Janssen Inc. v. Apotex Inc.

Janssen Inc. v. Apotex Inc.
Court (s) Database
Federal Court Decisions
Date
2019-10-29
Neutral citation
2019 FC 1355
File numbers
T-1661-17
Notes
A correction was made on November 22, 2019. A correction was made on May 25, 2020.
Decision Content
Date: 20191029
Docket: T-1661-17
Citation: 2019 FC 1355
BETWEEN:
JANSSEN INC. and
JANSSEN ONCOLOGY, INC.,
BTG INTERNATIONAL LTD.
Applicants
and
APOTEX INC. and
THE MINISTER OF HEALTH
Respondents
REASONS FOR JUDGMENT
TABLE OF CONTENTS
SECTIONS:
PARAGRAPH #
I. Introduction
[1] - [6]
II. Background
[7]
A. Procedural History
[7] - [11]
B. Facts
[12]
(1) The Witnesses
[12] - [14]
(2) Scientific Background
[15]
(a) Prostate Cancer Treatment
[16] - [20]
(b) Clinical Trials
[21]
(c) Steroid Hormone Synthesis
[22] - [29]
(3) The 422 Patent and Asserted Claims
[30] - [38]
(4) The Cougar Trials
[39] - [44]
(5) APO-ABIRATERONE and ZYTIGA
[45] - [50]
III. Issues
[51]
IV. Analysis
[52]
A. Expert Evidence
[52] - [59]
B. Burden of Proof
[60] - [63]
C. Claim Construction
[64]
(1) The Person of Ordinary Skill
[64] - [71]
(2) The Common General Knowledge as of the Filing Date and Publication Date
[72] - [80]
(a) Apotex
[81] - [92]
(b) Court’s Conclusions re Disputed General Knowledge
[93] - [115]
(3) Claim Construction Analysis
[116] - [127]
D. Patentable Subject Matter
[128] - [142]
E. Obviousness
[143] - [145]
(1) POS/Common General Knowledge
[146]
(2) Inventive Concept
[147]
(3) Difference: State of Art/Inventive Concept
[148] - [152]
(4) Obviousness/Degree of Invention
[153] - [159]
(5) Court’s Conclusions on Obviousness
[160]
(a) Step 1: POS and Common General Knowledge
[160]
(b) Step 2: Inventive Concept or Claim Construction
[161] - [163]
(c) Step 3: Differences between the State of the Art and Inventive Concept
[164]
(i) State of the Art
[165] - [168]
(ii) Prior Art on the Anti-Cancer Effect of Glucocorticoids
[169] - [177]
(iii) Differences between the SOA and the Invention
[178]
(d) Step 4: Obviousness/Degree of Invention
[179] - [181]
(e) Obviousness in the Prior Art and Common General Knowledge
[182] - [193]
(f) Obvious to Try Consideration
[194] - [203]
F. Inutility
[204] - [224]
G. Infringement
[225] - [246]
H. Listing Eligibility
[247] - [259]
V. Conclusion
[260] - [261]
PHELAN J.
I. Introduction
[1] This is an application brought under subsection 55.2(4) of the Patent Act, RSC 1985, c P‑4 [Act] and subsection 6(1) of the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133, as they appeared on September 20, 2017 [Regulations], to prohibit the Minister of Health from issuing a Notice of Compliance to Apotex Inc [Apotex].
[2] The Regulations prior to amendment in 2017 apply because the Respondent, Apotex, served its Notice of Allegation [NOA] on the Applicant, Janssen Inc [Janssen], on September 19, 2017, two days before the new Regulations came into force on September 21, 2017. According to the transition provisions in subsection 9(1) of the Regulations Amending the Patented Medicines (Notice of Compliance) Regulations, 2017, SOR/2017-166, the old Regulations continue to apply for a matter relating to a notice of allegation served on the first person before the amendments came into force.
[3] The nub of the dispute is the function of prednisone [PN] as an anti-cancer agent and/or as a means to treat the side effects caused by abiraterone acetate [AA].
[4] The Applicants [collectively, “Janssen”] state that Canadian Patent No. 2,661,422 [422 Patent or the Patent] claims the invention of the combination of AA and PN for the treatment of prostate cancer, meaning that both compounds work in combination to have an anti-cancer effect. The Respondent, Apotex, asserts that Janssen is merely combining two elements that were known to have separate anti-cancer effects and do not work synergistically. Apotex also claims that both Janssen’s and Apotex’s AA drug products are not proposed for the same use as that claimed by the 422 Patent because the Apotex drug products indicate AA as the anti-cancer treatment with PN prescribed only to treat adverse side effects.
