2019 FC, 2019 FC 1355

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/ C 17,20 -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/ C 17,20- lyase inhibitor or therapeutic agent means an amount of the 17α-hydroxylase/ C 17,20- 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/ C 17,20- 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: 1 . Attard 2008 : The study concluded that the combination of corticosteroids with AA prevents mineralocorticoid excess and " “may maximize efficacy” " . 2 . Attard 2009 : This

article concluded that the combination of AA with low-dose corticosteroids could maximize efficacy and minimize toxicity. 3 . Ryan 2010 : This

article concluded that the impact of concurrent PN on response to treatment or long-term toxicity was not known. 4 . 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. 5 . 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. 6 .

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. 7 . 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 asthe ZYTIGA Product Monograph. APO-ABIRATERONE is described as being used in combination with PN to treat metastatic prostatecancer. It describes what AA does to suppress androgen levels, but does not describe PN as having an anti-cancer effect.

PN is describedas 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 theZYTIGA Product Monograph. III. Issues [51] The issues to be addressed in this decision are: 1. The acceptance and weight of the parties’ expert evidence; 2. The burden of proof of Apotex’s allegation of invalidity of the 422 Patent; 3.

Claim construction including the appropriate persons of ordinary skill in the art, the applicable common general knowledge andthe proper claim construction; 4. The validity of the 422 Patent as non patentable subject matter; 5. The obviousness of the 422 Patent; 6. The non utility of the Patent (Apotex’s assertion of insufficiency and overbreadth has been discontinued as referenced in its writtensubmissions); 7. The infringement of the 422 Patent; and 8. 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’sexpert endocrinologist, cannot.

Unlike Apotex which contends that the Person of Ordinary Skill in the Art [POS] would not include anendocrinologist, 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 ofcongenital 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, (SCC), [1994] 2 SCR 9 at p 24, 114 DLR (4th) 419, the Court cannot accept an expert’s conclusions without making its ownindependent 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 tocredibility 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 theinvention 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. Itmay be a factor in giving weight but the Court is more interested in the substance of the opinion and the reasoning behind theconclusions. 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 lesscluttered opinion. In the present case I do not favour Apotex’s experts simply because they were blinded.

I would favour their opinionson the POS and common general knowledge because they offered stronger reasons for their position. Some of Apotex’s witnesses, Namfor 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 noted that the side effects of KC and AG supported the development of AA as a more selective inhibitor. [ 86 ] On the matter of PN and glucocorticoids in treating prostate cancer, by August 2007, PN was known for its use as an anti-cancer agent, glucocorticoid replacement therapy, and for the palliative treatment of end-stage prostate cancer. PN and other glucocorticoids were described as having anti-cancer activity, causing PSA decreases of more than 50% in some patients, and lowering adrenal androgen levels.

PN was included in several Phase III trials in combination with other drugs because it was useful for pain relief and exhibited anti-cancer activity. [ 87 ] PN was also used in combination with KC and AG to replace glucocorticoids that were suppressed as a side effect of KC and AG. PN was also the standard of care for palliative treatment for end-stage prostate cancer patients. Therefore Apotex argues PN was used as the control for any study when evaluating new drugs. [ 88 ] Further, Apotex argues that PN was a common glucocorticoid treatment and would be the logical choice for prostate cancer patients

because of its palliative and anti-cancer effects. Studies of PN showed PSA declines of more than 50%, although there was no shown survival benefit. [ 89 ] In terms of the use of AA in prostate cancer treatment, Apotex says that AA was developed as a progression of the work with KC and AG. It inhibited CYP17 more selectively than AG or KC. According to Attard 2005, inhibition of the CYP17 enzyme was the " “logical target” " for treating CRPC. Some side effects were still expected from AA, although it was more selective than AG or KC.

O’Donnell 2004 showed that when administered to men with recurring prostate cancer, AA could cause sustained suppression of testosterone. The authors of O’Donnell 2004 noted that AA was potentially useful in the secondary hormone treatment of prostate cancer and that the side effects of AA may require glucocorticoid replacement.

Subsequent commentary about the O’Donnell 2004 study prior to 2007 described AA treatment as being under development with clinical trial results keenly awaited where patients would be monitored for glucocorticoid insufficiency. [ 90 ] AA was different from other options for CRPC treatment. Attard 2005 described AA as having a mechanism of action particularly attractive for use in CRPC treatment.

