Pfizer Canada Inc. v. Canada (Health)

Pfizer Canada Inc. v. Canada (Health)
Court (s) Database
Federal Court Decisions
Date
2008-01-04
Neutral citation
2008 FC 13
File numbers
T-16-06
Decision Content
Date: 20080104
Docket: T-16-06
Citation: 2008 FC 13
Ottawa, Ontario, January 4, 2008
PRESENT: The Honourable Mr. Justice Barnes
BETWEEN:
PFIZER CANADA INC. and
WARNER-LAMBERT COMPANY, LLC
Applicants
and
THE MINISTER OF HEALTH and
APOTEX INC.
Respondents
REASONS FOR JUDGMENT
Introduction
[1] These proceedings were commenced by Pfizer Canada Inc. and Warner-Lambert Company, LLC (collectively, Pfizer) against the Minister of Health and Apotex Inc. (Apotex) under the Patent Medicines (Notice of Compliance) Regulations SOR/93-133 as amended (NOC Regulations). Pfizer seeks an order prohibiting the Minister from issuing a Notice of Compliance (NOC) to the Respondent, Apotex, until the expiry of Canadian Patent No. 2,021,546 ('546 Patent). Pfizer asserts that the '546 Patent is a valid selection patent which will be infringed if Apotex is permitted to produce the protected compound, atorvastatin calcium (marketed as LIPITOR). Apotex, in turn, contends that the '546 Patent is invalid on several grounds including double patenting and the absence of a valid selection.
Background
[2] For the purposes of this decision, three related patents are at issue: U.S. Patent 4,681,893 ('893 Patent), Canadian Patent 1,268,768 ('768 Patent), and Canadian Patent No. 2,021,546 ('546 Patent). All of these patents were issued to Warner-Lambert Company. In 1999, Pfizer acquired Warner-Lambert and its subsidiaries, including Parke-Davis.
[3] The '893 Patent application was filed with the U.S. Patent Office on May 30, 1986 and issued on July 21, 1987. The corresponding Canadian application that led to the '768 Patent was filed in Canada on May 7, 1987, issued on May 8, 1990 and recently expired on May 8, 2007. I will refer to these patents collectively as '893 Patent.
[4] The '893 Patent is a genus patent that claims a class of compounds known as statins, which act to reduce cholesterol. The compounds described by the patent include those having the following structural formula:
[5] In the above structure, X is --CH2--, --CH2CH2--, --CH2CH2CH2-- or --CH2CH(CH3)-- and the R1, R2, R3 and R4 groups can be any one of a number of enumerated substituent groups.
[6] The class of compounds claimed by the '893 Patent includes the 4-hydroxypyran-2-ones, the corresponding ring-opened acids, and the pharmaceutically acceptable salts thereof. Practically, the compounds are most often used in their salt form. The pharmaceutically acceptable salts described in the patent include sodium, potassium, calcium, magnesium, aluminum, iron, and zinc ions.
[7] The '893 Patent also claims the individual enantiomers as well as racemic mixtures of the compounds described by the formula set out above. In particular, the patent covers the racemic mixture of atorvastatin.
[8] Several years after the '893 and '768 Patent applications were filed, Pfizer filed a related patent application that issued as the '546 Patent. The '546 Patent claimed a narrow subclass of the compounds previously described in the '893 Patent based on a claimed unexpected advantage.
[9] One of the compounds taught by the claims of the '546 Patent is atorvastatin calcium, which is a salt. Atorvastatin is the medicinal ingredient in the anti-cholesterol drug LIPITOR.
[10] The '546 Patent application was filed in Canada on July 19, 1990, based on a priority date of July 21, 1989. The patent was laid open to the public on January 22, 1991 and issued on April 29, 1997. It will expire on July 19, 2010.
[11] The '546 Patent claims one primary compound and several variations thereof. The basic compound is [R-(R*,R*)]-2-(4-fluorophenyl )-β,δ-dihydroxy-5-((1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid. It exists in two primary
forms, covered by claims 2 and 3. Claim 2 protects this basic compound. This is often described as the acid form of atorvastatin, or more often, simply as atorvastatin:
[12] Claim 3 covers the lactone form, (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]- 1H-pyrrole-3-carboxamide, known as atorvastatin lactone:
[13] The remaining claims identify particular salt forms of claim 2. The most important of these claims for the purposes of this proceeding is claim 6, the hemicalcium salt of atorvastatin (i.e. LIPITOR) which, according to Pfizer, is the best-selling drug in history.
