ELI LILLY CANADA INC. Applicant v. MYLAN PHARMACEUTICALS ULC AND THE MINISTER OF HEALTH, 2015 FC 125

Date: 20150202 Docket: T-298-13 Citation: 2015 FC 125 Ottawa, Ontario, February 2, 2015 PRESENT: The Honourable Mr. Justice de Montigny BETWEEN: ELI LILLY CANADA INC. Applicant and MYLAN PHARMACEUTICALS ULC AND THE MINISTER OF HEALTH Respondents and ICOS CORPORATION Respondent Patentee JUDGMENT AND REASONS [ 1 ] This is an application by Eli Lilly Canada Inc. (Lilly) for an order under

section 55.2(4) of the Patent Act , RSC 1985, c P-4, and

section 6 of the Patented Medicines (Notice of Compliance) Regulations , SOR/93-133, to prohibit the issuance of a Notice of Compliance (NOC) to Mylan Pharmaceuticals ULC (Mylan) for a generic version of tadalafil, sold by Lilly under the brand name CIALIS, until after the expiration of the Canadian Patent 2,371,684 (the ‘684 Patent).

The ‘684 Patent is directed to a unit dosage form of tadalafil, including the use of that unit dosage form for the treatment of erectile dysfunction (ED). [ 2 ] Mylan, on the other hand, submits that the ‘684 Patent is a selection patent and that its utility was neither demonstrated nor soundly predicted at the filing date, and that the utility is not met today.

In the alternative, if the ‘684 Patent is not interpreted as a selection patent, it is argued that the claimed invention is anticipated by the Canadian Patent No. 2,226,784 (the ‘784 Patent) and is clearly obvious. [ 3 ] For the reasons that follow, I have come to the conclusion that the Applicant has not met its burden of proof on the balance of probabilities to establish for the purpose of these proceedings that the ‘684 Patent is valid, and that an order prohibiting the Minister of Health from issuing an NOC should issue. I.

Background [ 4 ] The compound tadalafil was claimed and disclosed in Canadian Patent No. 2,181,377 (the ‘377 Patent), which was published in July 1995. The use of tadalafil for the treatment of ED was claimed and disclosed in the ‘784 Patent, which was published in February 1997 and was the subject of another application to prohibit the issuance of an NOC to Mylan (see 2015 FC 17 ). The ‘784 Patent disclosed that oral administration was the preferred route, and it disclosed unit doses of tadalafil from 0.2 to 400 mg. [ 5 ] Another compound, sildenafil, had previously been developed for the treatment of ED.

Sildenafil was known to treat ED by the same mechanism of action as tadalafil – inhibition of the PDE5 enzyme. The mechanics of ED and of PDE5 inhibitors are described in my previous decision dealing with the ‘784 Patent. [ 6 ] By the time the ‘684 Patent was filed, sildenafil had been approved by regulatory authorities for the treatment of ED. Sildenafil was marketed in doses of 25 mg, 50 mg, and 100 mg.

VIAGRA (the commercial name under which sildenafil was sold) had shortcomings, including high rates of flushing, blue-green vision and an interaction with nitrates that caused a drastic drop in blood pressure over nitrates alone (Pullman affidavit, paras 70-72, 78, Application Record (AR) Vol 2, pp 358-359). Indeed, sildenafil was marketed with a labeled contraindication for concomitant administration with nitrates. [ 7 ] Sildenafil also had other, less serious shortcomings, as it was sometimes associated with such adverse events as headache, back pain, rhinitis and conjunctivitis.

The medication also had to be taken within one hour of the anticipated sexual activity (Goldstein affidavit, para 107, AR Vol 2, pp 257-258). Finally, it was known that sildenafil should be taken on an empty stomach, because a high- fat meal can interfere with absorption (Goldstein affidavit, para 331, AR Vol 3, p 515). For those reasons, a great amount of research started into other PDE5 inhibitors, and even other neurotransmitters. [ 8 ] Tadalafil was such a potent, selective and reversible PDE5 inhibitor. Early studies with tadalafil used large doses, including doses up to 100 mg.

Studies testing the safety of tadalafil went up to 500 mg doses. The selection of these large doses was based on the only approved PDE5 inhibitor known at the time, sildenafil, and the similar potencies of the two compounds. It was also known that with sildenafil, the effectiveness of the compound was proportional to the dose. [ 9 ] One of the earliest efficacy studies, using protocol LVBI, used a 100 mg dose of tadalafil.

The objective of that study was to evaluate the tolerability, safety and efficacy of a single dose of 100 mg of tadalafil compared to placebo in a three-center, two-by-two crossover study in patients with ED. The study concluded that tadalafil significantly enhanced erectile function in response to visual sexual stimulation in patients with mild to moderate ED at single doses of 100 mg. This was the very first proof of concept study in patients to show evidence of activity (Pullman affidavit, para 31, AR Vol 3, p 543 and Exh “B”, Vol 15, p 3485; Pullman cross- examination, pp 47-49, AR Vol 28, p 6413-6415).

[ 10 ] Lilly chose to use the 100 mg dose for tadalafil because they were expecting its response to be similar to sildenafil, since the two compounds have more or less the same potency. Potency is described by the use of a test to determine the IC 50, or the concentration of a test drug that is necessary to inhibit 50% of the enzyme activity. The most common dose for sildenafil is a 100 mg dose, although the typical starting dose is 50 mg. Dr.

Pullman’s choice of a starting dose for tadalafil was also informed by people with experience in pharmacokinetics who would have looked at scaling from animals to humans (Goldstein affidavit, paras 269-270, 370, AR Vol 3, pp 505, 524; Pullman affidavit, para 29, AR Vol 2, p 350).

Mylan agrees that to determine the starting dose, “[t]he skilled person would also be guided by looking at dosage levels for similar products, such as sildenafil, that were known to treat the same condition by the same mechanism of action” (Notice of Allegation (NOA), Potter affidavit, Exh “B”, AR Vol 1, p 111). [ 11 ] Another study conducted between November 1997 and April 1998, referred to as LVBH, showed that the quantity of tadalafil absorbed appeared to increase proportionally with doses from 10 mg to 50 mg.