Although other compounds might have shown more potent inhibition of the CYP17 enzyme, only AA had been tested in humans, as reported in O’Donnell 2004. [ 91 ] Apotex argues that the 422 Patent did not claim the invention of AA to treat prostate cancer. Instead at para 35 of the 422 Patent disclosure, it cited the 213 Patent as indicating that CYP17 inhibitors were useful in the treatment of hormone dependent cancers like prostate cancer. No prior art or witness has indicated that AA was viewed by any in the field as a failure. [ 92 ] AA was not known to preferentially inhibit the 17,20-lyase activity of CYP17.

O’Donnell 2004 indicated that AA could affect patients’ cortisol levels and could be expected to possibly cause adrenal insufficiency or mineralocorticoid excess, which might require glucocorticoid replacement therapy. De Bono’s trials showed that there was an expectation of side effects that may have required glucocorticoid replacement. (

b) Court’s Conclusions re Disputed General Knowledge [ 93 ] As noted earlier, the parties’ positions on common general knowledge and prior art do not clearly distinguish between what is prior art and what is common general knowledge. They say in argument that they are basically the same. [ 94 ] However, legally they are not the same. " “Prior art” " is any publically available teachings, even if it is obscure or not generally accepted: Mylan Pharmaceuticals ULC v Eli Lilly Canada Inc , 2016 FCA 119 at para 23 , [2017] 2 FCR 280 [ Mylan ].

Common general knowledge is the " “knowledge generally known by persons skilled in the relevant art at the relevant time” " : Apotex Inc v Sanofi- Synthelabo Canada Inc , 2008 SCC 61 at para 37 , [2008] 3 SCR 265 [ Sanofi ]. [ 95 ] The Federal Court of Appeal in Mylan at para 25 described the use of prior art and common general knowledge as follows: Prior art is used for specific purposes in patent law, such as to found an allegation that prior art anticipated the invention or rendered it obvious.

The common general knowledge informs the way in which the claims and specifications are read, because it is to the skilled person that the patent is addressed. Any inquiry in patent law that is performed from the perspective of a skilled person will import the common general knowledge. [ 96 ] Outlined below is the Court’s conclusion on the common general knowledge. The relevant prior art is discussed in the obviousness analysis to follow later in these Reasons. [ 97 ] The relevant date for common general knowledge for claim construction is the Publication Date, February 28, 2008: see Free World at para 54 .

The relevant date for obviousness and utility is the common general knowledge as of the Filing Date, August 23, 2007. The parties did not indicate that the common general knowledge was different between the Filing Date and the Publication Date. Janssen’s expert, Dr. So, provided his view on common general knowledge and claims construction from the publication date. His evidence did not indicate that the common general knowledge changed between August 2007 and February 2008.

Therefore, the Court accepts that the common general knowledge of the POS was essentially the same between the two dates. [ 98 ] The Court does not accept Janssen’s proposed method of determining the common general knowledge by referring to the nearly 20,000 articles on prostate cancer treatment that were available on PubMed in 2007 and suggesting that a POS would not have been able to focus on adrenal androgen inhibitors.

The idea that a POS would merely have searched the words " “prostate cancer” " and " “treatment” " as a way to keep up to date with the latest research on end-stage prostate cancer treatment is not realistic. On the other hand, Nam’s evidence that a POS would have focussed on AA specifically as a potential treatment option is also difficult to accept, although the O’Donnell 2004 report was clearly part of the prior art. It is not established that O’Donnell 2004 was considered to be part of common general knowledge.

There was not enough evidence to show any general acceptance of AA as a treatment for prostate cancer as of 2007. [ 99 ] However, the Court would find that as of 2007, the POS would know that suppressing residual adrenal androgens could be useful in the treatment of mCRPC and was an active area of research.

I accept that the mechanisms for the development of mCRPC were not fully known, however residual adrenal androgens were thought to likely play a role. [ 100 ] Although no clinical trial had shown a survival benefit and the drugs used had shown significant side effects, the fact that researchers continued to explore the area of residual androgens and secondary hormonal therapy for prostate cancer between the 1990s and 2000s indicates that researchers had not moved away from the theory. [ 101 ] Lam 2006, a review

article cited both by Rettig and Nam, concluded that secondary hormonal therapy was an " “active area of research” " and stated in its abstract that secondary hormonal therapy was " “an excellent therapeutic option in patients with AIPC whose primary hormonal therapy [had] failed.” " This

article also noted that KC, as an adrenal androgen inhibitor, was the most active second

line hormonal therapy despite its significant side effects. [ 102 ] Further, the Court finds that the POS would know that, as of 2007, adrenal androgen inhibitors such as KC and AG could have some short-term anti-cancer effects for late-stage prostate cancer patients, although with serious side effects.