[14] The “unexpected” finding of the '546 Patent was the “surprising inhibition of the biosynthesis of cholesterol” provided by atorvastatin beyond what would have been anticipated from the prior art including the '893 Patent.
Cholesterol-Inhibiting drugs
[15] Atorvastatin is a member of a class of pharmaceuticals known as statins, or HMG-CoA reductase inhibitors which are used to reduce cholesterol. Cholesterol is synthesized in most body tissues and is required for normal physiological functioning. It is carried through the bloodstream by two types of molecules: high density lipoproteins (HDL) and low density lipoproteins (LDL). LDL are known as the carriers of “bad” cholesterol because they can form a plaque on artery walls. This condition is known as atherosclerosis. If a clot forms, it is more likely to block off one of these narrowed arteries, and result in heart attack or stroke. It is thus desirable to reduce production of LDL.
[16] A large amount of the body’s cholesterol is synthesized in liver tissue. The enzyme HMG-CoA reductase is referred to as the rate-limiting step, or the “bottleneck” in the cholesterol production pathway. HMG-CoA reductase catalyses the first reaction necessary in cholesterol synthesis, which is the production of mevalonic acid from HMG-CoA. This enzyme is the target of statins. Where statins are present, HMG-CoA reductase will bind preferentially with them over the HMG-CoA. This effectively slows cholesterol synthesis because there is not enough HMG-CoA reductase to perform the reactions. This is known as competitive inhibition.
Stereochemistry and naming of compounds
[17] A discussion of LIPITOR requires some background in stereochemistry, which is the study of the spatial arrangements of atoms within molecules. Molecules are described using chemical formulae that identify the individual atoms that make up the molecule. A given molecular formula may represent more than one possible arrangement of the atoms, in the sense that the atoms can be connected in different sequences with one another. Molecules with different absolute arrangements of atoms are called isomers. However, atoms may also be connected in the same order, but with differing three-dimensional arrangements. Two such molecules would be referred to as stereoisomers, which can be further classified as being disastereomers or enantiomers, depending on their characteristics. For the purposes of the '546 Patent, we are only interested in the latter.
[18] As molecules are three-dimensional in nature, and paper is only two-dimensional, chemists use certain conventions to depict the three-dimensional structure of molecules. As can be seen below, in general, a bond that is in the same plane as the paper is drawn as a
stick. To show a bond that reaches out of the page, a bold wedge is used. Where the bond goes below the plane (i.e., into the page), diminishing parallel dashes are used.
[19] The two molecules shown above are examples of enantiomers. The term “enantiomer” is used to describe the relationship between two stereoisomers which are mirror images of one another (that is, they cannot be superimposed on one another). A more obvious example of enantiomers is a pair of hands. The right and left hands are mirror images of one another and cannot be superimposed. Chemists refer to this non-superimposability as chirality.
[20] Enantiomers have identical chemical, spectral and physical properties but often possess different biological properties. For example, use of the drug thalidomide was curtailed when it was discovered that the supposed inactive enantiomer caused serious birth defects.
[21] A stereoisomer can exist in a racemic mixture (sometimes called a racemate), which is a mixture of equal parts of its two enantiomers. A racemate tends to have different physical properties from the individual enantiomers. Racemates can be separated or resolved to isolate the individual enantiomers.
[22] In the case of atorvastatin, there are not one but two chiral centres of interest, indicated by asterisks. The designation R(R*, R*) simply refers to the (R,R) enantiomer of a molecule with two stereogenic centres. The opposite of R(R*,R*) is S(R*,R*) which would
actually indicate the (S,S) form. The following are respectively the R(R*,R*) and S(R*,R*) forms of atorvastatin in its acid form:
[23] For the purposes of this proceeding, in which only one set of enantiomers is of interest, the different structures are simply referred to as “atorvastatin” (indicating the R(R*,R*) enantiomer) and “the S-enantiomer of atorvastatin” (indicating the S(R*,R*) enantiomer).
