Eli Lilly Canada Inc. v. Hospira Healthcare Corporation

Eli Lilly Canada Inc. v. Hospira Healthcare Corporation
Court (s) Database
Federal Court Decisions
Date
2016-01-15
Neutral citation
2016 FC 47
File numbers
T-366-14
Notes
A correction was made on August 4, 2016
Decision Content
Date: 20160115
Docket: T-366-14
Citation: 2016 FC 47
Ottawa, Ontario, January 15, 2016
PRESENT: The Honourable Mr. Justice Barnes
BETWEEN:
ELI LILLY CANADA INC.
Applicant
and
HOSPIRA HEALTHCARE CORPORATION
AND THE MINISTER OF HEALTH
Respondents
and
TAKEDA PHARMACEUTICAL COMPANY
LIMITED
Respondent Patentee
PUBLIC JUDGMENT AND REASONS
[1] This is an application by Eli Lilly Canada Inc. [Lilly] made under the Patented Medicines (Notice of Compliance) Regulations, SOR 93-133 as amended, [Regulations]. Lilly seeks an Order prohibiting the Minister of Health from issuing a Notice of Compliance [NOC] to Hospira Healthcare Corporation [Hospira] for its proposed generic version of pemetrexed disodium [pemetrexed] sold in Canada by Lilly under the brand name ALIMTA®. Pemetrexed is an anti-folate drug useful in the treatment of some cancers.
[2] The Respondent Patentee, Takeda Pharmaceutical Company Limited [Takeda], is the owner of Canadian Letters Patent 1,340,794 [the 794 Patent] covering pemetrexed. Lilly holds a license from Takeda to sell pemetrexed in Canada.
[3] The 794 Patent was filed in Canada on March 23, 1989 and issued more than a decade later on October 19, 1999. As an “Old Act” patent, it will expire on October 19, 2016.
[4] It is of some interest that Lilly had previously obtained a license to sell pemetrexed covered under a different patent, namely the Canadian Letters Patent 2,031,890 Patent [890 Patent]. The 890 Patent was issued to Princeton University on July 25, 2000 on the strength of work done by, among others, Lilly employees. As a “New Act” patent, Lilly benefited from the 890 Patent monopoly on pemetrexed until it expired on December 10, 2010. Hospira asserts that Lilly is effectively gaming the system by this attempt to extend the monopoly over pemetrexed by a further six years. It is not entirely clear on the evidence presented why these two patents were not subjected to a conflict proceeding; but for the reasons that follow, it is unnecessary to determine which of them takes priority.
[5] The parties and their witnesses joined issue on a significant number of evidentiary and legal issues and they filed voluminous records in support of their respective positions. As much as the Court would like to address every issue advanced, it does not enjoy the luxury of sufficient time to do so. For reasons of judicial economy and having regard to the summary and non-binding nature of the NOC proceedings, I intend to deal only with the single, determinative issue of sound prediction of utility.
[6] It is sufficient to resolve this application to determine whether the person of skill in 1989 could have soundly predicted the promised utility of the untested compounds falling within Claims 7 and 9 from the test data reported in the Patent and from what was known in the art.
[7] It is common ground that the asserted claims relate to a class of compounds that includes pemetrexed. The vast majority of the compounds covered by Claims 7 and 9 (including pemetrexed) were not specifically disclosed nor were they made or tested by Takeda before the filing date. To fulfil the utility requirement Lilly must, therefore, establish that the promised utility of the untested compounds would have been soundly predicted by the person of skill from the results Takeda obtained from its testing of some of the compounds falling within those claims. On my view of the evidence, Lilly has failed to meet its burden of proof on a balance of probabilities on this issue.
I. The 794 Patent [8] The Patent opens with the assertion that the “invention relates to the novel Pyrrolopyrimidine derivatives which are useful as antitumor agents, the production and utilization thereof”. What follows is a brief summary of what was known in the prior art about antifolate compounds and an assertion of the advantages of the claimed compounds as antitumor drugs of “major” clinical importance.
[9] At page 25, the effects of the compounds of the invention are described in the following way:
The compounds (I) of this invention show excellent antitumor effects and mouse tumor cell strains (P388, L1210, L5178Y, B16 melanoma, MethA, Lewis Lung Carcinoma, S180 sarcoma, Ehrlich Carcinoma, Colon38) and human tumor cell strains (HL60, KB, Lu65), decreased the tumor carried by warm-blooded animals [e.g. melanoma, sarcoma, mastocytoma, carcinoma, neoplasia, etc.] and prolong the life-span of tumor-carrying warm-blooded animals.