[5] A significant problem in this case is that the anti-cancer role of PN that is claimed in the 422 Patent when used in combination with AA appears to no longer be understood as the main role PN plays in cancer treatment. Instead, PN is now primarily understood to address the side effects caused by AA. The interpretation of how the combination is claimed in the 422 Patent – the claim construction – significantly impacts the Court’s findings.
[6] The relief sought is an order to the Minister of Health prohibiting the issuance of a Notice of Compliance [NOC] to Apotex for its drug APO-ABIRATERONE. Other relief in the nature of declaration was abandoned.
II. Background
A. Procedural History
[7] Cougar Biotechnology Inc, [Cougar] filed an application for Canadian Patent 2,661,422 on August 23, 2007, which was published on February 28, 2008, and issued on June 27, 2017. Its priority filing date based on a US Patent was August 25, 2006. Cougar was renamed Janssen Oncology Inc (one of the Applicants) in 2012. The 422 Patent is listed by Janssen Inc on the Patent Register for Janssen’s AA product, which has the brand name ZYTIGA. The first Notice of Compliance for ZYTIGA appears to have been issued on July 27, 2011. The 422 Patent was listed on the Patent Register for ZYTIGA when the patent was issued on June 27, 2017.
[8] On July 28, 2017, Apotex filed an Abbreviated New Drug Submission with the Minister of Health seeking a Notice of Compliance for APO-ABIRATERONE (250 mg oral tablets containing AA), using ZYTIGA as the Canadian reference product.
[9] On September 18, 2017, Apotex sent its NOA to Janssen alleging that the 422 Patent is invalid, would not be infringed by APO-ABIRATERONE, and is ineligible to be listed on the register. The NOA was received by Janssen on September 19, 2017.
[10] The new Regulations came into effect on September 21, 2017.
[11] Janssen filed its Notice of Application in this Court on November 1, 2017. Therefore, the “deadline date” for a decision if the Court is to prohibit issuing Apotex an NOC is November 1, 2019.
B. Facts
(1) The Witnesses
[12] Janssen’s fact witnesses are:
Dr. Ian Judson, a physician and former researcher involved in the development of AA monotherapy. He described the initial research and the publication of the O’Donnell 2004 article, an important piece of prior art in this case.
Dr. Johann de Bono who, while not the inventor, believes that he contributed to the invention of the Patent. He is a physician focussing on prostate cancer research.
Dr. Gloria Lee, a physician and former Vice President of Clinical Research and Development at Cougar, which sponsored the clinical trials leading to the invention claimed in the 422 Patent.
Dr. Robert Charnas, Global Regulatory Leader at Cougar who was responsible for the AA and PN project starting in 2008.
[13] Janssen’s expert witnesses are:
Dr. Matthew Rettig (medical oncologist).
Dr. Richard Auchus (endocrinologist).
Dr. Alan So (urologist).
Dr. Jan Sedgeworth (regulatory affairs consultant).
[14] Apotex’s expert witnesses are Dr. Robert Nam (uro-oncologist) and Dr. Gail Prins (endocrinologist). Important aspects of their expert reports are referred to in these reasons.
(2) Scientific Background
[15] The general scientific background that the experts agree on and that will aid in understanding the case is set out in the following paragraphs. This information forms part of the common general knowledge as of the Filing Date and the Publication Date.
(a) Prostate Cancer Treatment
[16] Prostate cancer is the most commonly diagnosed cancer in men and is the third leading cause of all cancer-related death in men in Canada. Prostate cancer results from the uncontrolled growth of cells in the prostate gland. In its early stages, prostate cancer is confined to the prostate gland. Early stage cancer might be left untreated and monitored by active surveillance. If prostate cancer spreads to other parts of the body, it is called metastatic prostate cancer.
[17] Male sex hormones (androgens), specifically testosterone, have long been known to promote prostate cancer. Therefore, the primary treatment for metastatic prostate cancer has been androgen deprivation therapy [ADT] through medical or surgical castration to suppress androgen production in the testes. Patients treated with ADT still have some residual androgens in their system because the adrenal gland produces about 10% of a man’s androgens. After some time, on average between 12 to 33 months, patients treated with ADT have their prostate cancer begin to progress again. When prostate cancer progresses after being treated with ADT, it is called castrate resistant prostate cancer [CRPC]; if it is also metastatic cancer, it is referred to as mCRPC. In earlier publications, CRPC was also referred to as “hormone refractory prostate cancer” or “androgen independent prostate cancer”, among other variations.