[24] In this proceeding, Pfizer relies upon internal experimental data to support the promises of the '546 Patent. Apotex challenges the reliability of Pfizer’s data and points to other research findings which, Apotex says, teach away from those promises. It is helpful, therefore, to understand the nature of the experiments conducted by Pfizer in connection with the claimed benefits of atorvastatin.
[25] In its drug development program, Pfizer used three different tests to assess the effectiveness of various drug candidates on cholesterol inhibition. The data referenced in the '546 Patent was derived from a Cholesterol Synthesis Inhibition (CSI) assay, but Coenzyme-A Reductase (COR) and Acute Inhibition of Cholesterol Synthesis (AICS) assays were also conducted.
[26] CSI and COR are both in vitro tests. In Pfizer’s drug development program for LIPITOR, CSI was the first assay carried out. It was used to determine the effect of a drug candidate on the entire cholesterol synthesis pathway. In this assay, samples of the test compound, ideally at known concentrations, were added to a preparation of whole rat liver microsomes and cell enzymes. After the synthesis of cholesterol had proceeded for a given period of time in two test tubes (one containing the test sample and the liver preparation, the other as a control, containing only the liver preparation) the amount of cholesterol in each tube was determined.
[27] The COR assays followed a similar process, but used a liver preparation which excluded enzymes other than HMG-CoA reductase. This way, the only step in cholesterol synthesis that could occur was the reaction of HMG-CoA into mevalonic acid, catalyzed by the HMG-CoA reductase. This reaction was allowed to proceed for a set period of time, after which the amount of mevalonic acid present was measured.
[28] In both the CSI and COR screens, the test value and the control value for each trial were compared to yield the percent inhibition of cholesterol (or mevalonic acid) synthesis. These values, for each of four different dilutions of test compound, were then graphed to find the concentration required for 50% inhibition of cholesterol - the IC50 value. This was the value of interest. A promising new medicine would hopefully generate a lower IC value indicating that a lower dosage would achieve the same reduction in cholesterol as other competing statins. A lower required dosage would typically improve the side-effect profile of the drug under consideration.
[29] Where positive results were obtained from the CSI and COR assays, a selected compound was then subjected to AICS screening. The AICS assay measured the amount of cholesterol produced by a rat in vivo after a single dose of the drug candidate. This would indicate whether and to what extent the sample could be absorbed through the digestive system and delivered to the liver, where cholesterol synthesis occurs. In other words, the AICS screen established whether a compound was bioavailable. In this case, the relevant data – calculated in the same way as the IC50 values above – is the ED50.
Expert Evidence
[30] With respect to the primary issue of the reliability of Pfizer’s experimental data, it is important to keep in mind that the scientific witnesses were not speaking as “persons skilled in the art” but, rather were addressing basic issues of scientific methodology and interpretation. These are factual issues to be determined on a balance of probabilities. For ease of reference, the expert witnesses relied upon by each party in connection with the issues relevant to this decision are identified below with brief outlines of their respective qualifications.
Pfizer’s Experts
[31] Dr. Bruce Roth: Dr. Roth is the listed inventor of the '546 Patent as well as 42 other patents. He has a Ph.D in organic chemistry and has been employed by Pfizer and Warner-Lambert since 1982, always working in areas related to blood cholesterol or atherosclerosis. Presently, he is the Vice-President of Chemistry, Pfizer Global Research and Development.
[32] Dr. Roger Newton: Dr. Newton obtained his doctorate in lipid biochemistry. From 1981 to 1998, he was an employee of Parke-Davis, the pharmaceutical research division of Warner-Lambert. Dr. Newton held various positions at Parke-Davis. He was chairman of the atherosclerosis drug discovery team which developed atorvastatin calcium. He was also “product champion” of atorvastatin calcium and as such was responsible for convincing senior management to pursue United States FDA approval. He is now a senior vice-president of a Pfizer, Inc. company.
[33] Dr. John Dietschy: Dr. Dietschy is a medical doctor and a professor of internal medicine at the University of Texas. He has been involved in statin research for more than 30 years and has won numerous awards for his research on the control of cholesterol.
[33]
[34] Dr. William Roush: Dr. Roush is the Executive Director of Medicinal Chemistry at the Florida campus of the Scripps Research Institute. He has over 30 years of academic experience in organic chemistry and medicinal chemistry and has published extensively in these areas, and specifically in the area of synthesis and evaluation of optically active compounds. Dr. Roush also works as a consultant for various pharmaceutical companies, including Parke-Davis and its successors.
