Janssen Inc. v. Apotex Inc.

Janssen Inc. v. Apotex Inc.
Court (s) Database
Federal Court Decisions
Date
2021-01-14
Neutral citation
2021 FC 7
File numbers
T-182-19, T-1893-19, T-84-19, T-978-19
Decision Content
Date: 20210114
Dockets: T-84-19
T-978-19
T-182-19
T-1893-19
Citation: 2021 FC 7
Docket: T-84-19
BETWEEN:
JANSSEN INC, JANSSEN ONCOLOGY, INC AND BTG INTERNATIONAL LTD
Plaintiffs
and
APOTEX INC
Defendant
Docket: T-978-19
AND BETWEEN:
JANSSEN INC, JANSSEN ONCOLOGY, INC AND BTG INTERNATIONAL LTD
Plaintiffs
and
DR REDDY'S LABORATORIES LTD
AND DR REDDY'S LABORATORIES, INC
Defendants
Dockets: T-182-19
T-1893-19
AND BETWEEN:
JANSSEN INC, JANSSEN ONCOLOGY, INC AND BTG INTERNATIONAL LTD
Plaintiffs
and
PHARMASCIENCE INC
Defendant
PUBLIC REASONS FOR JUDGMENT
(Identical to the Confidential Reasons for Judgment
issued on January 6, 2021)
TABLE OF CONTENTS
SECTIONS:
PARAGRAPH #
I. Introduction
[1] - [4]
II. Procedural History
[4] - [12]
III. Background
[13]
A. Parties/Claim
[13] - [19]
B. Overview
[20] - [30]
C. Witnesses
[31]
(1) Fact Witnesses
[31] - [35]
(2) Expert Witnesses
[36] - [37]
(a) Janssen’s Experts
[38] - [55]
(b) Defendants’ Experts
[56] - [73]
IV. Common General Knowledge/State of the Art
[74] - [77]
A. Re Abiraterone Acetate
[78] - [81]
B. Re Prednisone
[82] - [91]
V. The Invention
[92] - [108]
VI. Claim Construction
[109]
A. Person of Ordinary Skill
[109] - [110]
B. Claims
[111] - [124]
VII. Validity
[125]
A. Obviousness/Obvious to Try
[125]
(1) Framework
[125] - [137]
(2) Step 1 – State of the Art/Common General Knowledge – August 23, 2007
[138] - [162]
(3) Step 2 – The Differences between the State of the Art and the Asserted Claims
[163] - [169]
(4) Step 3 – Differences between the State of the Art and the inventive concept of the claim or the claim as construed
[170] - [180]
(5) Step 4 – Obvious/Degree of Invention
[181] - [183]
(6) “Self-Evident” Work
[184] - [189]
(7) Effort Required
[190] - [193]
(8) Motive
[194] - [199]
B. Utility
[200] - [210]
C. Sufficiency
[211] - [215]
D. Patentable Subject Matter
[216] - [223]
E. Listing
[224] - [228]
F. Non Asserted Claims/Counterclaim
[229] - [237]
VIII. Infringement
[238] - [260]
IX. Conclusion
[261] - [264]
PHELAN J.
I. Introduction
[1] This is a patent infringement action pursuant to s 6(1) of the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133 [NOC Regulations].
[2] These are the Reasons in respect of the Judgments issued January 8, 2021, dismissing the Plaintiffs’ action. The trial of these actions covered five weeks concluding at the end of November 2020. The statutory stay under the NOC Regulations expires January 9, 2021, and a decision was necessary before that date.
[3] This Court decided a similar NOC proceeding under the previous NOC Regulations where the dispute was conducted as an application. In that proceeding the Court granted the Plaintiffs’ application for a prohibition against granting a Notice of Compliance to one of the Defendant’s – Apotex Inc – for its proposed abiraterone acetate [AA] product (Janssen Inc v Apotex Inc, 2019 FC 1355). That judgment is under appeal. Those proceedings and judgment are referred to as the “2019 NOC”.
[4] The Patent at issue is a combination method and treatment for cancer, principally prostate cancer, by combining a 17α-hydroxylase/C17,20–lyase inhibitor such as AA with an anti-cancer agent or a steroid, in this case prednisone [PN].
II. Procedural History
[5] That NOC application was one of the last, if not the last, under the old NOC Regulations. New NOC approvals were sought by the Defendants for their respective AA products [Products]. This resulted in the subject action by the Plaintiffs.