[18] As of 2007, what caused prostate cancer to become castration resistant was not fully known. Whether residual androgens from the adrenal gland were thought to play a significant role in mCRPC is a major point of disagreement between the experts.
[19] Prostate specific antigen [PSA], a protein produced by the prostate gland, was measured to both initially detect prostate cancer and to indicate the response of prostate cancer to treatments in 2007. PSA response was used as a surrogate measurement for the effectiveness of prostate cancer treatments, although it was not perfectly correlated with other indicators of treatment success, like survival benefit. A significant PSA response in 2007 was defined as a decline in PSA levels by 50% or more confirmed by a second PSA measurement four weeks later.
[20] As of 2007, a new type of chemotherapy drugs called taxanes, and specifically docetaxel, had been shown to provide a modest survival benefit for patients with mCRPC. Docetaxel, however, had significant toxicity and side effects.
(b) Clinical Trials
[21] There are three types of clinical trials for cancer treatments. Phase I trials are small and short in duration; they are meant to determine safety and dosage of the drug. Phase II trials examine efficacy and side effects of the drug and would include several hundred patients studied over a few months to a few years. Phase III trials would have 300 to 3,000 patients and are designed to examine the drug’s safety, effectiveness, and an acceptable balance of costs and benefits.
(c) Steroid Hormone Synthesis
[22] Janssen’s expert, Auchus, provided a helpful overview of steroid hormone synthesis. Steroid hormones regulate a variety of processes in the body based on the receptor to which they bind. All steroid hormones are synthesized from cholesterol. There are three types of steroid hormones: mineralocorticoids, glucocorticoids, and sex steroids. Given their similar structure and overlapping synthesis pathways, the divisions between the categories of steroid hormones are not always absolute, as some steroids may have multiple overlapping functions. Steroid synthesis is complex. Steroid synthesis requires enzymes along each step of the synthesis pathways.
[23] In men, the testes produce sex steroids, or androgens, which are mainly testosterone, dihydrotesterone, dehydroepiandrosterone, and androstenedione. The testes produce most of a man’s testosterone.
[24] The adrenal gland also produces some androgens, as well as glucocorticoids and mineralocorticoids. Glucocorticoids are necessary for the body to respond to stress. The major glucocorticoid is cortisol. Corticosterone is the secondary glucocorticoid in humans. Mineralocorticoids, primarily aldosterone, regulate water and salt retention.
[25] Inhibiting an enzyme along the steroid synthesis pathway could affect several of the steroids downstream. The cholesterol side chain cleavage enzyme or desmolase, is necessary for the production of all adrenal steroids. Inhibiting desmolase would suppress all adrenal steroids.
[26] The 17α-hydroxylase/ C17,20-lyase [CYP17] enzyme has two activities in adrenal steroid synthesis: 17α-hydroxylase activity and 17,20-lyase activity. 17α-hydroxylase activity is necessary for the production of cortisol as well as androgens. 17,20-lyase activity only affects the production of androgens.
[27] The hormone, adrenocorticotropic hormone [ACTH], controlled by the hypothalamus and pituitary gland regulates the secretion of glucocorticoids and androgens from the adrenal gland. Mineralocorticoids are affected by the renin-angiotensin II-aldosterone system as well as by ACTH.
[28] When the adrenal gland’s ability to produce glucocorticoids and mineralocorticoids is impaired or when the body does not produce enough ACTH, this can result in a condition called adrenal insufficiency. Symptoms of adrenal insufficiency include low blood pressure, fatigue, anorexia, weight loss, abdominal pain, low blood sugar, low sodium, and hyperpigmentation. Adrenal crisis is a potential life-threatening condition when the body cannot produce enough steroids to respond to a serious stressor. Mineralocorticoid excess occurs when mineralocorticoids are overproduced causing symptoms such as high blood pressure, low potassium and fluid retention. Adrenal function can be tested using a Synacthen test which creates an artificial stress response to test whether cortisol levels respond to stress appropriately.