Apotex’s Experts
[35] Dr. Paul Grieco: Dr. Grieco has 35 years of experience in synthetic organic chemistry and medicinal chemistry, with formal education in chemistry and organic chemistry. He was Chairman of the Department of Chemistry at Indiana University from 1988-1997. He is now a Regents’ Professor in Montana.
[36] Dr. Robert Langer: Dr. Langer is an Institute Professor at the Massachusetts Institute of Technology (MIT). He has been recognized with a number of awards and in a number of popular magazines. He describes himself as an expert in areas including chemical engineering, biomedical engineering, biotechnology, pharmaceutical chemistry and formulation development. He has over 550 issued or pending patents worldwide. His formal education is in chemical engineering.
[37] Dr. John Keana: Dr. Keana is a Professor Emeritus at the University of Oregon, a consultant, and a member of the Editorial Board of Medicinal Chemistry and Drug Design Review online. He considers himself to be an expert in medicinal chemistry with a specialty in organic synthesis, stereochemistry, and lead optimization as related to drug discovery and development. He has a Ph.D in Chemistry.
Issues
[38] As in many applications of this kind, the parties have raised and argued numerous issues including the sufficiency of the Apotex Notice of Allegation (NOA), the legal significance of Pfizer’s dealings with the Patent Office and the substantive validity issues of selection, double patenting, obviousness and anticipation. For the reasons which follow, it is only necessary to deal with the issues of sufficiency of the NOA and whether the '546 Patent is a valid selection patent. With respect to the issue of selection, the principal question for determination is whether Pfizer has established that atorvastatin calcium has surprising or unexpected advantages sufficient to meet the legal requirements for a valid selection. This issue turns substantially on the adequacy and reliability of the experimental data marshalled by Pfizer to support the selection claims of the '546 Patent.
Analysis
Burden of Proof
[39] I am satisfied that Apotex has met its intermediate burden of proof and that Pfizer, in turn, has not satisfied the overall legal burden on a balance of probabilities that its '546 Patent is a valid selection patent.
The Expert Witnesses
[40] All of the scientific expert witnesses retained by the parties appear to be eminently qualified in their respective fields. I have identified nothing in the record to suggest that any of the witnesses was lacking in expertise or was unqualified to speak to the issues. My reasons for preferring the evidence of certain witnesses over that given by others are not, therefore, based on questions of qualification.
Sufficiency of NOA
[41] Pfizer argues that Apotex’s NOA is insufficient to support an attack on the reliability of the research data cited in the '546 Patent in support of the promise of atorvastatin’s unexpected and surprising cholesterol inhibiting properties. The basis of this insufficiency argument is that Apotex’s “bald allegation” that the '546 Patent is not a valid selection has no identified factual support. In the result, Pfizer says that the NOA could mean any number of things and Pfizer cannot be required to speculate on what was intended.
[42] In order to resolve this issue, it is necessary to consider Apotex’s NOA selection allegations in tandem with the language of the '546 Patent and in the context of the conduct of the parties in this proceeding.
[43] The issue of selection is dealt with in the following passage from Apotex’s NOA:
Furthermore, the '546 Patent cannot be said to be a selection patent since the '546 Patent merely at best verifies the known properties of the previously disclosed compounds taught in the '893 Patent (and in the '768 Patent), that is the R form enantiomer of atorvastatin, and inhibition of cholesterol synthesis with the R form enantiomer of atorvastatin, and pharmaceutical compositions comprising the R form enantiomer of atorvastatin for the inhibition of cholesterol synthesis.
There was no substantial advantage to be secured by the compounds claimed in the '546 Patent. The '546 Patent did not provide that the whole of the selected members possessed the purported substantiated advantage (if any).
The selection (if any) was not made in respect of a quality of a special character peculiar to the selected group.
All the advantages of the compounds claimed in the '546 Patent were known at the claim date of the '546 Patent and, if not, would have been obvious as evidenced by state of the art (common knowledge in the art) exemplified by the teachings of the references in Schedule A.
We rely on our discussion of the '893 Patent (the U.S. equivalent to the '768 Patent) under the heading “Anticipation” for this allegation and in respect of the '768 Patent as the teachings of the '768 Patent and the '893 Patent are equivalent.