[10] Subsequent passages from the disclosure refer to the “remarkable” antitumor effects of the compounds making them suitable for the treatment of tumors in warm-blooded animals.
[11] The Patent concludes with 36 claims, with Claim 1 incorporating all of the compounds claimed in Claims 1 to 29. Claim 30 concerns a method for making the compounds and Claims 32 to 36 relate to intermediates used in the synthesis of the compounds. Claim 31 relates to antitumor agents containing the compounds covered by Claims 1 to 29.
[12] Lilly asserts in argument only a subset of the compound claims[1], namely Claim 7 when read with Claims 4, 2 and 1 (Claim 7/4/2/1); Claim 9 when read with Claims 3, 2, and 1 (Claim 9/3/2/1); and Claim 11 when read with Claims 4, 2 and 1 (Claim 11/4/2/1). It also relies on Claim 31 as an aid to interpretation of the promised utility of the asserted compound claims. There appears to be no evidence in the record to support Lilly’s case for Claim 11/4/2/1 but, in the end, that is not a matter of any consequence.
[13] There does not appear to be any disagreement about the construction of the above-noted claims. There is also general agreement as to the attributes of the person of skill. I accept the following description of the person of skill set out at paragraph 16 of Dr. Kalman’s affidavit:
16. ‘794 Patent is directed to a person possessing the knowledge of the medicinal chemist having either a Ph.D. or a Master’s degree in medicinal or organic chemistry with additional knowledge in the area of folic acid biochemistry and cancer chemotherapy, in particular knowledge of chemistry and biology of antifolate and their different enzyme targets. This person would be part of a team that includes pharmacologists with experience in conducting and interpreting the in vitro assays referenced in the ‘794 Patent and also in vivo animal models; other pharmaceutical professionals involved in the drug formulation and metabolism; and clinical oncologists.
[14] Hospira and its expert witnesses also do not take issue with Lilly’s characterization of the inventive concept of the Patent which is said to lie in the unexpected discovery that classical antifolates bearing a 6/5 bicyclic pyrrolopyrimidine ring system had antifolate activity. I accept Dr. Jones’ evidence on this point at paragraph 123 to 129 of his affidavit including the observation that the previous limited efforts to explore 6/5 ring systems for antifolate activity had been unproductive. I also accept that for each of the compounds actually tested by Takeda before the filing date (to the extent that that was established) some measurable level of antifolate activity was obtained vis-à-vis at least one tumor cell line. The question that remains is whether those test data are sufficient to support a sound prediction of utility for the thousands of compounds left untested by Takeda.
II. Utility – The Expert Witnesses [15] Hospira’s case for a lack of sound prediction rests primarily on the evidence of Dr. Thomas Kalman and Dr. Roger Phillips supported, in part, by Dr. Michael Chong.
[16] Dr. Kalman is a Senior Professor in the Department of Chemistry and in the Department of Pharmacology and Toxicology (School of Medicine) at the State University of New York, Buffalo. He has considerable research and teaching experience dealing with the medicinal chemistry and pharmacology of anticancer drugs including antifolates.
[17] Dr. Phillips is a Professor of Cancer Pharmacology at the University of Huddersfield, England. He has extensive experience in the evaluation of potential and anti-cancer compounds with a particular focus on agents that target tumor metabolism. He has special expertise in assessing the predictive value of in vitro testing of anti-cancer drugs. He is widely published. He frequently acts as a referee assessing articles submitted for publication to several medical journals and he reviews grant proposals for, among others, Cancer Research UK.
[18] Both Dr. Kalman and Dr. Phillips are well qualified to speak to the issue addressed in their affidavits.
[19] Dr. Chong is a Professor in the Department of Chemistry at the University of Waterloo, Ontario. He is an organic chemist with research interests in synthetic organic chemistry and the preparation, identification and separation of compounds. Dr. Chong’s mandate included a comparative structural assessment of the compounds ostensibly tested by Takeda relative to the class of compounds claimed by the Patent. Dr. Chong was well qualified to address this issue and, for the most part, his opinions were not directly challenged by Lilly.