[29] Artificial glucocorticoids such as hydrocortisone, PN, and dexamethasone can be used to treat adrenal insufficiency and mineralocorticoid excess, which is called glucocorticoid replacement therapy. Glucocorticoid replacement theory has some risks and side effects. However, the experts differed as to whether glucocorticoid replacement therapy using artificial glucocorticoids would be preferred over other options.
(3) The 422 Patent and Asserted Claims
[30] The 422 Patent disclosure describes the field of the invention as being methods for treating cancer by administering a CYP17 enzyme inhibitor such as AA “in combination with at least one additional therapeutic agent, such as an anti-cancer agent or a steroid.” The Patent discloses a number of potential therapeutic agents including cytotoxic chemotherapy drugs and glucocorticoids for potential use in combination with a CYP17 enzyme inhibitor. One embodiment described is an amount of about 50 to 2000 mg per day of AA and an amount of about 0.01 to 500 mg per day of glucocorticoid including hydrocortisone, PN or dexamethasone.
[31] The range of PN covered by the Patent is significantly large. It would include the amounts Apotex proposes to be used for the treatment of side effects. Apotex’s amounts are at the low end (10 mg) of Janssen’s range.
[32] The 422 Patent disclosure defines several terms, including:
…the terms “treat”, “treating” and “treatment” include the eradication, removal, modification, management or control of a tumor or primary, regional, or metastatic cancer cells or tissue and the minimization or delay of the spread of cancer
…the phrase “therapeutically effective amount” when used in connection with a 17α-hydroxylase/ C17,20-lyase inhibitor or therapeutic agent means an amount of the 17α-hydroxylase/ C17,20-lyase inhibitor or therapeutic agent effective for treating a disease or disorder disclosed herein, such as cancer.
…the phrase “refractory cancer,” means cancer that is not responding to an anti-cancer treatment or cancer that is not responding sufficiently to an anti-cancer treatment. Refractory cancer can also include recurring or relapsing cancer.
[33] The 422 Patent disclosure cites three US Patents, including the US Patent 5,604,213 dated February 18, 1997 [213 Patent], for the method of making AA and other CYP17 inhibitors. It cites the 213 Patent as supporting the use of CYP17 inhibitors in the treatment of prostate cancer.
[34] The disclosure describes the amount of glucocorticoid to be used with a CYP17 inhibitor as “an amount that is sufficient to treat the cancer whether administered alone or in combination with a 17α-hydroxylase/ C17,20-lyase inhibitor.” The amount of CYP17 inhibitor is also described as being the amount sufficient to treat the cancer whether administered alone or in combination with an additional anti-cancer treatment.
[35] The 422 Patent disclosure describes the CYP17 inhibitor and the additional therapeutic agent as being able to be administered in separate compositions or in a single composition.
[36] The 422 Patent describes that a suitable daily dosage of the CYP17 inhibitor depends on a number of factors including the severity of the condition, the particular inhibitor, the method of administration, and the age, weight and response of the patient. Suitable dosages are given as generally ranging from 0.0001 to 1000 mg/kg/day. For treating cancer with a combination of a CYP17 inhibitor and PN, the recommended dosage range is 50 to 2000 mg per day of AA and 0.01 to 500 mg per day of PN or 500 to 1500 mg per day of AA and 10 to 250 mg per day of PN.
[37] The claims at issue in these proceedings are claims 3, 6, 7, 14, and 15 [Asserted Claims]. The Asserted Claims are all directed towards the use of a therapeutically effective amount of AA and a therapeutically effective amount of PN to treat prostate cancer, refractory prostate cancer, and refractory prostate cancer that is resistant to one or more anti-cancer agents.
[38] These Asserted Claims, which refer to the definitions earlier outlined, read as follows:
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.
(4) The Cougar Trials
[39] In 2004 Cougar received a licence to develop and commercialize AA. The first of Cougar’s clinical trials of AA began in December 2005.
[40] The first trial (COU-AA-001) was led by de Bono. It was designed to evaluate AA therapy for men with mCRPC who had not had chemotherapy treatment. De Bono’s hypothesis was that adding a glucocosticoid like PN or dexamethasone could reduce production of the upstream precursor adrenal steroids, reverse resistance to AA and therefore have an anti-cancer activity.
[41] The results of the study were that the single patient studied had a positive turnover response when given AA and dexamethasone. The results were presented at the Prostate Cancer Foundation Scientific Retreat on October 11, 2007, and published in Attard 2008 – Journal of Clinical Oncology on October 1, 2008.