However, in the majority of subjects, a less than dose proportional increase in area under the curve (AUC) was observed when the dose was increased from 50 mg to 100 mg. AUC is used to describe the total amount of drug absorbed by the body. This was true for both single dose and multi-dose administration, and all doses were safe and generally well tolerated. This study taught that a lower daily dose of tadalafil can provide a constant therapeutic effect without reaching a toxic level (see Pullman affidavit, paras 35-39, AR Vol 3, p 544 and Exh “C”, AR Vol 15, p 3538). [ 12 ] In

summary, Phase II clinical trials and the pharmacokinetic profile surprisingly started to show that, despite it being equipotent with sildenafil, tadalafil did not need higher doses, and using more drug made it less reliable. This was apparently the genesis and the basis for Dr. Pullman’s hypothesis that with tadalafil, unlike sildenafil, less is more. It was believed that 50 mg and 100 mg were not optimal dosage strengths and that lower doses may be more desirable (Pullman affidavit, paras 44-47, AR Vol 2, pp 352-353).

In later testing, it was decided to use even lower doses of tadalafil and to look at their safety and efficacy. These are described as Examples 5, 6 and 7 in the ‘684 Patent, to which I will now turn. II. The ‘684 Patent [ 13 ] The ‘684 Patent is entitled “Compositions Comprising Phosphodiesterase Inhibitors for the Treatment of Sexual Dysfunction” . It was filed in Canada on April 26, 2000 and has a priority date of April 30, 1999. There are two inventors, one of whom is a witness in this proceeding, Dr.

William Pullman. [ 14 ] The ‘684 Patent is directed to a unit dosage form of tadalafil, including the use of that unit dosage form for the treatment of ED. The very first paragraph of the Patent states that the unit dosage form herein described provides a benefit in therapeutic areas where inhibition of PDE5 is desired, “with minimization or elimination of adverse side effects resulting from inhibition of other phosphodiesterase enzymes” . [ 15 ] The Background of the Invention

section explains that despite its commercial success, sildenafil has “fallen short” due to its significant adverse side effects. The patentee focuses on three side effects: “Adverse side effects limit the use of sildenafil in patients suffering from vision abnormalities, hypertension, and, most significantly, by individuals who use organic nitrates” (‘684 Patent, pp 2-3). [ 16 ] The Patent goes on to describe the shortcoming of sildenafil for patients taking nitrates, because of the significant drop in blood pressure that can result from the interaction of these two drugs.

For that reason, “the package label for sildenafil provides strict contraindications against its use in combination with organic nitrates (…) and other nitric oxide donors in any form, either regularly or intermittently, because sildenafil potentiates the hypotensive effects of nitrates” (‘684 Patent, p 3). [ 17 ] The Patent then goes on to state that the patent applicants have discovered that tadalafil “can be administered in a unit dose that provides an effective treatment without the side effects associated” with sildenafil (‘684 Patent, p 4). The penultimate paragraph of the Background

section states: Significantly, applicants’ clinical studies also reveal that an effective product having a reduced tendency to cause flushing in susceptible individuals can be provided. Most unexpectedly, the product also can be administered with clinically insignificant side effects associated with the combined effects of a PDE5 inhibitor and an organic nitrate. Thus, the contraindication once believed necessary for a product containing a PDE5 inhibitor is unnecessary when Compound (I) [tadalafil] is administered as a unit dose of about 1 to about 20 mg, as disclosed herein.

Thus, the present invention provides an effective therapy for sexual dysfunction in individuals who previously were untreatable or suffered from unacceptable side effects, including individuals having cardiovascular disease, such as in individuals requiring nitrate therapy, having suffered a myocardial infarction more than three months before the onset of sexual dysfunction therapy, and suffering from class 1 congestive heart failure, or individuals suffering from vision abnormalities. (‘684 Patent, p 4) [ 18 ] In the

Summary of the Invention section, the invention is again described as a “pharmaceutical dosage form” , comprising about 1 to about 20 mg of tadalafil, in a unit dosage form suitable for oral administration. The term “oral dosage form” is described a little bit further as being used in a general sense to reference pharmaceutical products administered orally (including liquid formulations, tablets, capsules and gelcaps) (‘684 Patent, p 7). The following paragraph is the subject of conflicting

interpretations by the parties and is therefore worth reproducing: The present invention further provides a method of treating conditions where inhibition of PDE5 is desired, which comprises administering to a patient in need thereof an oral dosage form containing about 1 to about 20 mg of a selective PDE5 inhibitor, as needed, up to a total dose of 20 mg per day. The invention further provides the use of an oral dosage form comprising a selective PDE5 inhibitor at a dosage of about 1 to about 20 mg for the treatment of sexual dysfunction. (‘684 Patent, p 5)

[ 19 ] After providing the structural formula of tadalafil, the Patent defines a number of terms and abbreviations (see ‘684 Patent, p 7). The term “vision abnormalities” is defined as an “abnormal vision characterized by blue-green vision believed to be caused by PDE6 inhibition” , while the term “flushing” means “an episodic redness of the face and neck attributed to vasodilation caused by ingestion of a drug, usually accompanied by a feeling of warmth over the face and neck and sometimes accompanied by perspiration” .

The “package insert” is also described as the “information accompanying the product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding the use of the product” . [ 20 ] Another paragraph that has been the subject of much discussion and to which I will deal with in the analysis portion of these reasons relates to the package insert: Significantly, the package insert supports the use of the product to treat sexual dysfunction in patients suffering from a retinal disease, for example, diabetic retinopathy or retinitis pigmentosa, or in patients who are using organic nitrates.

Thus, the package insert preferably is free of contraindications associated with these conditions, and particularly the administration of the dosage form with an organic nitrate. More preferably, the package insert also is free of any cautions or warnings both associated with retinal diseases, particularly retinitis pigmentosa, and associated with individuals prone to vision abnormalities. Preferably, the package insert also reports incidences of flushing below 2%, preferably below 1%, and most preferably below 0.5%, of the patients administered the dosage form.

The incidence rate of flushing demonstrates marked improvement over prior pharmaceutical products containing a PDE5 inhibitor. (‘684 Patent, pp 8-9) [ 21 ] The Detailed Description then discusses the container used in the

article of manufacture, the oral dosage forms and the excipients, none of which is at issue in the present application. The next section, dealing with Preparations, is not at issue either in this application. [ 22 ] The first four examples set out in the ‘684 Patent relate to different formulations containing tadalafil. More relevant for the purposes of this application are Examples 5, 6 and 7, which relate to testing of tadalafil. I will now summarize each of them on the basis of what is disclosed in the Patent.

Of course, the teachings of these clinical trials are the subject of strong disagreement between the parties, and I will address these issues in my analysis. [ 23 ] The first clinical study, referred to as LVAB, describes a randomized, double-blind, placebo-controlled, two-way crossover design clinical pharmacology drug interaction study that evaluated the hemodynamic effects of concomitant administration of tadalafil and short-acting nitrates on healthy male volunteers.