The POS would have especially considered KC as a potential last-resort treatment option because its mechanism appeared to be better understood than the mechanism of action for AG. [ 103 ] This finding aligns primarily with the evidence put forward by Nam who cited a number of studies as well as the US National Cancer Care Network recommendations at the time to show that KC was a recommended treatment for advanced prostate cancer as of 2007, despite the lack of demonstrated survival benefit. [ 104 ] KC was known to inhibit desmolase, CYP17 enzyme, and 11β-hydroxylase.

AG was known to inhibit desmolase, 11β- hydroxylase, and aromatase. Both drugs therefore were known to be relatively unselective and inhibit a number of adrenal steroids. [ 105 ] The Court also finds that the POS would know to prescribe a glucocorticoid if administering KC or AG, because of the known adrenal insufficiency caused by the drugs. Although Rettig initially suggested that KC and AG were not known to be clinically effective for the treatment of prostate cancer, he also admitted that at the time he would prescribe KC with a glucocorticoid as a " “last resort” " for his patients with CRPC.

While not as damning an admission as Apotex contends, it shows the general direction of the Common General Knowledge. [ 106 ] Although one must be careful to not equate a specific person with the POS, Rettig’s practice supports Nam’s opinion that the POS would have at least known about KC as an option for treatment with the potential for significant side effects that could be partially treated with co-administration with a glucocorticoid. [ 107 ] In addition to the number of studies from the 1980s to 2000s cited by Nam, O’Donnell 2004 further supported that it was " “common practice to administer supplementary hydrocortisone” " when treating prostate cancer with KC or AG.

Although O’Donnell 2004 indicated that some older studies showed that glucocorticoids might not be necessary, the common general knowledge by 2007 appeared to be that glucocorticoids should be co-administered with KC and AG. [ 108 ] However, I cannot find that KC or AG were known to cause mineralocorticoid excess as common general knowledge. Auchus explained that the inhibition of desmolase by KC and AG were known to suppress all adrenal androgens, therefore neither would be expected to cause mineralocorticoid excess – as mineralocorticoids would also be expected to be suppressed.

In addition, Prins appeared to be generalizing broadly when she suggested that both KC and AG could cause mineralocorticoid excess. She noted in her cross- examination that at low doses, KC primarily inhibits the CYP17 enzyme, however it is unclear what she meant by low doses and whether this compares to the doses given for treating prostate cancer. She admitted that AG did not inhibit the CYP17 enzyme and that KC also inhibited corticosterone. [ 109 ] This appears to then agree with Auchus’s conclusion that KC and AG could be expected to cause adrenal insufficiency, but not necessarily mineralocorticoid excess.

There was some prior art, such as De Coster 1987, which indicated that KC could possibly cause mineralocorticoid excess. However, other more recent articles, such as Lam 2006 and Small 2004, appeared to more generally indicate that KC was known to suppress all adrenal steroids and therefore cause adrenal insufficiency. [ 110 ] With respect to PN in the treatment of prostate cancer, I would find that a POS would know that PN was used for its palliative effects and in glucocorticoid replacement therapy.

PN was the standard of palliative care for end-stage prostate cancer, which meant that it was usually given to patients in the control arm of studies.

The POS would know that PN was a potential anti-cancer agent, but with only moderate and short-term effects. [ 111 ] Although PN was known for its palliative effects in prostate cancer patients and its reduction of adverse side effects from chemotherapy, the Court concludes that PN on its own for effective prostate cancer treatment was not part of the common general knowledge at the relevant dates. [ 112 ] Unlike KC, AG, and AA, there was little evidence presented that indicated that PN was being actively researched as a cancer therapy on its own in 2007. According to Lam 2006, a review

article on secondary hormonal therapy, glucocorticoids had not been significantly studied separately for their anti-cancer effects because they were usually used as a control arm for other trials. The

article did suggest that they should be considered " “active hormonal agents for prostate cancer.” " Many of the studies cited by Nam mostly studied PN in combination with other drugs, and sometimes attributed some anti-cancer effects to the glucocorticoids. [ 113 ] In addition, I do not find that a POS in 2007 would have been overly concerned about side effects or carcinogenic effects from prescribing glucocorticoids like PN to patients with mCRPC.