[42] The Clinical Study Report completed in 2010 concluded that patients receiving AA then AA and dexamethasone in combination had approximately three months longer for PSA progression. De Bono described the results as “surprising and unexpected”.
[43] A further Phase II study (COU-AA-004) began in June 2007. It was intended to evaluate the combination of AA and PN to treat patients with mCRPC. It confirmed the effectiveness of this combination treatment.
[44] The final study results were reported in Danila 2010 in the Journal of Clinical Oncology. In Danila 2010, the authors referenced that previous work had indicated that low-dose steroids could reverse clinical resistance to AA and decrease steroid precursors upstream of CYP17. In later Phase III studies, the combination of AA and PN demonstrated an unexpected survival benefit in patients, which was the first non-cytotoxic secondary hormonal therapy to show survival benefit. These results were published between 2011 and 2015.
(5) APO-ABIRATERONE and ZYTIGA
[45] ZYTIGA is Janssen’s AA product, which comes in 250 mg uncoated and 500 mg coated oral tablets. In the first sentence of its Product Monograph under the Indications and Clinical Use section, ZYTIGA is “indicated in combination with prednisone for the treatment of metastatic prostate cancer (castration resistant prostate cancer)…”. The recommended daily dosage is 1000 mg of ZYTIGA with 10 mg of PN. The action and clinical pharmacology of AA, but not PN, is explained under the Action and Clinical Pharmacology section.
[46] In the Warnings and Precautions section, glucocorticoids are described as helping to prevent mineralocorticoid excess and adrenal insufficiency that may result from the administration of AA. The Consumer Information part of the ZYTIGA Product Monograph states that ZYTIGA in combination with PN is used to treat metastatic prostate cancer. It describes how ZYTIGA works to stop androgen production. The only explanation of how PN works in the Consumer Information section is under the “Proper Use of this Medication” section where it explains that PN is taken with ZYTIGA to help manage potential side effects.
[47] The ZYTIGA Product Monograph cites the following studies that examined the combination of AA with glucocorticoids:
Attard 2008: The study concluded that the combination of corticosteroids with AA prevents mineralocorticoid excess and “may maximize efficacy”.
Attard 2009: This article concluded that the combination of AA with low-dose corticosteroids could maximize efficacy and minimize toxicity.
Ryan 2010: This article concluded that the impact of concurrent PN on response to treatment or long-term toxicity was not known.
Attard 2010 is a letter to the editor in response to the Ryan 2010 article. It reports that studies suggested that concomitant use of glucocorticoids with AA could result in a longer term tumour response than AA alone.
Danila 2010 reported the final results of COU-AA-004. The study concluded that AA and PN were well tolerated together with encouraging anti-tumour activity. The conclusion of the study focussed on the benefits of PN in reducing mineralocorticoid excess.
De Bono 2011 reported the Phase III trial COU-AA-301, which found that the combination of AA and PN resulted in a survival benefit for patients with mCRPC. The study did not discuss whether PN also had an anti-cancer effect; it focussed on the role of PN in reducing mineralocorticoid excess.
Ryan 2013 reported the interim results of the Phase III trial COU-AA-302, which showed the survival benefit from the combination of AA and PN. The study noted in the conclusion that PN also had anti-tumour activity
[48] APO-ABIRATERONE is Apotex’s proposed AA product, which comes in 250 mg uncoated tablets. Similar to the ZYTIGA Product Monograph, APO-ABIRATERONE is “indicated in combination with prednisone for the treatment of metastatic prostate cancer (castration-resistant prostate cancer) in patients…”. The recommended daily dosage is 1000 mg of APO-ABIRATERONE with 10 mg of prednisone. The mechanism of action for AA as a CYP17 inhibitor is described. No anti-cancer effects of PN are described.
[49] The Consumer Information section of the APO-ABIRATERONE Product Monograph contains essentially the same information as the ZYTIGA Product Monograph. APO-ABIRATERONE is described as being used in combination with PN to treat metastatic prostate cancer. It describes what AA does to suppress androgen levels, but does not describe PN as having an anti-cancer effect. PN is described as being a medication taken with AA to help manage potential side effects under the “Proper Use of this Medication” section.
[50] The APO-ABIRATERONE Product Monograph cites the ZYTIGA Product Monograph as well as the same studies cited in the ZYTIGA Product Monograph.