[6] The actions were against each Defendant individually but the trial was conducted as one action. It was led in large measure by Apotex and subject to limited specific aspects related to each Defendant, Apotex and its draft Product Monograph served as a notional surrogate for all Defendants. The cooperation and professionalism of counsel facilitated the orderly and complete hearing of this dispute in these difficult COVID-19 times and the use of Zoom technology.
[7] There were no issues raised with respect to any form of estoppel as between the 2019 NOC and this action. The parties treated the matter as an entirely new proceeding as does this Court.
[8] The old NOC application regime had been much criticized and was replaced. The new actions afforded the parties and the Court an opportunity to obtain further and better evidence by way of production and discovery and new submissions.
[9] The parties took advantage of these more complete procedural rights. They also advanced new and better evidence in such areas as biostatistics and endocrinology. Previous witnesses were open to examination on a more complete record resulting from the pre-trial discovery process.
[10] The Court has had the advantage of hearing directly from witnesses. It has had better evidence, current legal teachings and more focused argument.
[11] Therefore, unless specifically adopted from the 2019 NOC – as in the case of claim construction – the findings and comments in that decision are irrelevant to the trial. This new process is somewhat like the previous right to sue for relief despite the findings in a related NOC proceeding.
[12] Under this new action process, the Court (especially where the judge on the previous NOC is the same as on the trial) is required to approach the case afresh with “a mind willing to understand and be persuaded”. The Court must come to the process with understanding but without conclusions.
III. Background
A. Parties/Claim
[13] Janssen Oncology, Inc [Janssen] and BTG International Ltd are the owners of Canadian Patent No. 2,661,442 [422 Patent or Patent]. The 422 Patent was issued from an application filed on August 23, 2007 and published February 28, 2008 – the differences in dates have no impact in this case.
[14] When the Patent application was filed in 2007, the proposed patent described and claimed a large number of combinations of a CYP17 inhibitor – including AA – and one or more of a therapeutic agent including anti-cancer agents. At least one embodiment combined the inhibitor with PN as an antibiotic but in the embodiment in respect to anti-cancer agents, PN is not mentioned.
[15] In 2011, before the 422 Patent was issued, the Plaintiffs obtained approval for its AA formulation ZYTIGA to be administered with PN to treat side effects. It then filed revised claims with the Patent Office to claim the combination of AA and PN to treat cancer as specified in the Asserted Claims.
[16] Janssen alleges that the Defendants have or will infringe Claims 3, 6, 7, 14 and 15 [the Asserted Claims].
[17] These claims read:
3. Use of a therapeutically effective amount of abiraterone acetate or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of prednisone, for the treatment of a prostate cancer in a human.
6. The use according to any one of claims 1-3, wherein the therapeutically effective amount of the abiraterone acetate or pharmaceutically acceptable salt thereof is 1000 mg/day.
7. The use according to any one of claims 1-3, wherein the therapeutically effective amount of the abiraterone acetate or a pharmaceutically acceptable salt thereof is in at least one oral dosage form comprising about 250 mg of abiraterone acetate or a pharmaceutically acceptable salt thereof.
14. Use of a therapeutically effective amount of abiraterone acetate or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of prednisone for the treatment of a refractory prostate cancer in a human.
15. The use according to any one of claims 12-14, wherein the refractory prostate cancer is not responding to at least one anti-cancer agent.
[18] The Defendants allege that each of the Asserted Claims is invalid. Apotex has also alleged in a counterclaim that the “Non Asserted” Claims are also invalid.
[19] The issue of invalidity is dispositive of the Plaintiffs’ Statement of Claim. However, to facilitate appellate review (which the Court was advised the Plaintiffs would seek no matter the result), the Court has dealt with the Infringement issue as well.
B. Overview
[20] Prostate cancer, the uncontrolled growth of cells in the prostate gland, is the most commonly diagnosed cancer in men and the second leading cause of cancer-related deaths in men. While early prostate cancer may be treated or not and monitored, at some point the cancer may spread to other parts of the body – becoming metastatic cancer.
[21] Most men with metastatic prostate cancer are treated with androgen deprivation therapy [ADT] because the male sex hormones (androgens) specifically testosterone promote prostate cancer.
Since the 1940s the primary treatment for metastatic prostate cancer by ADT was through medical or surgical castration to suppress androgen production in the testes. Patients treated with ADT still had some residual androgens in their system because the adrenal gland produces 10% of circulating androgens in men.