It is the only study prior to the filing date assessing the interaction of tadalafil and nitrates, and it is the subject of Example 5 in the ‘684 Patent. [ 24 ] The subjects received either 10 mg tadalafil or placebo daily for seven days. On the sixth or seventh day, the subjects received sublingual nitroglycerin while lying on their back on a tilt table.

The nitroglycerin was administered 3 hours after tadalafil dosing, and all subjects kept the nitroglycerin tablet under their tongue until it completely dissolved. [ 25 ] According to the ‘684 Patent, this clinical study showed that tadalafil was well tolerated and that there were no serious adverse events.

Tadalafil demonstrated minimal, if any, effect on mean systolic blood pressure, and mean maximal nitroglycerin-induced decrease in systolic blood pressure. [ 26 ] Example 6 describes two randomized, double-blinded placebo-controlled clinical studies of tadalafil for the treatment of ED (these studies are referred to as LVBG and LVBF). Doses from 5 to 20 mg of tadalafil were efficacious and demonstrated less than 1% flushing and no reports of vision abnormalities.

The ‘684 Patent describes how tadalafil significantly improved the percentage of successful intercourse attempts as measured by Questions 3 and 4 of the International Index of Erectile Function (IIEF). The IIEF was developed to create a brief, reliable, self-administered measure of erectile function that is cross-culturally valid and psychometrically sound, with the sensitivity and specificity for detecting treatment-related changes in patients with ED.

Although the IIEF contains 15 questions, two key questions are evaluated for many studies: question 3 measures the ability to penetrate their partner, and question 4 measures the ability to maintain an erection after penetrating their partner. [ 27 ] Example 7 of the ‘684 Patent describes a randomized, double-blind, placebo-controlled study of tadalafil administered on demand to patients with male ED: this is the LVAC study. “On demand” is defined as intermittent administration of tadalafil prior to the expected sexual activity.

Example 7 concludes that this study demonstrated that all four doses of tadalafil, namely 2 mg, 5 mg, 10 mg, and 25 mg, taken on demand , produced significant improvement, relative to placebo, in the sexual performance of men with ED as assessed by the IIEF. The Patent states that treatment with nitrates was not allowed in this study. [ 28 ] Following Example 7, the ‘684 Patent includes two tables of combined results from clinical studies – a table reporting efficacy results (p 31) and a table reporting side effects (p 32).

The Patent does not indicate which clinical studies are included in these combined results, although Dr. Pullman indicates in his affidavit that the tables use the cumulative responses from Examples 6 and 7 (Pullman affidavit, para 71, AR Vol 2, p 358). It appears from the first table that all unit doses of 2, 5, 10, 25, 50 and 100 mg of tadalafil show statistically significant change from placebo, on the basis of the IIEF erectile function domain previously referred to.

This first table also appears to demonstrate the plateau effect described in some of Lilly’s earlier studies, where there is a sharp rise in efficacy at low doses but efficacy levels off between the 10 and 25 mg doses. [ 29 ] According to the Patent, the second table shows an increase in adverse events at 25 mg through 100 mg unit doses, without the corresponding increase in efficacy as shown in the previous table. It is also worth mentioning that the incidences of flushing and vision abnormalities were very low.

There is, however, no direct comparative testing between tadalafil and sildenafil in this table, nor anywhere else in the Patent. [ 30 ] Before stating the claims of the Patent, we find the following paragraph: In accordance with the present invention, a unit dose of about 1 to about 20 mg, preferably about 2 to about 20 mg, more preferably

about 5 to about 20 mg, and most preferably about 5 to about 15 mg, of Compound (I) [tadalafil], administered up to a maximum of 20 mg per 24-hour period, both effectively treats ED and minimizes or eliminates the occurrence of adverse side effects. Importantly, no vision abnormalities were reported and flushing was essentially eliminated.

Surprisingly, in addition to treating ED, with at about 1 to about 20 mg unit dose Compound (I), with a minimum of adverse side effects, individuals undergoing nitrate therapy also can be treated for ED by the method and composition of the present invention. (‘684 Patent, pp 32-33) [ 31 ] Claims 1 to 8 claim pharmaceutical unit dosage forms and claims 9 to 18 claim use of a unit dose. Claims 1 to 6 claim a pharmaceutical unit dosage form suitable for oral administration, and differ only by the amount of tadalafil they contain. They are not restricted to any particular use.

The different dosage ranges or specific dosages are the following: 1 to 20 mg (claim 1); 2 to 20 mg (claim 2); 5 to 20 mg (claim 3); 2.5 mg (claim 4); 5 mg (claim 5); and 10 mg (claim 6). Claim 9 recites a dosage form of any one of claims 1 through 6 for use in treating sexual dysfunction. Claim 10 recites a dosage form of claim 9 wherein the sexual dysfunction is male ED. All of these claims are reproduced in the Annex of these reasons. [ 32 ] Lilly does not assert claim 1, because there is no efficacy data to support it. Lilly therefore asserts claims 2 to 6, 9 and 10.

Indeed, claim 10 depends on claim 9, which itself depends on claims 2 to 6. III. The evidence A. Lilly’s witnesses [ 33 ] Lilly has put forward one fact witness, Dr. William Pullman, who is also one of the named inventors of the ‘684 Patent. Lilly has also offered two expert witnesses, Dr. Gerald Brock and Dr. Irwin Goldstein. Dr. William Pullman [ 34 ] Dr. Pullman is a clinical pharmacologist. He joined Pfizer in 1992, where he was responsible for the Phase II trials and the authorship of the Phase III development plan in the VIAGRA sildenafil team. Following his time at Pfizer, Dr.

Pullman began to work with Eli Lilly Australia in 1995, and then moved to the United States to begin work with Eli Lilly & Co. as head of Clinical Pharmacology. As a result of his previous experience with VIAGRA sildenafil, he assisted in securing an in-license opportunity with ICOS Corporation, and became the Director, Medical Affairs, for the Lilly-ICOS joint venture. His affidavit reviews his involvement with Lilly’s clinical trials of tadalafil.

He presents a number of the clinical trials related to dosing levels, some of which form the examples to the ‘684 Patent, and the implications for tadalafil’s side effects. Because he had determined that tadalafil was effective at lower doses, Dr. Pullman saw its potential to avoid some of sildenafil’s side effects, including possibly nitrate interaction.