III. Issues
[51] The issues to be addressed in this decision are:
The acceptance and weight of the parties’ expert evidence;
The burden of proof of Apotex’s allegation of invalidity of the 422 Patent;
Claim construction including the appropriate persons of ordinary skill in the art, the applicable common general knowledge and the proper claim construction;
The validity of the 422 Patent as non patentable subject matter;
The obviousness of the 422 Patent;
The non utility of the Patent (Apotex’s assertion of insufficiency and overbreadth has been discontinued as referenced in its written submissions);
The infringement of the 422 Patent; and
The eligibility of the 422 Patent to ground a prohibition order.
IV. Analysis
A. Expert Evidence
[52] The first issue under this heading is Janssen’s assertion that while each of the other experts could assist the Court, Prins, Apotex’s expert endocrinologist, cannot. Unlike Apotex which contends that the Person of Ordinary Skill in the Art [POS] would not include an endocrinologist, Janssen put forward Auchus’ evidence as part of its argument that an endocrinologist would be part of the POS.
[53] Janssen’s objection to Prins is that she gave conflicting evidence on questions of primary importance regarding the impacts of congenital CYP17 deficiency on aldosterone levels and that she does not have any special knowledge to help the Court.
[54] Consistent with the Supreme Court’s teachings in R v J-LJ, 2000 SCC 51 at para 56, [2000] 2 SCR 600, and R v Mohan, [1994] 2 SCR 9 at p 24, 114 DLR (4th) 419, the Court cannot accept an expert’s conclusions without making its own independent assessment of the evidence – aided by the expert evidence. Each of the experts has provided the Court with useful evidence. The Court must weigh and consider the opinions on each of the issues separately.
[55] There is no reason not to admit Prins’ evidence. While some of her evidence was inconsistent or confusing, those matters go to credibility and weight not to admissibility. Otherwise she is qualified to give evidence on endocrinology of prostate cancer treatments. Her qualifications as a PhD rather than a medical doctor do not render her incapable of giving expert evidence.
Her evidence may suggest that the invention was not as obvious as Apotex contends.
[56] The more important issue is whether endocrinology is relevant to this matter and whether a POS would include an endocrinologist. That issue is discussed later but I have concluded that an endocrinologist is not part of a POS.
[57] The second issue under this heading is the significance of the fact that Apotex’s experts were “blinded” – they did not know the invention when giving evidence on “the state of the art” and on “obviousness – common general knowledge”.
[58] There is some authority in this Court that favours blinded witnesses. However, I am of the view that blinding can be overrated. It may be a factor in giving weight but the Court is more interested in the substance of the opinion and the reasoning behind the conclusions. In that respect my conclusion is similar to that in Shire Canada Inc v Apotex Inc, 2016 FC 382, 265 ACWS (3d) 456.
[59] Blinding may in some cases be unhelpful because the opinion lacks proper context. In other cases blinding will produce a less cluttered opinion. In the present case I do not favour Apotex’s experts simply because they were blinded. I would favour their opinions on the POS and common general knowledge because they offered stronger reasons for their position. Some of Apotex’s witnesses, Nam for example, provided confusing and at times contradictory statements on utility and non-infringement.
B. Burden of Proof
[60] The parties are not seriously in dispute as to the legal test; they are at odds as to whether the test has been met.
[61] As Janssen argues, that in accordance with the Act, the 422 Patent is presumed to be valid in the absence of evidence to the contrary. Apotex has the burden of giving its allegations an air of reality by leading evidence that is not clearly incapable of establishing the allegations (see Leo Pharma Inc v Teva Canada Limited, 2015 FC 1237, 262 ACWS (3d) 1024, aff’d 2017 FCA 50).
Once that burden is met, Janssen must show on the balance of probabilities that the allegations are not justified.
[62] It is fair to say that in large measure Apotex has met the burden of “an air of reality” on the issue of validity. On the matter of infringement, Apotex is not as strong. However, this case does not turn on the narrow knife edge of burden of proof.
[63] On the issue of eligibility for patent listing, the burden is different. This is so because the allegation is not one listed in s 5(1) of the Regulations. As a result, Apotex has the burden of showing that the 422 Patent is not eligible for listing on the patent register.