[22] When the prostate cancer begins to progress after ADT, it is referred to as “castration-resistant prostate cancer” [CRPC] and if the cancer has metastasized, it is referred to as mCRPC.
[23] A standard measurement in the treatment of prostate cancer is “PSA” level – prostate-specific antigen (a protein produced in the prostate gland). It is used to detect prostate cancer and to indicate the response to prostate cancer treatments. The PSA response was used as a surrogate measurement for the effectiveness of prostate cancer treatment although not a perfect indicator of such – it did not indicate survival benefits. A surrogate for survival benefit was necessary because the only way to determine such benefit is for the patient to die.
The issues of PSA and survival benefits arose in this trial with several of the Plaintiffs’ experts equating or measuring the usefulness of an anti-cancer drug against observed survival benefits rather than an anti-cancer effect as per the Patent.
[24] By August 2007 (the threshold date for this matter), a group of cytotoxic chemotherapy drugs called taxanes, and more specifically docetaxel (approved in 2004), showed a modest survival benefit in mCRPC patients. Its method of action was different from hormonal therapies like ADT.
[25] Docetaxel’s survival benefit was a “new paradigm”, as Dr. Nam explained, for the treatment of patients with mCRPC. However, there were significant side effects in many patients. A further major problem was that mCRPC patients stop responding to treatments with docetaxel which eventually leads to death.
[26] Before 2007, aminoglutethimide and ketoconazole were used in prostate cancer therapy but neither improved survival. They were understood to be non-specific inhibitors of adrenal steroid synthesis and had serious side effects, including glucocorticoid deficiency which sometimes required concomitant glucocorticoid use. Neither compound was said to cause mineralocorticoid excess (an area of debate) but as Dr. Bantle pointed out, even if mineralcorticoid levels remained normal, low levels of glucocorticoid had their own serious side effects.
[27] PN, a glucocorticoid, was used to palliate prostate cancer patients and alleviate side effects of treatment. It was an old drug – available since the 1950s. It was known to have some anti-cancer effects but how and how much was not known. PN did offer palliation, relief from side effects and some anti-cancer effects (sometimes called anti-tumour activity) but not an established survival benefit. PN had not been approved as an anti-cancer drug.
[28] As disclosed in the 422 Patient, CYP17 inhibitors, of which AA is one, had been shown to be useful in treating prostate cancer. AA was a newer drug than PN.
[29] The CYP17 enzyme (17α-hydroxylase/C17,20–lyase) has two activities in adrenal steroid synthesis: 17α hydroxylase activity is necessary for the production of cortisol and androgens while 17,20‑lyase activity only affects the production of androgens.
[30] Attached as Schedule A to these Reasons is a chart of the relevant pathways produced in Dr. Bantle’s expert report and of considerable help to this Court.
C. Witnesses
(1) Fact Witnesses
[31] Dr. Johann de Bono, Regius Professor of Experimental Cancer Medicine in the U.K., is a prostate cancer researcher, physician and a named inventor of the 422 Patent.
[32] The Defendants attempted to discredit his inventorship; however, he was added as an inventor by Order of Justice Heneghan (Janssen Oncology, Inc and BTG International Ltd v Canada (Attorney General) (June 15, 2018), T-1495-17 (Federal Court)) and it is not for this Court to go behind that Order.
However, the Court is aware that Dr. de Bono’s work was to develop a hypothesis which was not the patent eventually filed. He himself was surprised to learn of the 422 Patent.
[33] Dr. de Bono leads the Prostate Cancer Team at the Institute of Cancer Research [ICR] at the Royal Marsden Hospital.
He gave direct useful evidence as to the trials which led to the 422 Patent. He traced the process of his hypothesis that glucocorticoid supplementation could reverse resistance to AA by reducing the body’s production of upstream adrenal steroids [1] . In that regard, while he used dexamethasone because it was available at ICR, as he admitted any glucocorticoid would do. PN was not then available in the UK.
[34] Dr. Gloria Lee, a physician and former Vice President of Clinical Research and Development at Cougar Biotechnology Inc [Cougar], the sponsor of the clinical trials that led to the 422 Patent. Her evidence gave context and details of the four (4) Cougar studies – COU‑AA‑001, 002, 003 and 004 as well as the 2008 Protocol Amendment.