The affidavit describes the results of the trials with respect to side effects. [ 35 ] In his affidavit, he states that he was aware of all of the clinical data up to and including the filing of the New Drug Application (NDA) with the US Food and Drug Administration (FDA) in 2001 (Pullman affidavit, para 14, AR Vol 2, p 347). On cross- examination, however, he recognized that he had no personal knowledge of the initial clinical testing of tadalafil, including studies testing multiple doses of tadalafil (Pullman cross-examination, pp 215-216, AR Vol 28, pp 6581-6582).

This clinical testing was performed by two different companies (GlaxoSmithKline (GSK) and ICOS) prior to the involvement of Lilly. Dr. Pullman learned of these studies and was aware of their general findings in the context of the due diligence work that he oversaw before Lilly decided to enter into a joint venture with ICOS. While it is no doubt true that Lilly could have put forward a fact witness with knowledge of GSK or ICOS clinical testing, it is of no significance in the context of the present application and Mylan has certainly not impugned Dr.

Pullman’s credibility with respect to this particular aspect of his testimony. [ 36 ] Of more concern is the fact that Dr. Pullman professed to know nothing of two nitrate studies (LVBY and LVCM) that were conducted by Lilly prior to filing the NDA and that were apparently provided to the FDA. On cross-examination, Dr. Pullman stated that he was only aware of the nitrate study (LVAB) that is the subject of Example 5 in the ‘684 Patent (Pullman cross-examination, pp 202- 206, AR Vol 28, pp 6568-6572).

This lack of knowledge, combined with the refusal by Lilly’s counsel of all questions relating to the FDA, despite evidence that Dr. Pullman met with the FDA prior to filing the ‘684 Patent to discuss the LVAB study on August 30, 1999, most certainly undermines Dr. Pullman’s evidence with respect to post-filing issues such as the sequence of events leading to tadalafil’s nitrate contraindication.

Little weight will therefore be given to his view that a “class contraindication” of PDE5 inhibitors with nitrates emerged within the FDA in view of the experience with VIAGRA (see Pullman affidavit, para 82, AR Vol 2, p 360). Dr. Gerald B. Brock [ 37 ] Dr. Brock is a urologist, specialized in erectile dysfunction. He was involved in clinical trials of sildenafil and tadalafil, among other drugs. He consults for many pharmaceutical companies, including Lilly.

His evidence consists of an affidavit and cross- examination, with exhibits. [ 38 ] After providing background information on ED and the state of the art up to 1995, essentially repeating his affidavit in Court file T-296-13, he then gives his construction of claim 10, the claim he has been asked to limit himself to, as it is dependent upon claim 9, itself dependent upon claims 2-6. He construes claim 10 as having the following essential elements: a. a pharmaceutical unit dosage form; b. comprising an amount of tadalafil; c. which amount of tadalafil is selected from the following list

i. about 2 to about 20 mg; ii. about 5 to about 20 mg; iii. about 2.5 mg; iv. about 5 mg; and v. about 10 mg; d. for use in treating male erectile dysfunction; e. in a patient where inhibition of PDE5 provides a benefit; and f. said unit dosage form being suitable for oral administration. (Brock affidavit, para 84, AR Vol 2, p 194) [ 39 ] Relying on the specification of the ‘684 Patent, he construes the term “pharmaceutical unit dosage form” as being one that is used to a maximum daily dose of 20 mg per day.

Although the Patent does have a maximum daily dose, there is no requirement that the medication be taken daily, or on demand. [ 40 ] Opining on anticipation, he states that the ‘784 Patent does not describe efficacy at low doses and a daily dose maximum of 20 mg to avoid or minimize certain side effects, and finds therefore that the invention of claim 10 of the ‘684 Patent is not disclosed and enabled in the ‘784 Patent.

He states at paragraph 94 of his affidavit: While the ‘784 Patent describes an efficacious product across the wide range of dosages, the ‘684 Patent describes the surprising efficacy at the low doses and the reduced side effects, such as flushing and vision disturbances for example. While this purpose behind the invention of the ‘684 Patent is not set out in the claims, including claim 10, it is the rationale for the dose limitations discussed above.

Therefore, it is not surprising that the ‘784 Application does not disclose these dose limitations because the issue of reducing these side effects is not discussed in the ‘784 Application either. (Brock affidavit, para 94, AR Vol 2, p 196) [ 41 ] With respect to obviousness, he first reviews and comments on the prior art cited by Mylan. On that basis, he finds that the prior art suggests a dosage range only as narrow as 0.2 to 400 mg, instead of a maximum daily dose of 20 mg as set out in claim 10.

The concept that the limitation of the doses as is done in claim 10 would provide the benefit that it does would not have been considered by a person of skill in the art (PSA). As the only approved oral ED medication, sildenafil would have been used to help guide the research with future medications. Since sildenafil was prescribed with 25, 50 and 100 mg doses, with the 100 mg dose being the most common, and the normal starting dose being 50 mg, it would be expected that other PDE5 inhibitors with a similar potency would be dosed the same.

In his view, there was no motivation to limit doses as was done in claim 10. [ 42 ] Moreover, a person of skill in the art would have considered flushing to be an inherent side effect of PDE5 inhibition at the time, and would not have expected to see the lack of flushing with tadalafil as reported on the table at page 32 of the ‘684 Patent. Similarly, it was not obvious that tadalafil could minimize or eliminate abnormal vision, as it was theorized that sildenafil’s relative lack of selectivity for PDE6 was the basis for abnormalities related to colour vision.

The finding that tadalafil did not demonstrate any vision abnormalities at any dose was not only positive but was not obvious because vision abnormalities were viewed at the time as an uncommon, transient effect; Lilly had identified and avoided a problem that did not yet form a part of the prior art. [ 43 ] Finally, Dr. Brock expresses the view that the utility of the invention as claimed in claim 10 was demonstrated by the Canadian filing date. That view is based on his review of the results in the ‘684 Patent and of the clinical trial reports as appended to the affidavit of Dr. Pullman.

In his view, the purpose of the invention (which is the claimed pharmaceutical unit dosage form) is to minimize or eliminate the adverse side effects known to occur with the administration of sildenafil while still providing an effective dose. These side effects are characterized to include facial flushing, vision abnormalities and a significant decrease in blood pressure when tadalafil is administered with organic nitrates.

The promise would not be interpreted as a promise to minimize or eliminate all side effects, in his view, since a person skilled in the art would understand that this is not possible when using a drug that inhibits PDE5. [ 44 ] On the basis of clinical trials, Dr.