We also rely on our discussion of the state of the art, the common general knowledge of a person skilled in the art discussed under the obviousness section of this Notice of Allegation for this allegation.
[44] Apotex contends that the reliability of the research data is put in play by the allegation that there was no substantial advantage achieved by the invention and by its further reference to the “purported” substantiated advantage. Apotex also notes that the only evidence cited in the '546 Patent to support the promise of an unexpected advantage was the CSI data, so its allegation of “no substantial advantage” could only involve a challenge to that evidence.
[45] If I were convinced that Pfizer had been misled by the absence of an explicit challenge to the research data in the NOA, I would not hesitate to grant the relief it seeks. In these circumstances, however, I can find no evidence of prejudice to Pfizer and nothing to indicate that it misunderstood the nature of Apotex’s selection challenge.
[46] I have no difficulty with the basic premise of Pfizer’s argument that a NOA must contain both the legal and factual bases of each allegation. This requirement is, of course, directed at ensuring that a patentee has sufficient information to allow it to determine whether to seek a prohibition order: see Pharmascience v. Sanofi-Aventis Canada Inc., 2006 FCA 229, 352 N.R. 99 at paras. 23-24.
[47] On the issue of the sufficiency of the NOA, Pfizer's Notice of Application asserted that "atorvastatin calcium has substantial and unexpected advantages which were neither known in the art nor obvious”. In support of this allegation, Pfizer retained, among others, Dr. Dietschy to review Apotex’s NOA. At para. 16 of his affidavit, Dr. Dietschy described his mandate as follows:
I have been asked by counsel for Pfizer to comment on the data in the 546 Patent as well as other data referred to in this affidavit and to state my opinion whether, on the basis of that data, the inherent activity of atorvastatin - that is, its ability to inhibit cholesterol biosynthesis - is unexpected compared to the inherent activity of a racemic mixture of atorvastatin and the S-(R*,R*) enantiomer.
[48] Dr. Dietschy went on to opine that Pfizer's research data were adequate to support the promises of the '546 Patent. Apotex responded with its own evidence on this issue and the witnesses from each side were cross-examined. Not surprisingly, Pfizer has not produced any evidence that it was caught off-guard by the brevity of the Apotex allegations. Indeed, it was well aware that the adequacy of its research data had been a recurring theme in litigation involving this patent. Pfizer made an informed decision to address this issue in this proceeding and, having put the issue in play, it cannot later argue that Apotex is precluded from challenging the research data which ostensibly supported the selection promise of the Patent: see Aventis Pharma Inc v. Apotex Inc., (2005), 43 C.P.R. (4th) 161 (F.C.) at para. 106 and Novopharm Limited v. Pfizer, (2005), 42 C.P.R. (4th) 97 (F.C.A.) at para. 17.
[49] In the result, I reject Pfizer’s argument and find that Apotex’s NOA is sufficient to support its challenge to the research data relied upon by Pfizer to support the claims of the '546 Patent.
The Law of Selection
[50] It is well understood that the selection of a chemical compound from a previously identified class of related compounds can be inventive and, therefore, patentable if the selection is both unobvious and advantageous. The criteria for creating a valid selection patent are described in the leading case of Pfizer Canada Inc. v. Canada, 2006 FCA 214, [2007] 2 F.C.R. 137:
3 There are two general classes of chemical patents. The first is the 'originating patent' where there is an originating invention involving the discovery of a new reaction or a new compound. The second is the 'selection patent', which is based on a selection from related compounds derived from the original compound and which have been described in general terms and claimed in the originating patent (see In the Matter of I.G. Farbenindustrie A.G.'s Patents, (1930) 47 R.P.C. 283 at page 321 per Maugham J.).
4 While there is little Canadian jurisprudence on the subject of selection patents, its elements are well defined in I.G. Farbenindustrie. Lord Diplock cited this decision with approval in the House of Lords where he stated that the 'inventive step in a selection patent lies in the discovery that one or more members of a previously known class of products possess some special advantage for a particular purpose which could not be predicted before the discovery was made' (see Beecham Group Ltd. v. Bristol Laboratories International S.A. [1978] R.P.C. 521 at page 579). All claimed members of the known class must have the advantage and the advantage must not be one that those skilled in the art would expect to find in a large number of the previously disclosed class (i.e. a quality of special character) (see I.G. Farbenindustrie at page 323).