[35] Dr. Robert Charnas was the Global Regulatory Leader at Cougar (now Janssen Oncology Inc) and was responsible for the regulatory submission for the ZYTIGA (the Plaintiffs’ AA product) project. Like Dr. Lee, his evidence encompassed the Cougar Studies and the Protocol Amendment but also the two Phase II studies COU-AA-301 and 302 which compared the efficacy of the combination of PN and AA in mCRPC patients with PN and placebo.
(2) Expert Witnesses
[36] This case was largely driven by expert evidence. It is the Court’s task to assess this difficult evidentiary field, both as a whole and individually with each expert.
[37] There were areas of weakness, lack of clarity and other such issues with respect to most experts but the Court must assess credibility and weight against something less than perfection.
(a) Janssen’s Experts
[38] Dr. Geoffrey Gotto is currently the Medical Director at the Clinic for Advanced Metastatic Prostate Cancer in Calgary and a Clinical Associate Professor at the University of Calgary. He was qualified as an expert in urologic oncology, including clinical matters involving the diagnosis and treatment of prostate cancer including surgery and prescribing of medical interventions. This expertise includes an understanding of prescribing decisions by Canadian urologists for the treatment of prostate cancer. His evidence in general covered details of the use made of a drug’s product monograph, data supporting ZYTIGA’s product monograph, the instructions to be taken from a product monograph, the Apotex and other Defendants’ Product Monograph instructions to urologists, and a comparison of product monographs.
[39] Dr. Gotto was helpful in providing context and understanding of the drugs from an urologist’s perspective. His involvement with Janssen, while not ideal in terms of objectivity, did not imperil his credibility. He was challenged in explaining the roles of AA and PN to the extent that product monographs spoke of PN in terms of side effects. Despite these statements, the product monograph in Dr. Reddy’s indicated that PN is to be used to treat prostate cancer for its anti-cancer effects when used in combination with AA. His equivocating on PN’s anti-cancer effects was unsatisfactory and suggested a protectiveness of the Plaintiffs and their position.
[40] Jane Costaris is the President of Regulatory Solutions Inc and was qualified as an expert in regulatory affairs and quality compliance for the pharmaceutical, natural health product, and medical device industries. She has expertise in federal and provincial regulatory submissions for drug and health products in Canada, including both new drug submissions and supplemental new drug submissions, as well as submissions for subsequent entry/generic products. In addition, she has expertise in preparing advertising/marketing materials for drug products in Canada. She gave general evidence on regulatory matters with Health Canada and specifics on the particular Product Monographs in issue in this litigation. Her evidence was generally uncontroversial.
[41] Dr. Matthew Rettig is a medical oncologist with 25 years’ experience in prostate cancer and a key witness for the Plaintiffs. He was qualified as an expert in medical oncology, and in particular the diagnosis, treatment, and management of urologic cancers including the treatment of prostate cancer. This expertise includes: (a) the design, conduct, and interpretation of results from clinical trials from a clinician’s perspective; (b) the use of agents in the treatment of prostate cancer, palliation of prostate cancer, and management of side effects associated with prostate cancer treatments; and (c) understanding prescribing decisions by medical oncologists for the treatment of prostate cancer.
[42] Dr. Rettig was involved on behalf of Janssen as a local co-investigator and principal investigator for clinical trials relating to AA and PN, particularly the 301 and 302 studies and principal investigator in the 004 study (one of the core subjects of this litigation). It was an unfortunate closeness to the subject of what should be an objective opinion. His evidence covered a broad range of topics from common general knowledge [CGK], the POS (person of ordinary skill in the art), construction of words in the Patent, through to infringement. In summary, his opinion is that:
arriving at the 422 Patent’s claimed invention would have required inventiveness and would not have been obvious to a POS as of August 2007 – that it would not have been obvious to try the combination of AA and PN (or either agent alone) to treat cancer.
utility of the subject matter is demonstrated by the data in the possession of the inventors prior to August 2007 but not disclosed in the Patent.
the Asserted Claims cover the combination of AA and PN to treat prostate cancer. ZYTIGA is approved for this use.
as of 2007 a POS would have been able to practice the Asserted Claims based on the teachings of the Patent and the CGK.
a physician is not required or expected to use skill/judgment to put the subject matter into practice.
[43] Dr. Rettig’s report was well constructed, clear but flawed. His evidence is to be contrasted with Dr. Nam and Dr. Lipton on behalf of the Defendants. In his non-core area of expertise, endocrinology, his comments can be contrasted with Dr. Bantle.