Brock states that Lilly had enough information to demonstrate that oral doses of tadalafil of about 2 mg to about 20 mg would be efficacious to treat ED in men, and that these lower doses would also result in lower incidences of flushing and vision abnormalities, and lead to better results in subjects also taking nitrates as compared to sildenafil (Brock affidavit, para 211, AR Vol 2, p 225). In Dr.

Brock’s opinion, the ‘684 Patent does not promise to be “safer” than sildenafil, but promises only the efficacy at a very low dose together with the lower incidences of adverse effects that these lower doses provide (Brock affidavit, para 216, AR Vol 2, p 226). The reduction of flushing and colour abnormalities is clearly demonstrated by the clinical trials when compared to the prior art for sildenafil, in Dr. Brock’s view. As for the administration of tadalafil with nitrates, Dr.

Brock only comments that “tadalafil did not cause the same drop in blood pressure when administered with nitrates that was seen with sildenafil” , as shown by Example 5 of the Patent (Brock affidavit, para 220, AR Vol 2, p 227). [ 45 ] Mylan argued that Dr. Brock has extensive ties to Lilly, having received payment from Lilly for consulting services and providing lectures to physicians, and had access to inside information prior to the filing date. Indeed, Dr.

Brock confirmed on cross- examination that he sat on the Lilly-ICOS advisory board at the relevant dates for the ‘684 Patent (1999-2000), and that he was a principal investigator on the clinical trial (LVAC) that is included as Example 7 of the ‘684 Patent. I do not think, however, that this is sufficient to diminish the weight of his evidence. [ 46 ] First of all, most experts in the field are consulted and remunerated by the industry, and this does not in and of itself disqualify

them as experts. Dr. Brock has read and understood the Code of Conduct for Expert Witnesses, and has agreed to be bound by it. As for the insight he would have gained into the strengths and weaknesses of tadalafil as a result of sitting on the advisory board and acting as an investigator on clinical trials of tadalafil, I accept his statement on cross-examination that a study investigator only sees a very small part of the whole study, and that it doesn’t make a huge difference in terms of one’s insight into the actual study (Brock cross- examination, pp 243-245, AR Vol 23, pp 5100-5102). I also note that Dr.

Brock was not specifically asked how the information he may have gained as a result of sitting on the advisory board may have had an impact on the opinion that he gave. For all of the above reasons, plus the fact that Dr. Brock has been accepted as a qualified expert in other cases before this Court (most notably in the case dealing with the application from Pfizer to seek an order prohibiting the Minister from issuing an NOC for sildenafil: Pfizer Canada v Apotex , 2007 FC 971 ), I would reject Mylan’s attempt to impugn the credibility of Dr. Brock. Dr. Irwin Goldstein [ 47 ] Dr.

Goldstein is a urologist, specialized in sexual dysfunction, and is a Clinical Professor of Surgery at the University of California – San Diego. Like Dr. Brock, he has been involved in clinical research dealing with sildenafil and tadalafil, and has appeared as an expert witness for Pfizer in the sildenafil litigation mentioned in the previous paragraph of these reasons. [ 48 ] In his 116-page affidavit, Dr. Goldstein reviews the state of the art and gives his opinion on every issue in dispute.

He gives a basic science tutorial and describes ED treatment before and after 1995; that part of his affidavit is mainly a repetition of the one he gave in Court file T-296-13. He then reviews the common general knowledge in April 1999 (the relevant date for considering obviousness) and April 2000 (the relevant date for utility). He discusses the breakthrough occasioned by sildenafil, as it was previously thought that an oral medication could not be used to treat erectile dysfunction, and of the great amount of research that followed because of the characteristics that still made sildenafil less than ideal.

He then reviews Mylan’s prior art, giving more detail on vision abnormalities and flushing. He is of the view that in April 1999, the larger differential in IC 50 between PDE5 and PDE6 for tadalafil versus sildenafil could have led a person skilled in the art to hypothesize that there could be less effect of tadalafil with respect to colour vision abnormalities, but that any difference between the two drugs would need to be confirmed in human studies in light of all the conflicting evidence.

The same is true for flushing, which was thought to be inherent to PDE5 inhibition but was less of an issue with tadalafil. [ 49 ] Dr. Goldstein subsequently reviews Mylan’s documents on the art after 2000, as well as Lilly’s confidential clinical trial results that were obtained before the filing of the ‘684 Patent (these are the studies that were summarized above, referred to as LVBI, LVBH, LVBG, LVBF, LVAC, LVAB and LVAI, as well as other studies that are not relevant for the purpose of the present application). Dr.

Goldstein then construes claims 2-6, 9 and 10, including the term “unit dosage form” , in much the same way as Dr. Brock. [ 50 ] Dealing with anticipation, Dr. Goldstein opines that the dosage strength of 2 to 20 mg or any subset within that range, and the daily dose maximum of 20 mg, are essential elements of claim 10 of the ‘684 Patent and would not be found to be disclosed in the ‘784 Patent by a person skilled in the art.

In the eventuality that disclosure would be found, he further states that there are no instructions in the ‘784 Patent that a person skilled in the art could follow to arrive at the claimed subject matter of claim 10 of the ‘684 Patent: A POSITA could not arrive at the dosage strengths covered by claim 10 of the ‘684 Patent by using the teachings of PA3 [‘784 Patent] and conducting routine work that is not prolonged or arduous. This work would not be routine and it would necessarily be prolonged and arduous.

This information could only be determined by designing and performing complex experiments, as Lilly had to do, reviewing those results, and then repeating the cycle taking into account what has been learned. Lilly spent years performing clinical trials across continents and in hundreds if not thousands of patients. At paragraph 270 I further describe how Lilly’s clinical trials were not simple and routine.

Knowing that work has to be done is not the same as knowing how to perform the experiments, and what results those trials will provide. (Goldstein affidavit, para 359, AR Vol 2, pp 328-329) [ 51 ] As for obviousness, Dr. Goldstein opines that a person skilled in the art would find the dose limitations of 2 to 20 mg and the daily maximum dose of 20 mg to be inventive and not obvious. It would not have been self-evident to a person skilled in the art that such dose limitation would still be effective in treating ED and would lead to a better side effect profile than sildenafil.

The driving force behind the work that led to the invention of claim 10 of the ‘684 Patent was the desire to obtain a product with a better side effect profile than sildenafil. Yet in April 1999, not enough was known about inhibition of the PDE family of enzymes to know that any PDE5 inhibitor could be developed with better results in respect of flushing or vision problems. According to Dr. Goldstein, the clinical trials that were developed and conducted to determine the effectiveness of low doses of tadalafil and its better side effect profile than sildenafil were not simple and routine. [ 52 ] Dr.