Rettig and Auchus did not cite any recent articles that indicated any concerns about PN for use with prostate cancer, especially since Rettig admitted that PN was used for palliative effects in prostate cancer patients and to reduce side effects from chemotherapy.

As put forward by Nam, it seems logical that a POS would be less concerned with the potential long-term effects of PN when treating a patient with end-stage prostate cancer than when treating a patient with another disorder. [ 114 ] In respect of AA’s use in prostate cancer treatment, Apotex has not shown that O’Donnell 2004 was part of the POS’s common general knowledge as of 2007. Although O’Donnell 2004 was cited in a few review articles between 2004 and 2006, AA had not been generally accepted by people engaged in the art as an anti-cancer drug.

There is no evidence that AA was being used by urologists or medical oncologists as a treatment for prostate cancer other than in the O’Donnell study and the Cougar trials. [ 115 ] It was common general knowledge that a more selective adrenal androgen inhibitor than KC and AG could more effectively treat prostate cancer with fewer expected side effects.

(3) Claim Construction Analysis

[116] As noted in paragraph 38, the claims at issue are 3, 6, 7, 14 and 15.

Each of the claims refer to the use of a therapeuticallyeffective amount of AA (or an acceptable salt thereof) and a therapeutically effective amount of PN for the treatment of a prostate cancerin a human. [Underlining by Court] [117] The dispute between the parties is whether each of AA and PN amounts must be therapeutically effective in the treatment, asargued by Apotex, or whether the combination of the two drugs to treat prostate cancer is the proper construction. [118] A patent must be read purposefully with the knowledge of a POS with a mind willing to understand who is trying to achievesuccess and is not looking for difficulties or seeking failure.

Claim construction is a question of law (Whirlpool Corp v Camco Inc, 2000SCC 67 at paras 43, 49-50, 61, [2000] 2 SCR 1067). [119] It is essential to refer to the definition of terms in the Patent: a) "“therapeutically effective amount of AA”" and "“therapeutically effective amount of PN”": an amount of AA effective fortreating prostate cancer and an amount of PN effective for treating prostate cancer. b) "“treatment”" (and "“treating”") includes the eradication, removal, modification, management or control of a tumour or primary,regional or metastatic cancer cells or tissues and the minimization or delay of the spread of cancer. c) "“refractory prostate cancer”": prostate cancer that is not responding to an anti-cancer treatment or prostate cancer that is notresponding sufficiently to an anti-cancer treatment, which can also include recurring or relapsing prostate cancer. [120] Interpreting the claims is the judge’s function although they can be assisted by the expert evidence.

In this case the relevantexperts are at odds. [121] On a plain reading of the claim, the amounts of AA and PN are circumscribed by the adjectival phrase "“therapeutically effectiveamount”". Nam read the claim as reading in the word "“each”". While Janssen thinks that this is a damaging error in

interpretation. I findit to be a reasonable one. [122] The inventors chose to fence in the amount of each substance with the descriptor. Janssen’s

interpretation would have the effect ofreading out "“therapeutically effective amount”". Janssen would have it that any amount of either, so long as used in combination to treatcancer, is sufficient to fall within the claim. [123] Given that at the time PN was known by POS to have palliative effectives, the insertion of words that indicate that the role of PN(and AA) are to attack the cancer and in a meaningful way, gives meaning and significance to the descriptor. [124] It is evident that the claim is to the cancer fighting feature of PN not its palliative effects. [125] In my view, Apotex’s

interpretation is the correct one. Even if there was some confusion or ambiguity, recourse to the Disclosureconfirms as reference that the amount of inhibitors or of steroid is an amount sufficient to treat cancer, whether administered alone or incombination. However, there is no need to refer to the Disclosure. [126] The Asserted Claims claim the use of therapeutically effective amounts of AA and of PN in combination to treat prostate cancer. [127] This raises the question of whether the 422 Patent claims a combination of AA and PN that has an effect beyond the known effectsof its component parts.

Although this is a question of claims construction, it is discussed below as a separate matter. D. Patentable Subject Matter [128] It was Janssen’s position that the Asserted Claims are patentable subject matter because the combination of AA and PN resulted inan anti-cancer effect that was not observed when either drug was administered alone.

The combination is patentable because theelements cooperated in an unexpected manner or cooperated in a known way to give an unexpected result. [129] There is legal support for this proposition in Gilead Sciences Canada Inc v Canada (Minister of Health), 2012 FC 2, 403 FTR 86.Janssen’s authority, Bridgeview Manufacturing Inc v 931409 Alberta Ltd (Central Alberta Hay Centre), 2010 FCA 188, 191 ACWS (3d)235 [Bridgeview], is more focussed on obviousness than patentable subject matter. [130] Apotex argues that the Asserted Claims claim non-patentable subject matter as the subject matter of the Asserted Claims is thecombination of two known anti-cancer agents..