[44] Dr. Rettig’s evidence was seriously undermined in cross-examination. It was not just questions of wording choices and nuance but he was required to concede and have struck or changed from his report major conclusions particularly as related to the “obviousness” issue in respect of aminoglutethimide’s anti-cancer effects, the same in regard to ketoconazole, the known requirement to have glucocorticoid replacement for aminoglutethimide and ketoconazole, and the role of PN for an anti-cancer effect. He made other major concessions in these important areas.
[45] Among the many reversals and clarifications of his report is that he was forced to admit that PN was known to have an anti-cancer effect; that aminoglutethimide was known to have anti-cancer treatment effects in prostate cancer; and that ketocconazole had an anti-cancer effect.
[46] His explanation for this changing of opinion from “not have an anti-cancer effect” to “have an anti-cancer effect” was that he had in mind known survival benefit not anti-cancer effect. This may be true in his mind but it is unsatisfactory given his evidence about the claims. Despite these revisions to his report, he maintained his opinion that it was not obvious to try to combine AA and PN as claimed because there was no motivation to do so. It is a tenuous opinion at best and not one on which the Court can rely.
[47] His utility analysis, while nevertheless helpful, was shaky because it proceeded on an error in understanding of the applicable law. He admitted to understanding that the criterion was “a scintilla of evidence of utility” rather than “a scintilla of utility”.
[48] I do not reject his report in whole and I generally accept his opinion in some areas of validity (e.g. utility) and in respect of infringement. However, I find in many areas of validity, particularly the obviousness analysis, that the Defendants’ relevant experts are more credible and where the two sides part, I generally accept the Defendants’ experts.
[49] Dr. Karla Ballman is the Chief of the Division of Biostatistics (a new field in this litigation) in the Department of Population Health Sciences at Weill Cornell Medical College. She was qualified as an expert in biostatistics, in particular cancer biostatistics. She has expertise in clinical trial design and analysis of clinical trial data and interpretation of results from a biostatistician’s perspective, including mathematical modelling, statistics, probability, data analysis and experimental design.
[50] She provided useful and clear evidence on the relevance of biostatistics and the meaning which can be drawn from the Cougar studies and from such publications as Attard 2009, Danila 2010 and Reid 2010. Her evidence was confirmatory of PN’s role as providing an anti-cancer effect in the combination of AA and PN for the treatment of prostate cancer.
[51] Dr. Ballman was prepared to make these conclusions in contrast to the Defendants’ biostatistician, Dr. McKeague. She was required to make the assumption that dexamethasone and PN are members of the same class and behave similarly. While the Defendants criticize that assumption, she accepted it based on her considerable experience in the area of oncology. In that regard, Dr. Ballman’s experience, in my view, allowed her to bring professional judgment to areas of uncertainty which others highly qualified in their specific field but not as experienced in oncology, could not. Her evidence was helpful and persuasive.
[52] Dr. Richard Auchus is a clinical endocrinologist, practising and researching steroid hormone synthesis for over 25 years. He was said to have extensive experience diagnosing and treating patients with adrenal conditions. He was qualified as an expert in clinical endocrinology and research and clinical management of endocrinologic disorders involving steroidogenesis, including androgen synthesis and action. This expertise includes diagnosing and treating patients with congenital and non-congenital conditions involving changes in steroid hormone production, including adrenal insufficiency and disorders of mineralocorticoid production.
[53] Dr. Auchus disclosed his extensive involvement over the years for Cougar (now Janssen) including with respect to AA – whether to administer a glucocorticoid with AA, one of the central issues in this case. While this disclosure was made in this case, he did not disclose this level of involvement in the 2019 NOC where he was a witness. His direct and substantive involvement and relationship with a participant calls into question – at least on an objective view – whether he could provide the kind of unbiased opinion contemplated by the Code of Conduct for Expert Witnesses. The Court was not comfortable with this level of involvement and it affected the weight which could be given to his evidence.
[54] Dr. Auchus was of the view that a glucocorticoid did not have to be co-administered when AA is used. He drew a distinction between ketoconazole/aminoglutethimide and AA and called into question the teachings of O’Donnell 2004. He discounted the use and need for Synacthen tests. His principal points were undermined in cross-examination including that a glucocorticoid might have to be administered for other side effects. He had his theory, the correctness of which is not for resolution here, but his evidence of what a POS would know and do, was unconvincing.