5 Selection patents exist to encourage researchers to further use their inventive skills so as to discover new advantages for compounds within the known class. A selection patent can be claimed for a selection from a class of thousands or for a selection of one out of two (see for example I.G. Farbenindustrie at page 323 and E.I. Dupont de Nemours & Co (Witsiepse's) Application, [1982] F.S.R. 303 (H.L) at page 310).
…
21 It is important at the outset to establish that empirical research for the purpose of making a selection from a class is not verification. Lord Wilberforce in Beecham (supra at paragraph 4) noted that the selection of some from a larger number of possible components and the exploration of their appropriateness by empirical investigation is a different thing from verification and leads to different results (at page 568).
22 The empirical investigation leading to an invention protected by a selection patent must involve "at the least the discovery that the selected members possess qualities hitherto undiscovered, particular to themselves and not attributable to them by virtue of the fact of their belonging to a class specified by an earlier invention" (see Dreyfus and Other Applications (1945), 62 R.P.C. 125 at page 133 per Evershed J.).
23 In Pope Alliance Corporation and Spanish River Pulp and Paper Mills, Limited, [1929] A.C. 269 (H.L.) Viscount Dunedin at pages 250-251 noted that "invention is merely finding out something which has not been found out by other people." An inventor is entitled to a patent where he can show that his efforts led to a discovery of certain knowledge central to his invention. It is no answer that others by experiment might have also found it (see also T.A. Blanco White, Patents for Inventors and the Protection of Industrial Designs, 5th edition: (London: Stevens & Sons, 1983) at page 99).
24 On the other hand, verification means confirming predicted or predictable qualities of known compounds; i.e. components that have already been discovered and made. No one can claim a selection patent merely for ascertaining the properties of a known substance (see SmithKline Beecham Pharma Inc. v. Apotex Inc. (2002), 21 C.P.R. (4th) 129 (FCA) at paragraph 21).
…
31 To meet the statutory requirement in subsection 34(1) of the Patent Act, R.S.C. 1985, c. P-4 (old Act) that a patent be 'useful', the selected species must have an advantage over the class as a whole (see Consolboard Inc. v. MacMillan Bloedel (Saskatchewan) Ltd., [1981] 1 S.C.R. 504 at pages 525-526). That case broadly defined the utility required for valid patent as discussed in Halsbury's Laws of England (3rd ed.), vol 29 at page 59:
...it is sufficient utility to support a patent that the invention gives either a new article, or a better article or a cheaper article, or affords the public a useful choice.
However, there are no special legal requirements regarding what particular type of advantage is required. The test for advantage is understood to include a disadvantage to be avoided, as is the case here (see I.G. Farbenindustrie at page 322).
[51] The often-cited case of In the Matter of I.G. Farbenindustrie A.G.’s Patents, (1930) 47 R.P.C. 283 refers to three general propositions that must be satisfied to create a valid selection patent. Firstly, the patent must disclose a substantial advantage to be secured by the selected members (or conversely the avoidance of a substantial disadvantage); secondly, all of the selected members must possess the claimed advantage; and, thirdly, the selection must be in respect of a quality of a special character that is peculiar to the selected group. The Court concluded its selection discussion with the following admonition:
I must add a word on the subject of the drafting of the specification of such a patent. It should be obvious, after what I have said as to the essence of the inventive step, that it is necessary for the patentee to define in clear terms the nature of the characteristic which he alleges to be possessed by the selection for which he claims a monopoly. He has in truth disclosed no invention whatever if he merely says that the selected group possesses advantages. Apart altogether from the question of what is called sufficiency, he must disclose an invention; he fails to do this in the case of a selection for special characteristics, if he does not adequately define them. The cautions repeatedly expressed in the House of Lords as regards ambiguity have, I think, special weight in relation to selection patents. (Natural Colour etc. Ld. v. Bioschemes Ld.,(1915) 32 R.P.C. 256, at p. 266; and see British Ore etc. Ld. v. Minerals Separation Ld., (1910) 27 R.P.C. 33, at p. 47)
The Application of Selection Principles to the '546 Patent
[52] It is common ground that atorvastatin calcium was a compound that fell within the broader class of compounds described by Pfizer’s '893 Patent. Also falling within the scope of the '893 Patent were the S-enantiomer of atorvastatin calcium, the racemic mixture and several thousand other compounds. The '893 Patent claimed that all of the compounds of that invention “are useful as hypo-cholesterolemic or hypolipidemic agents by virtue of their ability to inhibit the biosynthesis of cholesterol”. At the time, it would have been expected by persons skilled in the art that atorvastatin would have cholesterol lowering effects but at a level approximately double that of the racemic mixture.