[20] Lilly’s case for sound prediction primarily rests on the opinion of Dr. Terrence Jones. Dr. Jones is a medicinal and synthetic organic chemist with experience in the design and synthesis of novel antifolates for cancer treatment. Between 1996 and 2004, he was the Chief Scientific Officer at Angstrom Pharmaceuticals and since 2004 he has worked part-time as a pharmaceutical consultant. He has published a number of scientific papers and served as a reviewer for the Journal of Medicinal Chemistry. Although Hospira challenged Dr. Jones’ objectivity, I am satisfied that he is qualified to speak to the issues addressed in his affidavits. Based on the answers he gave under cross-examination, I also have no reason to doubt his objectivity.
[21] Dr. Wuest’s evidence focused mainly on questions of sufficiency. As a synthetic organic chemist, he was well-qualified to address those matters: see his affidavit at paras 1-6. However, his ability to provide an opinion about the utility of the claimed compounds was very much in doubt. He has no experience in working with folic acids or with antifolates and only became acquainted with the area after being retained by Lilly (see pp 5062-5064 Application Record). Because of that lack of relevant experience, I am not prepared to ascribe weight to Dr. Wuest’s evidence where it conflicts with that of Dr. Kalman and Dr. Phillips on matters pertaining to utility.
[22] Dr. Rick Van Etten is both a cancer clinician and researcher. He is the Director of the Chao Family Comprehensive Cancer Center at the University of California (Irvine) where he is also a Professor of Medicine in the Division of Hematology/Oncology. He has considerable experience conducting animal and human clinical trials in the area of cancer treatment.
[23] The scope of Dr. Van Etten’s mandate concerning utility was stated to be limited to Claim 31 (see p 738 Application Record at para 9). Nevertheless, he went on to address utility more generally with reference to a “subset” of Formula I compounds. His opinions on this issue lack analysis and detail and for that reason, they are largely unhelpful.
III. The Promise of the Patent [24] The parties and their expert witnesses disagree about the scope of the promise of the Patent. There are no material differences concerning the construction of the claim language per se.
[25] Hospira argues for a heightened promise of utility and Lilly seeks to effectively read the promise down to a “scintilla” of utility. This is potentially relevant to the determination of whether a person of skill could have made a sound prediction of utility for the untested compounds, including Pemetrexed, on the strength of the data obtained for the tested compounds.
[26] This is a case where the opinions of the expert witnesses bearing on the construction of the promise of the Patent were largely unhelpful. Dr. Jones approached this issue on the basis of advice that a mere scintilla of utility would suffice and he concluded that the promise of the compound claims was only that some antifolate activity in vitro was either shown or could be soundly predicted from Takeda’s in vitro data. It appears that he made little effort to examine the claims on the basis of all of the language of the specification and relied primarily on the advice of counsel (see his evidence of pp 5762A-5773 of the Application Record and para 156 of his affidavit).
[27] Dr. Kalman’s evidence was unhelpful because he relied too heavily on language in the specification that could only be interpreted as a goal or aspiration and he conceded that he had not been instructed to attempt to distinguish between goals and promises. Under cross-examination, he also retreated in some measure from the opinion set out in his affidavit (see, for example his answers at pp 7560-7561 of the Application Record). Dr. Phillips was not extensively cross-examined on this issue but, he too, appears not to have understood the distinction between aspirational language and explicit promises.
[28] In my view, the person of skill would construe the promise of the Patent as falling between the positions advanced by the parties and their experts.
[29] Lilly’s case for a truncated promise of utility with respect to the claimed compounds is based, in part, on the absence of any asserted utility in the claim language. Only Claim 31 speaks to utility as antitumor agents containing an antitumor effective amount of the compounds defined in Claims 1 to 29.
[30] I do not give much weight to the absence of an explicit promise of utility in the compound claims. The discovery of a new molecule without disclosing how it might be put to some useful purpose will not support a patent. Accordingly, when a compound claim is silent as to use, the person of skill must resort to the specification to determine the utility promise of the claim. Once there, the person of skill must consider all of the language of the specification with a view to forming a purposive construction: see Whirlpool Corp v Camco Inc, 2000 SCC 67, [2000] 2 SCR 1067, and Shire Biochem Inc v Canada, 2008 FC 538 at paras 21-23, 328 FTR 123.