[55] Dr. Auchus’ evidence was almost completely at odds with Dr. Bantle on the key issues in this case. On many of these issues, the Court had to choose as between these witnesses. On the strength of Dr. Bantle’s evidence in the contrast of the weakness of Dr. Auchus’, this Court has relied more heavily on Dr. Bantle’s evidence.
(b) Defendants’ Experts
[56] Dr. Robert Nam is a professor of surgery at the University of Toronto, Head of the Genitourinary Cancer Program, Odette Cancer Centre as well as other relevant positions. He works in the fields of oncology and epidemiology maintaining a practice significantly focused on prostate cancer management. He was qualified as an expert in the field of urologic oncology and specifically the treatment of patients with prostate cancer (including advanced or metastatic prostate cancer), and clinical epidemiology of prostate cancer.
[57] Dr. Nam’s evidence was wide ranging including the CGK of a POS noting that by August 2007, dexamethasone, hydrocortisone and PN were the most common glucocorticoids used in prostate cancer treatment. He addressed issues of PSA as a surrogate indicator of treatment effectiveness and PN as having an anti-cancer effect. He pointed the way in the analysis of obviousness (obvious to try) to the conclusion that the Asserted Claims were obvious. He reviewed the relevant literature and test results as part of forming his opinion.
[58] He also covered off other areas tangentially, such as biostatistics. The Court found his evidence helpful and persuasive where it was grounded in his main areas of experience and expertise. It was forceful when read in conjunction with Dr. Lipton’s evidence. As contrasted with Dr. Rettig, the Court put more reliance on Dr. Nam’s evidence alone and in conjunction with Dr. Lipton.
[59] Dr. Allan Lipton is a professor at the Department of Medicine, in the Division of Hematology and Oncology at Pennsylvania State University. He has experience in the treatment of prostate cancer with adrenal steroid synthesis inhibitors and corticosteroids (e.g. glucocorticoid) with a focus for 40+ years on prostate cancer care and research. He was qualified as a medical doctor who is expert in the field of medical oncology and specifically in the treatment of patients with prostate cancer.
[60] Dr. Lipton, whose evidence is also considered in the context of Dr. Nam, covered the background of the disease and the treatment. He opined that by 2006, it was well known that CYP17 inhibitors (such as ketoconazole and aminoglutethimide) were useful in the treatment of prostate cancer because they impaired the production of adrenal steroids and thus prevented the conversion to testosterone. However, they also impaired the production of cortisol, resulting in the overproduction of ACTH, and the rise in mineralocorticoids with life threatening effects. It was known that glucocorticoids could address these issues; reduce mineralocorticoids, deal with adrenal insufficiency and hypertension.
[61] He spoke to the knowledge of a POS and that as of 2006, the prior art provided three independent motivations to combine AA with PN for prostate cancer – 1) PN would provide glucocorticoid replacement to address known AA side effects; 2) PN would provide palliative relief and improve quality of life; and 3) both PN and AA were known as active anti-cancer agents with different methods of action in treating prostate cancer. The Court puts considerable weight on this conclusion as it summarizes the weight of the evidence on this issue of motivation.
[62] Dr. Lipton canvassed the relevant literature and addressed the expectation that AA could treat prostate cancer, as a known CYP17 inhibitor since 1994. Likewise, he concluded that by 2006 (or even earlier) a POS would have known that PN alone could be used as an active anti-cancer agent. He traced the reasons why it would have been obvious to try to create the combination as found in the Patent.
[63] The Court found Dr. Lipton’s evidence, while not without some blemishes, to be thorough, knowledgeable and balanced. The Court places considerable reliance on that evidence.
[64] Dr. John Bantle is a medical endocrinologist, has held numerous positions in the Department of Medicine at the University of Minnesota Medical School and is now a Professor Emeritus. He was qualified simply as an expert in the field of endocrinology. He has extensive knowledge and experience in the field since 1972.
[65] He outlined the background knowledge of AA particularly that by inhibiting CYP17 (crucial to the adrenal and glucocorticoid pathways), AA substantially inhibits the glucocorticoid and androgen pathways and thus the cholesterol molecules instead follow the mineralocorticoid pathway (see Schedule A) resulting in much higher, possibly excessive, mineralocorticoid levels. A resulting drop in adrenal androgens can be life threatening. Both disorders of mineralocorticoid excess and adrenal insufficiency are associated with a host of serious side effects. The Synacthen test – rejected as a useful tool in this case by Dr. Auchus – was used to determine cortisol response and thus adrenal insufficiency.