The 422 Patent claims the use of two anti-cancer agents together without suggesting anysynergistic result. As phrased by Apotex, to be patentable subject matter one drug plus one drug must be more effective than just twodrugs together. [131] I have concluded that the 422 Patent claims patentable subject matter and therefore Apotex’s allegation of non-patentable subjectmatter is not justified. [132] The parties appear to have mixed together their arguments on patentable subject matter and whether the utility of the combinationwas demonstrated.

To be a patentable combination, the 422 Patent must claim a combination with effects different from the sum of theeffects of the elements: R v American Optical Co, (CA EXC), [1950] Ex CR 344, 13 CPR 87 at 98-99; Eli LillyCanada Inc v Apotex Inc, 2018 FC 736 at paras 71-72, 156 CPR (4th) 387 [Eli Lilly]. The issue regarding patentability of the subjectmatter is whether the 422 Patent reads from the perspective of the POS as claiming a combination with synergistic effect or effectsbeyond those of either component drug.

The issue of whether any effectiveness of the combination was demonstrated or soundlypredicted is separately addressed in the discussion of utility. [133] For the claimed combination to be patentable, the Asserted Claims supported by the disclosure of the 422 Patent from the

perspective of a POS must claim that the combination of AA and PN has a greater effect than either component alone. [ 134 ] Unlike in Eli Lilly , the 422 Patent does not disclose any test data suggesting that there is a synergistic or interacting effect between a CYP17 inhibitor like AA and the other therapeutic agent, such as PN.

However, in Eli Lilly one of the components in the combination was already used as a monotherapy and the other component was part of a class that was commonly used as a monotherapy for treating the same condition. [ 135 ] In contrast, neither AA nor PN were known in the common general knowledge as an effective monotherapy for the treatment of prostate cancer, although pre-cursor adrenal androgen inhibitors were known to be used to treat prostate cancer in combination with glucocorticoids to treat side effects.

The 422 Patent at para 35 describes CYP17 inhibitors like AA as being useful for the treatment of prostate cancer as described in the 213 Patent. In addition, common general knowledge was that PN had a modest short-term anti-cancer effect, but was not a commonly used monotherapy for its anti-cancer effects. [ 136 ] The experts differed as to whether the 422 Patent disclosed a synergistic or enhanced effect when AA was combined with PN.

Rettig concluded that because a POS would understand that neither AA nor PN was effective or used as a monotherapy to treat prostate cancer, the combination of AA and PN indicated an anti-cancer effect when they were combined. Rettig did not specifically find that the language of the 422 Patent disclosed a synergistic effect of the two compounds, in his view the common general knowledge was that neither AA nor PN was effective at treating prostate cancer as a monotherapy. Nam disagreed, finding that the 422 Patent did not disclose or claim any synergistic effect between AA and PN.

He found that as both drugs were known to be useful as anti-cancer agents, their combination would be expected to just have additive anti-cancer effects. [ 137 ] The 422 Patent claims an enhanced effect when AA and PN are combined for the treatment of prostate cancer. Although the amounts of CYP17 inhibitor and glucocorticoid described in paras 43 and 54, respectively, indicate that each agent has some anti-cancer effect on its own, the Asserted Claims only describe the combined use of AA and PN.

Claim 15 in particular describes the use of the combination to treat prostate cancer that is not responding to at least one anti-cancer agent. Based on the definition of anti-cancer agent in the 422 Patent, this could include the use of any agent on its own that has an anti-cancer effect, including AA or possibly PN. [ 138 ] Paragraphs 6 and 7 of the 422 Patent state that patients administered hormone therapy show variable responses and may have cancer recur.

The 422 Patent indicates at paragraph 8 that the combination of a CYP17 inhibitor with another anti-cancer therapeutic agent could treat refractory cancer, which includes a cancer that is not sufficiently responding to an anti-cancer treatment. [ 139 ] To the extent that an anti-cancer treatment could include either treatment with AA alone or PN alone, then the 422 Patent would be read by the POS to claim that the combination of PN and AA treats prostate cancer in a way that overcomes resistance to other anti- cancer therapies, including AA or PN used on their own. [ 140 ] I note Nam’s conclusion that merely combining two drugs thought to possibly have anti-cancer effects would obviously result in their additive anti-cancer effect.