[31] Lilly’s argument that the promise of the Patent is limited to the bare requirement of measurable in vitro cytotoxic activity is untenable because it ignores clear and unambiguous language in the specification bearing on utility and, in particular, the opening sentence:
This invention relates to the novel pyrrolopyrimidine derivatives which are useful as anti-tumor agents, the production and utilization thereof. [Emphasis added]
[32] There are several other similar references found throughout the specification to the use or employment of the claimed compounds as antitumor agents often in conjunction with descriptors like “excellent” or “remarkable”.
[33] On the strength of this language the person of skill would include within the promise of the Patent the use of the compounds as antitumor agents. On this point, I agree with Dr. Phillips that the promise of antitumor activity would be understood by the person of skill to mean in vivo activity in relation to abnormal tissue (see paras 141-142 of his affidavit and p 7349 of his cross-examination). That was also the view of Dr. Van Etten when he equated the reference to “an anti-tumor agent” in Claim 31 to something that affects a tumor mass. This could be established by disclosed evidence of activity in vivo or by evidence of in vitro activity from which an extrapolation of in vivo activity could be drawn. I do not accept Dr. Jones’ evidence that antitumor activity means only that the claimed compounds would exhibit some degree of antifolate activity in vitro or that in vivo data are merely “icing on the cake” (see p 5766, Application Record). In vitro testing does not, absent a sound prediction, establish efficacy against a tumor mass.
[34] The person of skill would not, however, include within the promise of the Patent the highly subjective and qualitative references to “excellent” or “remarkable” nor would she consider that every one of the claimed compounds would be useful to treat tumors in warm-blooded animals. There is also nothing in the Patent establishing that the compounds enjoyed some relative advantage over methatrexate (see the evidence of Dr. Kalman at pp 7510 and 7561, Application Record) or that all of the claimed compounds had toxicities specific to tumor cells. Those references in the specification seem to me to be more in the nature of hopes or aspirations for some of the compounds and not promises for all of them.
[35] I also do not agree that any level of promised efficacy as an antitumor agent would be inferred by the person of skill from the activity data points expressed in the Patent. At the same time, I do not accept Lilly’s point that any measurable in vitro antifolate activity would satisfy the promise of the Patent. It strikes me that the person of skill would have an activity threshold in mind below which a compound would not be considered to be an antifolate agent with antitumor effects. Dr. Jones seemed to accept this point albeit not without some equivocation as to what the threshold would be.
[36] When Dr. Jones was questioned about an efficacy threshold, he expressed the view that a “scintilla” of antifolate activity was all the Patent promised. According to Dr. Jones a 10% reduction in tumor size met the required threshold (pp 2687-2688 Application Record) and antitumor activity as low as 0.5% might also have been seen by the person of skill to satisfy the utility requirement (p 5690 Application Record). At paragraph 264 of Dr. Jones’ affidavit he stated that “an antitumor agent is something that demonstrates an antitumor effect” but on cross-examination he qualified this evidence by saying “[a] reasonable IC50, for instance, of a compound against tumor cells and tissue culture would constitute an antitumor effect”. He went on to acknowledge that the person of skill would expect a level of activity that “might” render the compound useful for treatment (pp 5701-5702 Application Record). Ultimately Dr. Jones conceded in the following exchange that a compound IC50 value greater than 20.0 microgram per millilitre had no cytotoxic activity:
629 Q. So if you go to paragraph 215 of your affidavit, you state in the second sentence:
“Working Example 14 was found to have an IC50 value > 20.0 microgram per ml, a very high value, showing that it had no cytotoxic activity against this cell line.”
Do you see that?
A. Yes, I see that. Yes.
630 Q. Didn’t you just tell me that activity of 427 micrograms per ml was cytotoxic, and in your affidavit you’re saying greater than 20 micrograms per ml is not cytotoxic?
A. Yes, I see the disparity.
631 Q. So what number would you prefer to go with, the greater than 20 micrograms per ml IC50 value of being not cytotoxic, or the greater than the 427?
A. I have to stand by what I wrote in 215.
632 Q. Greater than 20 microgram per ml, IC50 value?
A. Greater than 20, yes.
Also see p 5773 Application Record.