[66] There was a sharp debate between Dr. Bantle, who believed that AA could lead to adrenal insufficiency by blocking cortisol production, and Dr. Auchus who believes that corticosterone which is not blocked can compensate for the lost cortisol. It is not for the Court to settle the scientific debate but to note that Dr. Bantle reflected the CGK at the time and what a POS would understand.
[67] Dr. Bantle opined that due to the similarity between ketoconazole and AA, a skilled endocrinologist would have been motivated to administer AA with concomitant glucocorticoid therapy. He also addressed some of the literature and concluded that O’Donnell, in addressing the need for further studies of AA, was directed more at when a glucocorticoid (such as PN) would be administered with AA rather than if a glucocorticoid was required “if at all”.
[68] Dr. Bantle’s report was thorough and balanced. He responded properly to questions and was unflappable. He exhibited the teacher’s desire to educate rather than to advocate. His evidence is, where necessary, favoured over his opposite number Dr. Auchus, discussed earlier.
[69] Dr. Ian McKeague is a professor of biostatistics at Columbia University. He was qualified as an expert in statistics, including biostatistics, clinical trial design, and statistical analysis of clinical trial results.
[70] Dr. McKeague was the counter expert to Dr. Ballman. He spoke to statistical principles, the AA clinical trials, the comparison of median TTTP and concluded that in looking at the publications Attard 2009 and Ryan 2011, there were too many differences to allow for a cross-study comparison and then proceeded to do what he criticized Dr. Ballman for doing, by doing his own cross-study.
[71] The critical difference between Dr. McKeague and Dr. Ballman is that Dr. Ballman had the subject matter (oncology) knowledge and experience to exercise her professional judgment. She could reach conclusions based on her knowledge and experience which Dr. McKeague was not prepared to and could not do. As indicated earlier, the Court is prepared to accept this exercise of judgment even with many of the frailties to which Dr. McKeague referred.
[72] Ms. Susanne Picard is a pharmacist and owner of SPharma Inc, a regulatory consulting firm covering a range of health products. She was qualified as a pharmacist and regulatory affairs consultant who is expert in the approval of pharmaceutical products and their labelling (including Product Monographs) by Health Canada, the regulations, guidances and protocols governing same.
[73] Ms. Picard’s evidence focused on the requirements for product monographs and the Defendants’ Product Monographs. She confirmed that based on her knowledge of the draft Product Monographs, none of the Defendants could be permitted to market their AA product (and in the case of Apotex, its PN product) as having an anti-cancer effect. There were inconsequential differences between the Defendants’ referenced Products.
IV. Common General Knowledge/State of the Art
[74] CGK is the information generally known at the relevant time by the person skilled in the field of art or science to which the patent relates. It does not include all the information in the public domain (Apotex Inc v Sanofi-Synthelabo Canada Inc, 2008 SCC 61 at para 37 [Sanofi]).
[75] The state of the art is a wider field (Hospira Healthcare Corporation v Kennedy Trust for Rheumatology Research, 2020 FCA 30 [Hospira FCA]) but in this case the parties are not disputing the state of the art largely represented by professional articles, abstracts and the like.
[76] During the trial the Court was referred to a number of pieces of prior art by Zoom screen share. As useful as the portions were, particularly in cross-examination, the full text of each must be considered to have an appreciation of the state of the art and the CGK.
[77] The Court was referred, often tangentially, to other publications. As an aside, but in the context of the timing of this trial, references were made to Fauci papers – the Dr. Fauci of COVID-19 fame.
A. Re Abiraterone Acetate
[78] Barrie 1994 concluded that AA was worthy of further study as a potential agent for the treatment of hormone dependent prostate cancer.
[79] O’Donnell 2004 (a British Journal of Cancer (2004) paper by the lead author O’Donnell) reported on the first human trial of AA. It was an AA monotherapy trial conducted by ICR. Aside from concluding that AA was safe and that there should be further study because of the enhanced testosterone suppression, it also suggested that AA was a suitable second-line (post-castration) treatment. It also identified that ketoconazole, while an unselective inhibitor, had an anti-tumour effect (a clinical benefit evidenced by a reduction in PSA). A more selective inhibitor could be a second-line agent.
[80] A few later publications speculated that AA might be a good subject for further study in humans noting it inhibited both the hydroxylase and lyase function of the CYP17 enzyme.