[53] The '546 Patent acknowledged the promised utility of the compounds described by the '893 Patent in reducing cholesterol in humans but it went on to assert an unexpected finding that atorvastatin calcium “provides surprising inhibition of the biosynsthesis of cholesterol”.
[54] The assertion in the '546 Patent that atorvastatin calcium exhibited unexpected and surprising inhibition of cholesterol biosynthesis was supported by experimental data set out in the following passage from the patent specification:
The compounds according to the present invention and especially according to the compound of the formula I inhibit the biosynthesis of cholesterol as found in the CSI screen that is disclosed in U.S. Patent No. 4,681,893. The CSI data of
the compound I, its enantiomer the compound II and the racemate of these two compounds are as follows:
Compound
IC50 (micromoles/liter)
[R-(R*R*)] isomer*
0.0044
[S-(R*R*)] isomer
0.44
Racemate
0.045
[*atorvastatin]
[55] These are critical representations for establishing the validity of the '546 Patent as a selection patent because, absent proof of a previously undisclosed and unpredictable special advantage (or a disadvantage avoided), Pfizer cannot re-patent atorvastatin calcium and Pfizer’s monopoly over that compound would have expired with the expiry of the '893 Patent. This is a point conceded by Pfizer or, as it was put by its counsel, “this case stands or falls on the issue of selection”.
[56] Before examining the accuracy of Pfizer’s empirical assertions, it is necessary to construe the promise made by the '546 Patent.
[57] According to Dr. Dietschy, the '546 Patent promised only that atorvastatin calcium produces “much greater” or “disproportionate” inhibitory activity than a person skilled in the art would have expected. This is somewhat different than the evidence of Dr. Roush who seems to have read the research data cited as being part and parcel of the promise of the Patent. His affidavit stated that “the ten-fold increase in activity is surprising and most certainly unexpected”. Pfizer argued that any material improvement over a two-fold increase in the inhibitory activity of atorvastatin calcium was essentially all that was promised. In that sense Pfizer now seeks to separate the inventive promise of the Patent from the data that were cited to support it.
[58] Although the '546 Patent did not expressly claim a ten-fold treatment advantage from atorvastatin calcium over the corresponding racemic compound, it is clear from the experimental data cited that a ten-fold in vitro advantage had been claimed. Although Dr. Roth was not speaking on behalf of a person skilled in the art, he described his initial findings as follows:
147. The data that I reviewed showed that there was almost a ten-fold difference in potency between the racemate and atorvastatin. These data were incorporated into a patent application for U.S. Patent 5,273,995 (995 Patent), which is the U.S. equivalent of the 546 Patent.
[59] It is implicit in the findings cited in the '546 Patent that the supposed unexpected efficacy of atorvastatin in vitro would result in substantially increased efficacy beyond the benefits already promised by the '893 Patent which included the expected two-fold advantage of atorvastatin over the racemic compound. The skilled reader of the '546 Patent would have no reason to question the validity of the data cited and would assume, in the absence of any qualifying statements, that Pfizer’s research findings were accurate and reproducible. In other words, a person skilled in the art would conclude that Pfizer had actually found that atorvastatin was approximately 10 times more effective than the racemate in inhibiting the production of cholesterol in vitro. In the result, I do not accept Pfizer’s attempt to decouple the promise of atorvastatin calcium’s surprising and unexpected activity from the research data it cited in the Patent; but, in the end, it does not matter, if the evidence relied upon by Pfizer is so unreliable or untrustworthy that it fails to establish anything beyond a two-fold increase in the efficacy in atorvastatin over the racemate.