As indicated in the expert evidence, PN and AA both affect the adrenal androgen synthesis pathway, and their full effects and interactions in this pathway were not commonly known in 2007. [ 141 ] It is sufficient in this case that the 422 Patent claims an improved anti-cancer effect than each of AA or PN treatments on their own.

Given that neither AA and PN had actually been shown to have a long-term anti-cancer effect, it may be impossible to ask that a patent predict and differentiate between an additive effect of AA and PN together and a synergistic effect. [ 142 ] The Court in Eli Lilly at para 91 did not require that the claim be one of synergy, as long as the claim disclosed a combination that was more effective than the sum of the effects of the agents used alone. In this case, the effects of the agents used alone were not well- established prior to the Filing Date.

The combination is claimed to be more effective and absent other evidence, Apotex’s allegation of non-patentable subject matter has not been justified. E. Obviousness [ 143 ] Janssen argues that Apotex’s allegation that the Asserted Claims would have been obvious to the POS as of the Claim Date (August 23, 2007) is not justified. The invention is not obvious under

section 28.3 of the Act . [ 144 ] There is no dispute as to the legal test as laid out in Sanofi at para 37 . The question in assessing obviousness is whether a POS would, in light of the state of the art and common general knowledge, and without knowledge of the invention as claimed, have come directly and without difficulty to the solution taught by the patent. The test for obviousness is set out in Sanofi at paras 67-69 : 1 . Who is the notional POS? What is the relevant common general knowledge of the POS? 2 . What is the inventive concept of the claim, or the claim as construed? 3 .

What are the differences between the state of the art and the inventive concept or the claim as construed? 4 . Without any knowledge of the alleged claimed inventions, would the differences between the state of the art and inventive concept have been obvious to the POS or do they require any degree of invention?

For combination inventions, a failure to identify the inventive concept may result in an erroneous focus on individual elements: Bridgeview at paras 51-52 . [ 145 ] To assess whether the claimed invention was obvious to try, the Court may apply a number of factors to assess whether it was " “very plain” " or " “self-evident” " that the invention would work: Pfizer Canada Inc v Apotex Inc , 2009 FCA 8 at para 29 , [2009] 4 FCR

(1) POS/Common General Knowledge [ 146 ] The parties’ positions on the POS and common general knowledge have already been outlined.

(2) Inventive Concept [ 147 ] With respect to the inventive concept, the parties essentially agree that the inventive concept of the Asserted Claims is the use of AA and PN, in therapeutically effective amounts, for the treatment of prostate cancer, including refractory prostate cancer. However, as in Claim Construction, Apotex maintained that " “therapeutically effective amount” " is the amount of AA or PN, each effective for treating prostate cancer, rather than an amount effective when the two drugs are combined.

(3) Difference: State of Art/Inventive Concept [ 148 ] The parties have very different views on the differences between the state of the art [SOA] and the inventive concept.

As earlier described, Janssen rejects Apotex’s assertion that the 59 documents that focussed on compounds inhibiting the CYP17 enzyme and blocking androgen production were representative of SOA. [ 149 ] In this regard, Janssen argues the following differences between the SOA in 2007 and the inventive concept: The role of residual adrenal androgens in CRPC was not known and there was no known benefit of reducing androgens below castrate levels; KC and AG were not known to have an anti-cancer effect and were known to have serious side effects. They were given to patients as a last resort.

AA was not a known anti-cancer treatment in 2007. Previous studies on AA showed a short-term reduction in testosterone levels, but not clinical efficacy in the treatment of prostate cancer. Unlike KC and AG, AA would not be expected to require glucocorticoid replacement because AA allowed some cortisol to be produced and did not at all inhibit the production of corticosterone. PN was not known to treat prostate cancer by contributing to any anti-cancer effect. AA was not known to cause mineralocorticoid excess or adrenal insufficiency.

Partial inhibition of cortisol production at times of stress did not cause adrenal insufficiency or mineralocorticoid excess. Different drugs or management options would be preferable over PN to manage mineralocorticoid excess or adrenal insufficiency. Prior art did not teach administration of a glucocorticoid like PN with AA. [ 150 ] Apotex argues that obviousness is not determined by referring to the prior art at large. Apotex as the second person must point to one or more elements of prior art that make the invention in the 422 Patent obvious.

