utilité.
27. (3) Le mémoire descriptif doit :
[…]
b) exposer clairement les diverses phases d’un procédé, ou le mode de construction, de confection, de composition ou d’utilisation d’une machine, d’un objet manufacturé ou d’un composé de matières, dans des termes complets, clairs, concis et exacts qui permettent à toute personne versée dans l’art ou la science dont relève l’invention, ou dans l’art ou la science qui s’en rapproche le plus, de confectionner, construire, composer ou utiliser l’invention;
Forme et durée des brevets 43. (1) Sous réserve de l’article 46, le brevet accordé sous le régime de la présente loi est délivré sous le sceau du Bureau des brevets. Il mentionne la date de dépôt de la demande, celle à laquelle elle est devenue accessible au public sous le régime de l’article 10, celle à laquelle il a été accordé et délivré ainsi que tout renseignement réglementaire.
Validité
(2) Une fois délivré, le brevet est, sauf preuve contraire, valide et acquis au breveté ou à ses représentants légaux pour la période mentionnée aux articles 44 ou 45. |
FEDERAL COURT
NAME OF COUNSEL AND SOLICITORS OF RECORD
DOCKET: T-2137-04
STYLE OF CAUSE: PFIZER, ET AL v. APOTEX, ET AL
PLACE OF HEARING: Toronto, Ontario
DATE OF HEARING: October 16 to 20, 2006
APPEARANCES:
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Robert MacFarlane Michael Charles Christine Pallota |
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Andrew Brodkin Richard Naiberg Sorelle Simmons
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FOR THE RESPONDENTS |
SOLICITORS OF RECORD:
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BERESKIN & PAR Toronto, ON |
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GOODMANS LLP Toronto, ON
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