[37] Needless to say, Dr. Jones’ evidence on this point was not entirely consistent. What the experts did seem to agree upon, however, was that the promise of efficacy had a qualitative aspect. In the absence of other evidence on point, I can only conclude that a compound with an IC50 value greater than 20.0 micrograms per millilitre would not be seen by the person of skill to be an antitumor agent.
IV. Utility – Legal Principles [38] Section 2 of the Patent Act, RSC 1985, c P -4, [Act] defines an invention as “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”. Subsection 34(1) of the Act requires a patentee to “correctly and fully describe the invention and its operation or use” and to “set forth clearly the various steps in a process, or the method of constructing, making or compounding a machine, manufacture or composition of matter”. Thus a patentee was required to explain how the invention could be made and effectively used.
[39] Subsection 34(1), however, did not impose on the patentee an obligation to extol the advantages of the invention or to make any particular promises concerning its usefulness. The decision by the Supreme Court of Canada in Consolboard Inc v MacMillan Bloedel (Saskatchewan) Ltd, [1981] 1 SCR 504, 1981 CanLII 15 (SCC), holds that a patentee is not bound to promise anything about the practical or commercial usefulness of an invention: also see Apotex Inc v Wellcome Foundation Ltd, 2002 SCC 77 at para 54, [2002] 4 SCR 153. The inventor need not even be aware of the advantages of the invention or the reasons why it works. However, to the extent the patentee makes a clear promise of utility, he will be held to it.
[40] A recent decision about the promise doctrine and utility can be found in Apotex Inc v Pfizer Canada Inc and G.D. Searle & Co, 2014 FCA 250 at para 64-67 and 71, [2014] FCJ No 1090, where the Chief Justice Noël stated:
64 Under the Act, an invention must be useful in order to deserve protection (s. 2). The courts, however, have long held that the minimum requirements for utility under the Act are fairly forgiving. First, the inventor need not expressly set out the utility of the invention in the patent (Consolboard Inc. v. MacMillan Bloedel (Saskatchewan) Ltd., [1981] 1 S.C.R. 504 at 525 and 526 [Consolboard]. It is merely required that, where the inventor is called upon to prove the utility of the invention, utility can be shown to be demonstrated or soundly predicted as of the patent's filing date (AZT). Second, the threshold that must be proven to establish utility is generally quite low, described as being no more than a "scintilla of utility" (Olanzapine).
65 The promise doctrine represents an exception to the above minimum statutory requirements. Though an inventor need not describe any particular utility for the invention, an inventor who explicitly promises a specific result will be held to that promise when called upon to prove utility (Plavix FCA at paras. 48 and 49). That the invention may well have satisfied the scintilla threshold is of no assistance in establishing utility where a promise, if it be made, cannot be met (Plavix FCA at para. 54).
66 The promise doctrine will hold an inventor to an elevated standard only where a clear and unambiguous promise has been made. Where the validity of a patent is challenged on the basis of an alleged unfulfilled promise, the patent will be construed in favour of the patentee where it can reasonably be read by the skilled person as excluding this promise. This approach can be traced back to the earliest mentions of the promise doctrine. In Consolboard, the source of the promise doctrine in Canadian law, the Supreme Court of Canada reiterated the longstanding principle that (Consolboard at 521, citing Western Electric Company, Incorporated, and Northern Electric Company v. Baldwin International Radio of Canada, [1934] S.C.R. 570 at 574):
...where the language of the specification, upon a reasonable view of it, can be so read as to afford the inventor protection for that which he has actually in good faith invented, the court, as a rule, will endeavour to give effect to that construction.
67 This rule in favour of saving an invention rather than invalidating it in case of ambiguity has been consistently applied by this Court. While the principle is sometimes invoked by reference to the original language found in Consolboard (Anastrozole at paras. 17 and 19) affirming AstraZeneca Canada Inc. v. Mylan Pharmaceuticals ULC, 2011 FC 1023, [2011] F.C.J. No. 1262 at para. 88), it is at other times given effect through the requirement that promises be "explicit" (see Olanzapine at para. 76, Eli Lilly and Company v. Teva Canada Limited, 2011 FCA 220, [2011] F.C.J. No. 1028 at paras. 18 to 21 [Atomexetine], Plavix FCA at para. 49). Drawing an analogy with the threshold test applicable to selection patents, the Court in Plavix FCA expressed the need for explicitness by saying that a promise must be supported by language "... at least as clear and unambiguous as that used to establish the advantages of the selection over the compounds of a genus patent" (Plavix FCA at para. 66). It follows that it is not enough to merely label a promise as "explicit" if it can only be supported on the basis of equivocal inferences and ambiguous indications (Plavix FCA at paras. 64-66).