The choice of these prior art elements are limited only by the fact they must be public prior to the claim date according to

section 28.3 (

b) of the Act . If there is a gap between the claimed subject matter and the prior art, then the assessment is whether the POS could bridge the gap using the common general knowledge and prior art that could be discovered by a reasonably diligent search: Ciba Specialty Chemicals Water Treatments Limited v SNF Inc , 2017 FCA 225 at para 62 , 152 CPR (4th) 239 [ Ciba ]. [ 151 ] Apotex asserts that the only difference between the SOA and the subject matter/inventive concept of the 422 Patent is that AA and PN had not actually been combined and administered in the treatment of prostate cancer.

Both AA and PN were already known as anti- cancer agents for the treatment of prostate cancer, as well as refractory prostate cancer. [ 152 ] The following points were already known in the prior art: AA reduced testosterone levels in prostate cancer patients and could be useful in secondary hormone therapy for patients with refractory prostate cancer, with additional clinical trials planned (O'Donnell 2004).

KC and AG were known to be beneficial in the treatment of prostate cancer and AA as a more selective inhibitor was expected to be just as effective or more effective than KC and AG (Potter 1995, O'Donnell 2004, 213 Patent). PN and other glucocorticoids had demonstrated anti-cancer activity, including observed PSA responses in patients with CRPC, both alone and in combination with other drugs, including KC (Sartor 1998, Fossa 2001, Berry 2002, Harris 2002, Small 2004, Lam 2006, Yano 2006).

(4) Obviousness/Degree of Invention [ 153 ] Janssen, in

summary on this issue, makes the following points: There is no suggestion in the art that combining AA and PN would be useful in treating prostate cancer especially where the cancer had progressed after being treated with each drug alone. The prior art suggested that there were hundreds of potential therapies with different mechanisms of action being explored to treat

prostate cancer as of 2007. There was no motivation to develop a secondary hormonal therapy for the treatment of prostate cancer. None of the decades of research had shown that secondary hormonal therapy could improve survival. There was little data to support that residual androgens were important in stimulating prostate cancer growth in mCRPC patients. Therefore, a skilled person would not have given PN or any glucocorticoids to a patient unless there was a clear clinical need. The inventors’ course of conduct was arduous and counter-intuitive. The clinical trials were expensive, time-consuming, and uncertain.

It would have been difficult to get approval to study the combination of two drugs that were unsuccessful when given individually. It would not be self-evident to combine two failed treatments with the expectation that they would have an effect in combination. De Bono’s study was the first study that suggested that a glucocorticoid with AA could reverse resistance and result in a prolonged response. [ 154 ] Apotex, on the other hand, argues that the subject matter of the Asserted Claims in the 422 Patent would be obvious at the claim date to a POS under

section 28.3 of the Act . [ 155 ] In its analysis of the Sanofi test, Apotex makes the following points: In determining the prior art, the person alleging obviousness can select the pieces of prior art that make the impugned invention obvious, limited only by

section 28.3 of the Act : Ciba at para 60 . In the second step of the Sanofi test, the Federal Court of Appeal in Ciba has indicated that the Court should usually focus on construing the claim rather than attempting to determine the broader inventive concept of the claims. The fourth Sanofi step is assessed by looking at whether the differences between the inventive concept (or the claim as construed) and the prior art can be bridged by a POS using only their common general knowledge and other information which they could have found by making a reasonably diligent search.

In determining whether the invention was obvious to try, the Court should consider whether a POS would find it more or less self- evident to try to obtain the invention, including assessing the extent, nature and amount of effort required to achieve the invention and the motivation to find the solution provided by the patent.

To be obvious to try, a POS just needs to have a fair expectation of success, but does not need to be able to predict success with certainty: AstraZeneca Canada Inc v Teva Canada Ltd , 2013 FC 245 at para 43 , 428 FTR 269. [ 156 ] Apotex goes on to argue that bridging this difference between the SOA and the inventive concept was obvious and obvious to try as there was no inventive ingenuity required to use two drugs known for anti-cancer effects together as anti-cancer agents in the treatment of prostate cancer. There was no reason that the known anti-cancer effects of PN and AA would be diminished when combined.

The POS would understand that AA and PN had different mechanisms for suppressing testosterone. [ 157 ] Apotex rejects the evidence of Rettig that a PubMed search produced 20,000 articles on prostate cancer and treatment is representative of what a POS would search for. The Court agrees with Apotex that a POS would have performed a more narrow search and been led to AA because of the Attard 2005 article.