Goldstein then addresses Mylan’s allegation that the concepts in the ‘684 Patent are not inventive; an argument that is no more at issue. With respect to utility, Dr. Goldstein opines that the data contained in the ‘684 Patent and discussed in Examples 5, 6 and 7 is sufficient without reference to the other clinical studies to conclude that the promise (which he identifies as being that the claimed unit dosage form when administered to patients for the treatment of ED will have a better side effect profile than sildenafil) is demonstrated.

In this connection, he adds: It is true that tadalafil may not be better in a statistically significant manner for all possible side effects, including those listed in the Table on page 32 of the ‘684 Patent, but the inventors in my opinion definitively demonstrated that tadalafil, when administered with the dosing restrictions set out in claim 10 of the ‘684 Patent as I have already discussed, clearly has fewer or lower incidences of side effects in respect to the ones that the inventors focused on, namely flushing, vision abnormalities and hypotension resulting from the concomitant use with nitrates.

As such, the promise of the patent is demonstrated. (Goldstein affidavit, para 379, AR Vol 2, pp 333-334) [ 53 ] Dr. Goldstein also addresses Mylan’s allegation that the utility of tadalafil was not demonstrated in the ‘684 Patent because comparative testing was not performed with sildenafil and no data were included on testing in patients with cardiovascular disease, with

or without organic nitrates. First, he states that the data in the published literature in the form of abstracts and full peer-reviewed research publications on sildenafil would have been readily available at the time of the ‘684 Patent application filing date, and reasonable comparisons could have been made to tadalafil. Second, he asserts that direct head to head studies with PDE5 inhibitors are rare in the post art and Mylan’s expectation that this type of study would be done routinely by a pharmaceutical company seems “unreasonable” (at para 381 of his affidavit). [ 54 ] Dr.

Goldstein adds that a person of skill in the art would not believe the ‘684 was promising to minimize or eliminate all adverse effects that were seen with sildenafil, as such a person knows that all drugs have side effects. A person of skill in the art would expect there to be some side effects from PDE5 inhibition, as drugs of the same class frequently have similar side effects. What would not have been obvious, therefore, would be tadalafil’s reduced flushing and the lack of blue vision, as these are the side effects that were considered inherent to the inhibition of PDE5.

Clinical studies such as those reported as Examples 6 and 7 have demonstrated that tadalafil minimizes the amount of flushing and that it essentially eliminated the blue vision abnormalities seen with sildenafil. These results are in accordance with what he has seen in his clinic. [ 55 ] As for Mylan’s argument that tadalafil is not better than sildenafil when the patient is also using nitrates, because both are labeled such that use with nitrates is not recommended, Dr.

Goldstein writes: While it is true that the specification at page 8 in the last paragraph does state that the package insert for tadalafil “preferably” will not contain a contraindication for the use of nitrates, this does not rule out that it could and it does not change the fact that the inventors demonstrated that tadalafil when administered with the dosage restrictions of claim 10 of the ‘684 Patent was better than sildenafil in this regard. In essence, tadalafil was better than sildenafil, but the standard for the FDA to allow it to avoid the contraindication in its label was higher.

This is apparent from Example 5 of the ‘684 Patent by itself and is further supported by the clinical trials that I discussed in this regard as well. (…) The “potentiation of hypotensive effects of nitrates” that is stated in the contraindication for tadalafil occurs under a daily dosing regimen of 20 mg of tadalafil. This daily dosing regimen has been shown to increase the steady state concentration of tadalafil in the blood by 60% compared to single use, on-demand dosing. Thus, the contraindication arises from an appropriate, but conservative public safety policy.

In my view, the actual data included in the ‘684 Patent and the post art confirms the utility of tadalafil in minimizing adverse effects, including interactions with organic nitrates. Warnings and contraindications imposed by drug regulatory policies do not necessarily define actual risk or utility. (Goldstein affidavit, paras 399 and 402, AR Vol 2, pp 338-339) [ 56 ] Finally, Dr. Goldstein comments on Mylan’s allegation that 1 to 2 mg dosage forms would not be effective for on demand therapy for the treatment of ED.

First, he points out that claim 10 is not limited to on demand therapy, and second, that the lowest dosage strength he was asked to consider (claims 2 and 4) is 2 mg. On the basis of the studies referred to in Examples 6 and 7, it is clear that the 2 mg dose had a significant improvement, relative to placebo, in the sexual performance of men with ED.

Even if the 2.5 mg tablet currently marketed was not specifically tested, there is no doubt that a person skilled in the art would know that a 2.5 mg dose (which contains 25% more active ingredients than a 2 mg dose) would also be effective for either on demand or daily treatment.

As for the adverse effect profile of a 2.5 mg dose, it would be between the adverse effect profiles for the 2 and 5 mg doses; as no flushing or vision abnormalities were seen at either of those doses, a person skilled in the art would know that the same would be true for the 2.5 mg dose. [ 57 ] Mylan’s counsel levelled the same concerns with respect to Dr. Goldstein’s impartiality as it did for Dr. Brock. For the reasons set out above, I find that Dr.

Goldstein’s access to confidential information prior to the filing date and his involvement with the development of tadalafil are insufficient to impact the weight of his testimony. As for the allegation that Dr. Goldstein provided his evidence with a view to upholding the validity of the ‘684 Patent, it is not borne out by a close reading of his affidavit or, for that matter, by his answers on cross-examination.

The volunteered statement that he made after the conclusion of his re-examination may have been somewhat improper, but it appears to have been given in good faith to bring clarity on an issue he was questioned about earlier; it can certainly not be interpreted as an attempt to stray from his role as an independent expert to that of a biased witness. B. Mylan’s witnesses [ 58 ] Mylan has put forward two expert witnesses: Dr. Arnold Melman and Dr. Evan Siegel. Dr. Arnold Melman [ 59 ] Dr.

Melman is a Professor of Urology at Albert Einstein College of Medicine in New York City and an attending physician in the Department of Urology at Mount Sinai School of Medicine and at Montefiore Medical Centre. [ 60 ] The gist of his opinion is found in his own

summary and is to the following effect.