[81] O’Donnell 2004 confirmed AA’s role in cancer treatment by noting AA’s ability to sustain testosterone suppression in castrate males, when given in 500-800 mg doses. It indicated AA could be a second-line treatment.
B. Re Prednisone
[82] With respect to PN, the relevant publications start with Tannock 1996 although PN was a known compound before then.
[83] Tannock 1996 was a publication study involving patients having refractory prostate cancer with pain. Patients received a chemo drug with PN or PN alone. The publication disclosed that, in combination with the chemo drug mitoxantrone, PN, dosed at 10 mg per day, would provide palliation to hormone-resistant prostate cancer patients.
[84] This was followed by Sartor 1998 which considered PN’s effect on PSA levels in patients with hormone refractory prostate cancer. It showed that 34% achieved a PSA decline of at least 50% and 14% achieved a PSA decline of 75%. The result was that 48% of the patients achieved greater than 50% PSA decline. Some criticism was leveled that the results did not reach Guidelines of 50% of patients but one cannot discount that the results were pointing to PN being tolerated and having an anti-cancer effect in a subset of prostate cancer patients.
[85] In Fossa 2001, the results were less encouraging with only approximately 20% of patients having a PSA decline of greater than 50%. However, it concluded that “… monotherapy with low cost PN should be considered as first-line, standard hormonal manipulation of HRPC but the combination with tolerable cytotoxic treatment should be explored further”.
[86] The following year in Fakih 2002, the authors concluded that a glucocorticoid may exert an anti-tumour effect on androgen-independent prostate cancer by suppression of adrenal androgens.
[87] Lastly, in this review of the literature related to PN, was Harris 2002 which was a prospective Phase II study. It concluded that “… glucocorticoids alone may have anti tumour effects mediated either by direct interaction with androgen receptors or by feedback inhibition of the hypothalamic-pituitary-adrenal axis”.
[88] To complete the picture, the prior art taught the use of combination agents to treat prostate cancer. Gerber 1990 dealing with ketoconazole and PN in refractory prostate cancer, noted that a small group of patients despite having had androgen ablation would benefit from ketoconazole and glucocorticoid treatment.
[89] O’Donnell 2004 referred specifically to AA and the need to determine if concomitant therapy with a glucocorticoid was required on a continuous basis at a time of psychological stress.
[90] Vidal 2004 (where Dr. de Bono was an author), in addition to addressing the use of low dose steroids as inhibiting key enzymes, noted that combining drugs could improve outcomes.
[91] The CGK addressed AA’s role, PN’s role and the use of the combination of compounds on the treatment of prostate cancer.
V. The Invention
[92] The inventors did not discover either of the drugs in this combination. AA was first synthesized and described in 1994. Ten (10) years later a small California company, Cougar Biotechnology, Inc was given the rights to develop AA. The first clinical trials sponsored by Cougar began in December 2005 and were led by Dr. de Bono.
[93] Before the clinical trials commenced, the state of the art known to a POS (it was generally agreed that there is no substantive difference between the state of the art and the CGK) was that despite castration, prostate cancer cells were still being stimulated by testosterone produced in the adrenal glands. Thus, hormonal therapies targeted at reducing adrenal androgens (testosterone) could still be useful for patients with androgen independent prostate cancer. It was also known that CYP17 inhibitors (aminoglutethimide and ketoconazole) had demonstrated modest anti-tumour activity due to their ability to suppress adrenal androgen synthesis. As such, more selective CYP17 inhibitors were sought.
[94] Prior to commencing the trials it was known that AA was a CYP17 inhibitor which could treat prostate cancer. Others had determined that AA was a potent irreversible CYP17 inhibitor. De Bono’s colleagues at ICR had conducted three Phase I trials administering AA to castrate and non-castrate prostate cancer patients.
[95] PN was also known to suppress the androgens that stimulate prostate cancer cell growth. For this reason, combined with the widely known palliative effects associated with them, PN and other glucocorticoids were frequently administered as the “standard of care” in advanced prostate cancer patients.
[96] Dr. de Bono knew all the above and that administering AA without a glucocorticoid could lead to endocrine toxicity. Although he knew that administering glucocorticoids including PN would protect patients from side effects, and despite pressure from his colleagues, Dr. de Bono resisted adding a concomitant glucocorticoid at the outset of the first study – COU-AA-001 [001 Study] because he wanted a “clean” study of AA unhindered by any other anti-cancer drug’s impact although he knew that administering glucocorticoids including PN would protect patients from side effects.
[97] The purpo