C. Claim Construction
(1) The Person of Ordinary Skill
[64] The definition of the POS is simple – its determination less so. As held in Free World Trust v Électro Santé Inc, 2000 SCC 66 at para 44, [2000] 2 SCR 1024 [Free World], such a person is “a hypothetical person possessing the ordinary skill and knowledge of the particular art to which the invention relates and a mind willing to understand a specification that is addressed to him”. The question is who works the patent in the real sense.
[65] According to Janssen’s experts, Auchus, Rettig and So, the POS for the 422 Patent is a physician specializing in urology or medical oncology with significant practical experience in the treatment of patients with prostate cancer. They would work in a team or have access to individuals with expertise in endocrinology, biochemistry, pharmacology, and/or molecular biology or a related field of science with experience in prostate cancer treatments or androgen synthesis and action.
[66] Apotex agrees that the POS is a notional person with skills in the art to which a patent relates and agrees that the 422 Patent is generally directed to medical doctors such as urologists and medical oncologists who are involved in treating patients with prostate cancer. However, it disagrees that the POS would have had access to individuals with expertise in endocrinology.
[67] There is no evidence that a urologist or oncologist would consult an endocrinologist to select a treatment for prostate cancer. Nam testified that he has never consulted an endocrinologist in practice. Dr. So also said that he considers himself and other urologists and medical oncologists who treat prostate cancer to be endocrinologists – therefore, they would not need to consult a board-certified endocrinologist.
[68] The fact that potentially an urologist or oncologist might consult an endocrinologist from time to time is not evidence that the POS includes such a skill in order to understand and use the Patent. There is no evidence that a POS needs to know in micro-detail how the drug works when treating a patient.
[69] I find that the POS would be a hypothetical physician specializing in urology or medical oncology with significant practical experience in the treatment of patients with prostate cancer. I agree with Apotex that little evidence supported that a urologist or medical oncologist would consult with an endocrinologist when making treatment decisions. Dr. So’s admission in cross-examination indicated that urologists and medical oncologists have enough endocrinology knowledge to interpret and apply the 422 Patent. As the 422 Patent focusses on the use of medications to treat cancer, it makes sense that the POS would be a physician who would be determining courses of prostate cancer treatment.
[70] The POS would have read any new scientific literature in the field, attended scientific conferences and meetings, and discussed new developments and ideas with colleagues.
[71] However, this does not mean that the Court cannot consider the evidence of Auchus and Prins. Expert evidence as to the state of the art does not need to come from a person who would be a POS as long as the evidence provided by the witnesses describes information that the POS would have known and understood at the relevant time: Halford v Seed Hawk Inc, 2006 FCA 275 at para 17, 54 CPR (4th) 130. Both Auchus and Prins provide some information about hormone synthesis that is helpful for the Court to understand and does not appear to go beyond the knowledge of the POS. I therefore dismiss Apotex’s contention that Auchus’ evidence should be rejected.
(2) The Common General Knowledge as of the Filing Date and Publication Date
[72] The scientific background described at the beginning of these Reasons appears to be accepted common general knowledge as of 2007 according to the expert evidence. The parties also agree that there is little difference between the common general knowledge and the state of the art. This section describes the contested parts of the common general knowledge.
[73] Janssen argues that the 59 documents put forward by Apotex that focus on CYP17 inhibitors and their ability to block androgen production are not representative of the state of the art, as they represent a small subset of the nearly 20,000 results of a search for “treatment” and “prostate cancer” in PubMed. Apotex’s experts could not fully explain how the 59 documents were gathered or why a POS would have searched for “abiraterone acetate” specifically in their keyword search. There was nothing to set AA apart from other compounds being investigated in 2007. A number of better compounds for inhibiting CYP17 were disclosed in the 213 Patent.
[74] Janssen argues that as of 2007, how or why patients developed CRPC was unknown, but that the prevailing view was that CRPC had become independent of androgens, so controlling residual androgens was not a priority. Researchers had moved away from secondary hormonal agents to treat mCRPC because there was no evidence of improved clinical outcomes, with one researcher even saying that further hormonal manipulations were “futile”. This is supported by the testimony of Rettig and Auchus. There were a number of theories for how CRPC developed including mutations to the androgen receptors, the over-expression of androgen receptors, the activation of the receptors by non-androgen compounds, or the prostate cancer cells becoming independent of the androgen receptor. There were over 200 experimental compounds being developed as of 2007.