…
71 This passage does not support the broad proposition advanced by Apotex. In my view, Gauthier J. (as she then was) was merely stating that, when a result or advantage is asserted in a patent's claims, it will generally be seen as a promise of utility. This is entirely consistent with Zinn J.'s warning in Fournier at paragraph 126 that statements going to utility are particularly vulnerable to being read as promises when they are expressed in a patent's claims. Apotex has failed to establish how any of the '576 Patent's claims can be shown to describe use in humans as a particular advantage of the claimed compounds.
[41] I accept Lilly’s view that a promise of utility is not to be inferred from the language of the specification. Instead it must be clearly and unequivocally found in the express language of the specification: see Sanofi-Aventis v Apotex, 2013 FCA 186 at para 64-65, [2013] FCJ No 856.
[42] Inutility must be assessed on a claim by claim basis although some promises will be construed as over-arching, applying across a subset of all of the claims: see AstraZeneca v Apotex, 2015 FCA 158 at paras 4-5, [2015] FCJ No 802. Utility must be proven with respect to the entirety of any particular claim. I do not agree with Lilly that the decisions in Fournier Pharma v Canada, 2012 FC 740, 413 FTR 239 and Searle v Novopharm, 2007 FC 81, [2007] FCJ No 120, stand for some different proposition. Both of those decisions turned on unique points of claim construction where alternatives were given. In Searle, Justice Roger Hughes recognized at paragraph 31 that, where a patent claim includes a class of compounds, proof of the utility of each will generally be required.
[43] Utility is to be assessed as of the date a patent is applied for and it cannot be supported by evidence arising after the filing date: see Bell Helicopter v Eurocopter, 2013 FCA 219 at para 131, [2013] FCJ No 1043.
[44] Utility must either be demonstrated or soundly predicted. Demonstrated utility is established with evidence showing that the embodiment in issue works as described in the patent. Where utility is predicted, there must be a factual basis for the prediction and an articulate and sound line of reasoning from which the desired result can be inferred. The requirements for sound prediction were described in Apotex v Wellcome, above, at para 70:
70 The doctrine of sound prediction has three components. Firstly, as here, there must be a factual basis for the prediction. In Monsanto and Burton Parsons, the factual basis was supplied by the tested compounds, but other factual underpinnings, depending on the nature of the invention, may suffice. 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. In Monsanto and Burton Parsons, the line of reasoning was grounded in the known "architecture of chemical compounds" (Monsanto, at p. 1119), but other lines of reasoning, again depending on the subject matter, may be legitimate. 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: H. G. Fox, The Canadian Law and Practice Relating to Letters Patent for Inventions (4th ed. 1969), at p. 167. 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. In this sort of case, however, the sound prediction is to some extent the quid pro quo the applicant offers in exchange for the patent monopoly. Precise disclosure requirements in this regard do not arise for decision in this case because both the underlying facts (the test data) and the line of reasoning (the chain terminator effect) were in fact disclosed, and disclosure in this respect did not become an issue between the parties. I therefore say no more about it.
[45] A sound prediction must be based on “a solid teaching” or a prima facie reasonable inference of utility: see Eli Lilly v Novopharm, 2010 FCA 197 at para 85, [2010] FCJ No 951. It is not established by speculation or lucky guesses: see Bayer Inc v Cobalt Pharmaceuticals, 2013 FC 1061 at paras 52-58, [2013] FCJ No 1152.
[46] Notwithstanding Justice Binnie’s remarks in Apotex Inc v Wellcome Foundation Ltd, quoted above, the issue of what the patentee must disclose to the public where utility is predicted remains somewhat controversial. In AstraZeneca v Apotex, 2014 FC 638, [2014] FCJ No 671, Justice Donald Rennie (as he then was), distinguished Apotex Inc v Wellcome Foundation Ltd, above, by limiting Justice Binnie’s remarks concerning disclosure to new use patents.