First of all, he is of the view that a skilled person in the art would understand the patentee to be promising that the claimed unit dose of tadalafil will reduce three adverse effects associated with sildenafil (flushing, vision abnormalities and the negative effects associated with nitrate interactions) to clinically insignificant levels. “Clinically insignificant levels” would mean that the adverse effects would occur with sufficient rarity, and/or would be sufficiently mild, such that they would not affect a clinician’s judgment when prescribing a treatment for erectile dysfunction.

As it relates more particularly to nitrate interaction, it would mean that a contraindication of tadalafil is not necessary. [ 61 ] Second, he believes this promise is not achieved because there is a strict contraindication by the regulatory authorities in both the United States and Canada against the co-administration of tadalafil and nitrates for all unit dosages claimed in the ‘684 Patent.

This contraindication, which is reflected in the US Product Label and the Canadian Product Monograph, is based on the results from studies that were sponsored by Lilly and results from the potential of tadalafil to amplify the hypotensive effects of nitrates. Those effects can

lead to clinically significant decreases in blood pressure and associated adverse events, including death. [ 62 ] Dr. Melman further states that as of the ‘684 Patent filing date, the patentee had not demonstrated that tadalafil could be safely co-administered with nitrates at any unit dose. As of that date, it was known that sildenafil interacted with nitrates because it is a PDE5 inhibitor. Since tadalafil is also a PDE5 inhibitor, a skilled person in the art would have expected tadalafil to have a similar interaction.

The only study that had been conducted on tadalafil and nitrates by the ‘684 Patent filing date (the LVAB study) used healthy volunteers and did not demonstrate a statistically significant difference in cardiovascular effects between tadalafil and sildenafil when used with nitrates. A skilled person would not have predicted either that tadalafil could be safely co-administered with nitrates, based on the information disclosed in the ‘684 Patent, given the known interaction of sildenafil and the limitations of Example 5. [ 63 ] Dr.

Melman then reviewed the ‘684 Patent, the skilled person’s knowledge about the use of PDE5 inhibitors to treat ED in April 1999 and April 2000, and the various clinical trials conducted by Lilly prior to filing the ‘684 Patent as disclosed by Dr. Pullman. In particular, Dr. Melman states that Example 5 only describes part of the LVAB study and does not discuss the sildenafil testing in the LVAB study. He stresses that it is apparent from the LVAB study that there was no statistically significant difference between the head to head comparison of tadalafil and sildenafil.

He adds that as of today, the claimed unit dose of tadalafil fails to achieve an improvement over sildenafil on the most important adverse effect identified in the ‘684 Patent – the interaction with nitrates. Both the Canadian Product Monograph and the US Product Label for CIALIS unequivocally state that tadalafil is contraindicated in patients using any form of nitrates, and as a clinician he states that he will not prescribe tadalafil to a patient who has been prescribed nitrates.

This contraindication is based on tadalafil-specific studies, which all show that tadalafil has clinically significant interactions with nitrates and should not be co-administered with nitrates, regardless of dose or dose regimen. Therefore, the contraindication is not simply a “class contraindication” applied reflexively to all PDE5 inhibitors. [ 64 ] Dr. Melman also comments on the publicly available version of the FDA Review of the New Drug Application for CIALIS (tadalafil), which confirms his opinion that tadalafil has clinically significant interactions with nitrates.

The FDA Review recommended, based on the studies conducted by Lilly, that short-acting nitrates be contraindicated up to 48 hours following a dose of CIALIS. [ 65 ] Dr. Melman also opines that the claimed unit dose of tadalafil does not produce an improvement over sildenafil with respect to nitrate co-administration; to the extent that there is any difference, tadalafil is contraindicated with nitrates for a longer period of time because of its longer half-life. [ 66 ] Finally, Dr. Melman reviews Dr. Brock’s and Dr.

Goldstein’s opinions and sets out several points of disagreement, particularly with respect to their views on the interaction between tadalafil and nitrates. In conclusion, he reaffirms that there was no evidence that tadalafil could be safely co-administered with nitrates at any unit dose as of the ‘684 Patent filing date. Given the frailties of the only nitrate study performed prior to the ‘684 filing date (LVAB), it has not been demonstrated either that the claimed dose of tadalafil had any improvement over sildenafil in terms of co-administration with nitrates.

He also expresses the view that as of April 2000, it could not be predicted from Example 5 that tadalafil could be safely co-administered with nitrates at any unit dose, or that the claimed dose of tadalafil would have any improvement over sildenafil in terms of co-administration with nitrates. Even as of today, tadalafil does not have a better overall side effect profile than sildenafil. With respect to the most important safety concern – the interaction with organic nitrate – both drugs are absolutely contraindicated.

With respect to other adverse effects, sildenafil has higher incidence rates for some adverse effects, whereas tadalafil has higher incidence rates for other adverse effects. Dr. Evan Siegel [ 67 ] Dr. Siegel is a toxicologist with expertise in drug development, including dose selection and side effects. He considers himself an expert in development and clinical testing of drugs across many areas. He does not have a particular specialization or experience in the field of sexual dysfunction. [ 68 ] After reciting his qualifications and mandate, Dr.

Siegel provides a general primer regarding the drug development process, particularly as it relates to the determination of an appropriate human dosage amount for a given drug, the relationship between dosing and adverse effects, and general information about different types of adverse effects. Of particular relevance is Dr. Siegel’s statement that in some cases, an adverse effect is severe and/or frequent enough that it warrants the inclusion of a caution, warning or contraindication on the product monograph, label or packaging.

Such notices are intended to alert patients and physicians to the potential harm that can result from use of the product. He states: I understand a contraindication to be the most severe notice about potential adverse effects associated with using the product. Essentially, a contraindication is a statement that advises prescribing healthcare providers and patients against using the product if the patient suffers from a certain condition or is taking another product that will interact negatively and potentially cause harm.

A contraindication effectively says “do not use this product if these circumstances apply”. (Siegel affidavit, para 70, AR Vol 18, p 4278) [ 69 ] Dr. Siegel then goes on to review the ‘684 Patent, including the clinical studies disclosed therein and offers his construction of the claims.

He understands the ‘684 Patent to promise that the unit dosages of tadalafil claimed (1 to 20 mg) provide an improvement over sildenafil by reducing three specific adverse effects (vision abnormalities, flushing, and the negative effects associated with co- administration with nitrates) to “clinically insignificant levels” , while higher dosages of tadalafil (such as 25 or 50 mg) do not provide this improvement. [ 70 ] Dr. Siegel responds to and critiques the Pullman affidavit, and sets out three issues with Dr.