[75] Although kenoconazole [KC] and aminoglutethimide [AG] had been investigated as potential prostate cancer treatments, they had not been shown to have a survival benefit or any meaningful outcome, nor had they been approved for prostate cancer treatment. Both agents inhibit the production of all adrenal steroid hormones and the enzyme responsible for the production of all glucocorticoids. Therefore KC was sometimes used off-label to manage overproduction of glucocorticoids and mineralocorticoids. Although KC inhibits the CYP17 enzyme, AG does not.
[76] It was known in 2007 that KC and AG caused side effects related to suppressed glucocorticoid production. Therefore glucocorticoids were sometimes administered with KC and AG treatments. O’Donnell 2004, however, reported that KC and AG could be administered effectively and safely without glucocorticoids.
[77] As of 2007, PN was sometimes used for its palliative effects in relieving pain and inflammation from cancer or for relief from the side effects of cytotoxic chemotherapy. It was not approved for any cancer treatment and was not known to provide a survival benefit in prostate cancer patients. Glucocorticoids were only administered as a last resort to cancer patients for palliative relief or when medically indicated for a clinical disorder. Glucocorticoids were associated with serious impacts, including limiting the ability for the adrenal glands to produce glucocorticoids.
[78] Mineralocorticoid excess was not usually treated with glucocorticoids; it was treated with mineralocorticoid receptor antagonists like eplerenone, anti-hypertensives, diuretics, and/or potassium supplements.
[79] Janssen says that nothing set AA apart from the other compounds being researched for the treatment of prostate cancer. In addition, there were a number of CYP17 inhibitors disclosed in the 213 Patent that were more potent inhibitors of CYP17 than AA.
[80] AA had been investigated in Phase I clinical trials for the treatment of prostate cancer, but had not been tested for its efficacy in the treatment of prostate cancer. It had a different mechanism of action than KC and AG as it only specifically inhibited the CYP17 enzyme. It preferentially inhibited the 17,20-lyase activity of CYP17, which allowed for the production of cortisol to continue. Corticosterone could also continue to be produced. AA was not expected to cause the same side effects as KC and AG and it was not expected to cause mineralocorticoid excess, adrenal insufficiency or low adrenal reserve. Importantly, at that time in 2007, there was no reason to think glucocorticoid replacement was needed with AA treatment.
(a) Apotex
[81] Apotex states that the state of the art and common general knowledge in 2007 indicated that treatment of CRPC required second-line hormone therapy to reduce residual androgens produced by the adrenal gland. The drugs used to inhibit residual adrenal androgens caused significant side effects and required glucocorticoid replacement therapy. O’Donnell 2004 stated that the testosterone suppression from AA treatment warranted further clinical study as a second-line hormonal treatment for prostate cancer. The 422 Patent itself also does not suggest that it is unique in discovering a link between androgens and mCRPC.
[82] There was a large body of literature indicating that reducing residual androgen levels would provide a clinical benefit. Rettig in challenging this notion has cited only an obscure article, Lara and Meyers 1999 to support his statement. In contrast, Lam 2006, whose authors included an inventor of the 422 Patent, stated that secondary hormonal therapy to lower androgen levels was thought to be a cornerstone of management for advanced prostate cancer and expressed the hope that further studies would show clinical response.
[83] Apotex argues that the use of KC and AG for prostate cancer treatment led to the development of AA. The use of AG showed short survival benefits and pain improvement when administered with glucocorticoids. Kruit 2004 indicated that PSA levels decreased when patients were treated with AG. The side effects from AG limited its effectiveness. KC was widely used for treating CRPC in the early 2000s as it inhibited the CYP17 enzyme and therefore suppressed the production of testosterone. In Lam 2006, KC was described as the “most active second line hormonal therapy.” Phase III clinical trials showed that KC had clinical benefit and PSA responses. Similarly, KC had side effects of adrenal insufficiency, which could be partially but not completely managed with a glucocorticoid.
[84] Apotex relies on Rettig’s admission on cross-examination that he had prescribed KC with PN to treat prostate cancer patients prior to 2007. In 2007, clinical practice guidelines used by oncologists suggested the use of KC for mCRPC patients. KC and AG were widely used off-label to treat prostate cancer patients. The context of that admission – a last desperate treatment – undermines the force of the statement Apotex would like it to be.
[85] The inventors of the 213 Patent described the activity and side effects of KC treatment as showing the need to design a drug like AA that inhibits the CYP17 enzyme more specifically. O’Donnell 2004 also no