The Genesis of the '546 Patent Data
[60] The process by which the data used in the '546 Patent came to light was somewhat unusual. According to Dr. Roth, “someone” in attendance at Pfizer’s Patent Review Committee, in response to a question by the Head of Preclinical Research, suggested that somewhere in the in vitro research data there may be evidence to show surprising biological activity for atorvastatin. Notwithstanding the fact that atorvastatin was Dr. Roth’s compound, he was not aware of that data but he was asked to look for it. It is also clear from Dr. Roth’s evidence that Pfizer was, at that point, looking seriously at the possibility of preparing a patent application for atorvastatin and that Dr. Roth’s search for supporting data was intended to determine if atorvastatin “possessed any surprising activities or properties that would make it patentable in and of itself”.
[61] Dr. Roth testified that he knew that atorvastatin was already covered generically by the '893 Patent so when he went to investigate the research data he would have known that Pfizer could not re-patent that compound in the absence of evidence of some unexpected biological activity.
[62] Such an approach raises a concern that the investigator is analyzing and selecting data after-the-fact to prove inventiveness in support of a business decision instead of confirming the novelty of the research findings as the data is being obtained. Such a look-back approach requires rigorous objectivity and unimpeachable fidelity to scientific methodology by the investigator to exclude the possibility of tunnel vision.
The Reliability of the '546 Patent Data
[63] Dr. Roth’s affidavit described the approach he took to selecting and analysing Pfizer’s research data. He acknowledged that an “optimal comparison” would have required head-to-head assays of both enantiomers of atorvastatin and its racemate but, at the time, he could not find such a comparison. He therefore compared the head-to-head assays for the sodium salts of the two enantiomers (CSI 120) with the average of the historical data from assays for the racemic sodium salt of atorvastatin (CSI Nos. 92, 93, 95, 102 and 118). The five assays of the racemic sodium salt were not run head-to-head and were conducted over a span of more than 3 years. Dr. Roth’s affidavit described the data he used as the “next best thing” and the “best available comparison”.
[64] Dr. Roth then dealt with the issue of combining within his racemic average the results of assays that were conducted differently. Four of those assays were run starting with racemic lactone while the fifth was run with purified racemic sodium salt. Dr. Roth was not concerned by this because the lactone rings were treated to open and create the sodium salt in situ, albeit that no tests were run by Pfizer to determine whether this conversion was successfully accomplished.
[65] Dr Keana was highly critical of the CSI assays run by Pfizer and sceptical of the results they produced. He stated that it was not good practice to rely upon the results obtained from a single CSI assay or to average single assay values that span a broad range. The variability range of the CSI data relied upon by Dr. Roth was, according to Dr. Keana, unacceptably large. Of particular note is the significant variability between the measured activity level for the purified racemic sodium salt and the average of the four values obtained from the racemic lactone. At a minimum, this should have led Pfizer to doubt the validity of these assays.
[66] Dr. Keana also concluded that the data used by Dr. Roth was unreliable because of the reported inability of the laboratory technicians to create true solutions for the tested compounds. These solubility problems, he said, are reflected in the technicians’ notes which used descriptors like “cloudy”, “milky”, “partially soluble” or “insoluble”. These descriptors indicated that true solutions were not achieved for many of the tested compounds which would have led to unreliable results. Dr. Keana’s affidavit described the problem as follows:
117. The point is that a single enantiomer may show greater than 2-fold increase in potency over the racemate simply because the racemate does not dissolve to the same extent as the single enantiomer and/or the racemate dissolves much slower from a suspension than the single enantiomer. An IC50 determination involves a reversible equilibrium. A racemate and the corresponding single enantiomer must be truly in solution in order to give a reliable IC50 value.
[67] According to Dr. Keana, these solubility problems could be aggravated by the well-known fact that significant solubility differences often exist between racemates and their corresponding enantiomers. Where only partial solubility is achieved for one or both of the comparators, the relative activity levels can be rendered meaningless. This point is made in the following passage from Dr. Keana’s affidavit:
146. The point is that a single enantiomer may show greater than 2-fold increase in potency over the racemate simply because the racemate does not dissolve to the same extent as the single enantiomer. That is, the opalescent or milky stock “solution” of the racemate is not a solution at all. Such mixtures are not true solutions even if they do not evidence “gross lumps”. The opalescence or milky nature is a result of light dispersion by small, likely colloidal particles. In such instances, a single enantiomer may well show a many-fold increase in potency over the racemate (even when the other enantiomer has no activity) simply because the racemate has dissolved to a lesser extent than the single enantiomer. A racemate and the corresponding single enantiomer must be truly in solution in order to give a reliable IC50