[47] Justice Rennie also drew support from Justice Johanne Gauthier’s concurring, separate reasons in Sanofi-Aventis v Apotex, 2013 FCA 186, [2013] FCJ No 856, where she questioned the general requirement for a heightened level of disclosure in sound prediction cases. Justice Rennie dealt with Eurocopter, 2013 FCA 261, 116 C.P.R. (4th) 161, by describing the contrary view there expressed as both obiter and a less than robust endorsement of the need for heightened disclosure in sound prediction cases: see para 157.
[48] While I have some sympathy for Justice Rennie’s and Justice Gauthier’s views, I am not persuaded that the state of the law on this issue has changed. In particular, it would take something more than Justice LeBel’s apparent reservations expressed in Pfizer v Novopharm, 2012 SCC 60 at paras 38-40, [2012] SCJ No 60, to displace the requirement for disclosure described by Justice Binnie in Apotex Inc v Wellcome Foundation Ltd, above, and, later, as clearly endorsed by the Federal Court of Appeal in Eli Lilly v Apotex, 2009 FCA 97 at paras 14-15, 78 CPR (4th) 388, in Eli Lilly v Novopharm, 2010 FCA 197 at para 83, [2012] 1 FCR 349 and in many decisions of this Court.
[49] In my view where utility is based on a sound prediction, there remains an obligation to disclose in the patent specification the factual basis and a sound line of reasoning supporting the prediction. That said, there is no requirement to disclose that which forms a part of the common general knowledge of the person of skill. Such knowledge may be relied upon by a patentee to strengthen its assertion of predicted utility: see Bell Helicopter v Eurocopter, above, at para 154.
V. Utility – The Evidence [50] I need not address the question of whether the testing of the compounds within the asserted claims demonstrated their promised utility. Pemetrexed and most of the other compounds covered by those claims were never tested. The utility of the untested compounds to fulfil the promise of the Patent necessarily rests on a sound prediction.
[51] As indicated above, I do not agree with Lilly that it is entitled to rely upon in-house test data or upon a sound line of reasoning that cannot be found in the Patent. The Patent discloses in vitro test results for a small number of compounds and it provides no line of reasoning from which the person of skill could draw a prima facie reasonable inference that the thousands of untested claimed compounds would be useful as antitumor agents in vivo or even in vitro.
[52] There is also no line of reasoning disclosed in the Patent from which the person of skill could extrapolate an in vivo antitumor effect from the reported in vitro data.
[53] Dr. Jones based his opinion of a sound prediction of utility substantially on data that was not disclosed in the Patent. He also relied, in part, on data that Lilly failed to prove was obtained before the filing date.
[54] Notwithstanding these fundamental flaws in Lilly’s case, I will address the evidence relied upon by Lilly in support of its argument for a sound prediction of utility.
[55] Lilly’s theory of sound prediction is based on the drawing of an inference of a scintilla of antitumor activity for the untested compounds from the fact that some structural changes to similar molecules had been shown to be tolerated and, in some measure, active as antifolates.
[56] The evidence Lilly presented in support of this theory was not compelling. Indeed, much of that evidence was surprisingly unresponsive to the very specific scientific points advanced by Hospira’s experts as to why the person of skill could not soundly predict antitumor activity either from the test data disclosed in the Patent or otherwise. I would add that Takeda’s evidence about whether it obtained all of the data it now relies upon before the Canadian filing date was highly dubious and unreliable. Insofar as Lilly’s experts relied upon that information, their evidence is substantially undermined.
[57] All of the witnesses agree that variations to the molecular structures of certain analogues to MTX and other antifolate compounds had been explored before 1989 and found to be tolerated. Both Dr. Kalman and Dr. Phillips accepted that antifolate activity had been observed in the face of a number of modifications to the structures of classical antifolates (see Dr. Kalman’s evidence at pp 7466-7467 Application Record and Dr. Phillips’ evidence at pp 7364-7365 Application Record). What Dr. Kalman and Dr. Phillips did not accept was that a person of skill could soundly predict from that evidence and from Takeda’s testing that similar or any activity would be expected for the claimed untested compounds.