Apotex generally challenges Rettig’s evidence on prior art and common general knowledge because he relied on documents supplied by counsel. [ 158 ] Apotex argues that de Bono’s clinical trials to test AA and PN were routine and would have been the same types of trials conducted to test AG and KC. The POS was extremely motivated to arrive at the solution in the 422 Patent and would have combined AA and PN to mitigate the predictable side effects of AA.

The solution of combining AA and PN to treat prostate cancer was one of a limited number of solutions following the experience with KC and AG. [ 159 ] Finally, in the same vein, Apotex argues establishing that AA and PN would be useful for the treatment of prostate cancer would have involved the same routine work already done with KC and AG in combination with a glucocorticoid. The clinical trials conducted by de Bono were routine and not inventive.

(5) Court’s Conclusions on Obviousness (

a) Step 1: POS and Common General Knowledge [ 160 ] As stated above, the POS is a physician such as a urologist or medical oncologist with significant experience treating prostate cancer. They would remain current with developments in the treatment of cancer and would have been aware that secondary hormonal therapy was an active area of research. They would know that KC, which was used as a last resort therapy, had to be used with glucocorticoids to prevent adrenal insufficiency. They would be aware that a more specific CYP17 inhibitor would likely be effective in reducing adrenal androgens with fewer side effects. (

b) Step 2: Inventive Concept or Claim Construction [ 161 ] Although Apotex has argued that the Federal Court of Appeal in Ciba at para 77 has recommended that the Court avoid using the " “inventive concept” " in the second step of the Sanofi test, the Federal Court of Appeal cannot overturn or change the Sanofi test set out by the Supreme Court of Canada. [ 162 ] As stated by Justice Fothergill in Apotex Inc v Shire LLC , 2018 FC 637 at paras 115-117 , 294 ACWS (3d) 606 [ LDX ], the Court should still attempt to determine the inventive concept of a patent, especially one concerning pharmaceutical compounds like in Sanofi .

In this case, as with the LDX case, the Court can identify the inventive concept of the Asserted Claims without distraction or engaging in unnecessary satellite debate.

[ 163 ] The inventive concept has already been discussed. (

c) Step 3: Differences between the State of the Art and Inventive Concept [ 164 ] The Court concludes that Apotex has stated the law correctly for determining the state of the art. The Federal Court of Appeal in Ciba at paras 60, 62 , confirmed that Apotex can choose the prior art elements that make the 422 Patent obvious as long as they were publically available prior to August 23, 2007. Although the 59 documents chosen by Apotex cannot be assumed to be common general knowledge without evidence of general acceptance by the notional POS, they all appear to be part of the prior art. (

i) State of the Art [ 165 ] It is not necessary to list all 59 documents cited by Apotex as part of the prior art. The following briefly describe the important pieces of prior art and/or what they stand for.

a) Studies of AA in the 1990s Barrie 1994, Potter 1995, and United States Patent 5,604,213 [213 Patent] issued in 1997 disclosed the use of AA for the treatment of hormone dependent cancers such as prostate cancer. AA was tested in vitro and in mice, which showed that AA did not inhibit the production of corticosterone and had less toxic effects than KC. The Potter 1995

article showed that AA had a slightly greater effect on 17,20 lyase activity than on 17α-hydroxylase activity, but this difference was not that significant. The 213 Patent is cited in the 422 Patent disclosure.

b) O’Donnell 2004 – a critical document in this case i . O’Donnell 2004 was the only reported trial of AA treatment of prostate cancer in humans prior to 2007. The introduction of the O’Donnell 2004

article explains that prior studies had shown that residual androgens from the adrenal glands provided an important alternative source of testosterone for surgically or medically castrated prostate cancer patients. It also indicates that KC and AG had been evaluated as adrenal androgen inhibitors, but although promising, they were relatively unselective inhibitors. The observed effects of KC and AG supported research to find a more selective inhibitor of the CYP 17 enzyme – like AA. ii .

The O’Donnell 2004 trials were designed to assess the dose of AA that would suppress testosterone levels in castrate and non-castrate patients and obtain safety, pharmacokinetic, and hormonal data. There were three Phase I trials reported in O’Donnell 2004. Study A was a single dose study of surgically or medically castrated men. Study B was a single dose study in non-castrate men. Study C was a multi-dose study over 12 days in non-castrate males. Cohorts within each study received different dosage levels. iii .

The studies showed that AA could reduce testosterone levels in castrate and non-castrate males below castrate levels, which supported the proposed mechanism of action of the drug on testosterone levels. The study did not evaluate the effect of AA on prostate cancer itself and O’Donnel

[…]