VI. Lilly’s Case for Sound Prediction [58] Dr. Jones’ affidavit states at paragraph 63 that “by the late 1980s a great deal was known regarding the relationship between the structure of classical antifolates and their antitumor activity”. This knowledge was said to have enabled medicinal chemists to understand how variations to the three structural elements of classical antifolates (the bicyclic heterocyclic, the bridge element and the benzoyl glutamate residue) would likely affect their antifolate activity. Dr. Jones broadly characterized the prior knowledge in the following way:
(a) It was known that the bridge “part” of classical antifolates could be varied significantly (made somewhat longer, or shorter, or with some added elements, etc.) without losing antifolate activity;
(b) It was also known that both di- and mono-antifolate esters (in the glutamate “part” of classical antifolates) could have antifolate activity;
(c) It was also known that different types of 6/6 fused ring structures in antifolates could be used without losing antifolate activity. However, it was not known that 6/5 fused ring structures might have any such activity as the only tested 6/5 classical structures had been shown to have no activity.
[59] Dr. Jones provided several prior art examples where variations to the bridge structures of classical antifolates were tolerated. This research indicated that one could vary the length of the bridge structure or its branches to create compounds that retained antifolate activity. He concluded the prior art review concerning bridge structure variations in the following way:
95. It was known prior to March 23, 1989 that compounds having a classical antifolate structure with bridges two, three or four atoms in length; and bridges with a variety of branches on different bridge atoms retained antifolate activity. In other words, the POSA of the ‘794 Patent would have understood that the bridge moiety of classical antifolates can be varied significantly.
[60] Dr. Jones dealt with the prior art knowledge concerning the glutamate element of classical antifolates, including ester forms, in a similar way. He pointed to evidence showing that “some antifolate esters have been found to be biologically active per se” and that “other antifolate esters may act as prodrugs” that convert to active forms after administration. He concluded with the observation that “by March 23, 1989, it was known that both di- and mono-antifolate esters showed activity both in vitro and in vivo”.
[61] Dr. Jones also considered what was known about variations to the bicyclic heterocycle element of classical antifolates bearing 6/6 and 6/5 fused ring systems. From that research he stated:
Generally speaking, variations [to 6/6 ring structures] was tolerated with retention of activity, although the only 6/5 ring system tested was shown not to be active.
[62] According to Dr. Jones, this research would have suggested to the person of skill that 6/5 ring systems “might be of questionable value” (see para 125 of Jones’ affidavit).
[63] Dr. Jones was asked by Lilly to examine different subsets of the Patent claims specifically Claim 7/4/2/1 and Claim 9/3/2/1. He stated that Claim 7/4/2/1 encompasses only 12 compounds… “and their esters, stereoisomers and salts”. He effectively excluded esters, stereoisomers and salts on the following basis:
168. In my view the inclusion of esters, stereoisomers and salts has little impact on the question of predictability of these compounds. As I have stated above, some antifolate esters have been found to be biologically active per se because they directly bind to and inhibit a folate enzyme. Other antifolate esters likely act, at least in part, as prodrugs, which are converted within or without the cancer cell by an esterase enzyme to compounds with a free glutamate residue. Thus to simplify discussion of claims 7/4/2/1 (and later claim 9/3/2/1) I have chosen to limit the glutamate moiety to the diacid form. This form is also specifically claimed and where it is not and is an ester instead, that ester is likely to be active per se or likely to be a prodrug convertible in vivo to the diacid. Moreover, even if the esters did not have biological activity per se, the ‘794 patent teaches that these esters are useful as intermediates in the synthesis of the diacids, for example, synthesis of Working Example 4 from Working Example 3.
169. In my review of Dr. Phillips’ and Kalman’s reports, they do not correctly discuss the state of the art with respect to the significant amount of work that showed that esters of MTX and its analogs also had activity. As I discussed earlier, esters of MTX had been identified as active against cells in culture and L1210 leukemia in vivo.
170. Insofar as salts, these are limited to “pharmaceutical acceptable salts” and therefore would be equivalent to the diacid form.
171. As for the stereoisomers of these 12 compounds, there are 2 potential chiral centres: the C5 carbon of the pyrroline ring and C1 of the methyl-propyl bridge. As I have discussed earlier, the two stereoisomers of tetrahydrohomofolate both showed antifolate activity. Thus, the chiral centre at the point of attachment of the bridge to the bicyclic ring was known not to be critical. Furthermore, both of the diastereoisomers of the antifolate DDATHF were shown to be equally cytotoxic. Stereoisomers on the bridge had also been investigated and it was known that both stereoisomers of 10-EdAM showed activity.
172. Thus, I will focus on the 12 diacids (not the esters, salts or diastereomers). [Footnotes omitted]
[64] For Claim 9/3/2/1