Pullman’s narrative: first, the Pullman affidavit omitted important parts of the tadalafil development story, such as animal testing and early human testing; second, this narrative is focused on efficacy, whereas the ‘684 Patent is directed to the avoidance of three specific adverse effects; and third, the Pullman affidavit does not adequately explain the interaction of tadalafil with nitrates. Much like Dr.

Melman, he is of the view that in the LVAB study, there were no statistically significant differences between the combined effect of tadalafil and nitrates versus the combined effect of sildenafil and nitrates. Moreover, the LVAB study did not demonstrate that tadalafil could safely be co-administered

with nitrates. He also disagrees with Dr. Pullman that tadalafil is contraindicated because it is in the same class as sildenafil; tadalafil is contraindicated with nitrates because it has been shown to have clinically significant interactions with nitrates. [ 71 ] Dr. Siegel agrees with Drs. Goldstein and Brock that the ‘684 Patent promises that the claimed unit dosage of tadalafil provides an improvement by reducing the three specific adverse effects (flushing, vision abnormalities and the negative effects associated with co-administration with nitrates) known to occur with sildenafil.

However, he disagrees with them on the degree of improvement that is promised. Based on the evidence in the ‘684 Patent and the evidence submitted by Lilly in this proceeding, he is further of the view that there was no basis on which to conclude that the unit dosages of tadalafil selected in the ‘684 Patent (1 to 20 mg) provided an improvement by reducing the three specific adverse effects relative to sildenafil, or relative to higher dosages of tadalafil (such as 25 or 50 mg).

Example 5, in particular, was conducted with healthy and relatively young male volunteers, not with chronic nitrate users or with patients suffering from ED. Moreover, the example only provides information about a 10 mg dosage of tadalafil. [ 72 ] In addition to these views, he is also of the opinion that there is no basis upon which to conclude today that any dosage of tadalafil, either within or higher than the selected dosage range, can be safely co-administered with nitrates. Accordingly, the claimed dosages of tadalafil do not exhibit a better adverse effect profile than sildenafil in this regard.

He bases this opinion on his review of the data provided in the ‘684 Patent, the evidence provided in the Pullman affidavit, and a review of several different sources of current information regarding tadalafil. He examines the FDA Review and the published literature post 2000 and comes to the same conclusions as Dr. Melman that a unit dose of 1 to 20 mg of tadalafil cannot be co-administered with nitrates and that the contraindication is the result of testing specifically directed towards the interaction of tadalafil and nitrates, not due to class labeling by regulators.

He concludes that portion of his affidavit by explaining why he disagrees with Dr. Brock’s and Dr. Goldstein’s views on the interaction of tadalafil and nitrates. [ 73 ] Assuming that the inventive concept of the ‘684 Patent is “selecting a dose of 1 to 20 mg of tadalafil that results in a generally improved adverse effect profile over higher doses of tadalafil” , Dr. Siegel opines that, as of April 30, 1999, it was obvious to use tadalafil to treat ED in the unit dosages claimed in that Patent.

Based on the disclosure of the ‘784 Patent, a drug development team would have been motivated to employ standard dose ranging techniques to determine the adverse effects associated with different dosages within this range and find the dosage(

s) that is most effective with the lowest incidence and severity of adverse effects in the cohort of patients intended for treatment. As he states: Determining the dosage amount of a known compound is routine work for a drug development team. The goal of this process is always the same: to determine the range of doses that maximize efficacy and minimize adverse effects. As a general matter, it was well-known that the incidence of adverse effects could be reduced by lowering the dosage amount and that this is always desirable, so long as the dosage amount remains effective.

The drug development team performing this routine work will inevitably observe specific adverse effects of the target compound because adverse effects are inherent properties of the compound. (Siegel affidavit, para 34, AR Vol 18, p 4270) [ 74 ] Dr.

Siegel is of the view that, based on the comparative in vitro potency of tadalafil and sildenafil, the relative molecular weights of these compounds, and the pharmacokinetic profile of sildenafil and tadalafil, a drug development team following the ordinary course of development would likely have begun human dosing of tadalafil at a significantly lower dose than the approved marketed dosages of sildenafil. Conducting routine pharmacokinetic testing in animals would have led a drug development team to further reduce the initial doses used in human testing.

Given that a drug development team will typically start human testing with a low, safe dose and then increase the tested dose slowly to determine a maximum tolerated dose, a skilled person would therefore have likely designed an initial dose escalation study to start at approximately 5 mg of tadalafil and move up to approximately 50 mg. IV.

Issues [ 75 ] Mylan argues that if the ‘684 Patent is construed as a selection patent of the ‘784 Patent, the promised utility (namely that tadalafil in specific doses will reduce specific side effects to clinically insignificant levels) was neither demonstrated nor soundly predicted at the filing date, mainly because of the ongoing and serious problem of nitrate interaction.

If the ‘684 Patent is not a selection patent, then Mylan argues alternatively that it fails for obviousness and anticipation by the ‘784 Patent, because the dose ranges of the ‘684 fall entirely within those disclosed in the ‘784, and it would have been obvious to test lower doses. [ 76 ] To respond to the lack of utility argument, Lilly ignores the selection patent doctrine and argues that the ‘684 Patent merely promises to reduce side effects while remaining effective. This promise was both demonstrated and soundly predicted.

Moreover, Lilly argues that the 684 Patent’s narrower dose range was not obvious because it required extensive and non-routine testing. [ 77 ] Lilly ignores the anticipation argument, because Lilly was allegedly advised that Mylan was dropping the issue. Two weeks before the hearing of this matter, Lilly brought a motion to strike from the record the portion of Mylan’s Memorandum of Fact and Law pertaining to anticipation (paragraphs 170-191 and accompanying footnotes).

Lilly acknowledged that Mylan did allege in its NOA the invalidity of the ‘684 Patent on the basis of anticipation, but argues that the issue was never put into play as Mylan’s affiants never opined on the anticipation allegation. Lilly also relies on the fact that it was stopped from asking questions relating to anticipation during the cross-examination of one of Mylan’s experts, allegedly because counsel for Mylan confirmed that “anticipation is no longer an issue in the case” . [ 78 ] As I previously indicated, this motion must be rejected for the following reasons.

First of all, it seems to me that much clearer evidence would be required to find that the anticipation allegation was abandoned by Mylan. In the portion of questioning relating to the legal principles exhibit, counsel for Lilly asked Dr. Siegel whether the anticipation analysis was performed on a claim-by-claim basis or on the patent as a whole, to which counsel for Mylan interjected: “I don’t think it’s an issue in the case, if that helps…” (Siegel cross- examination, AR Vol 32, p 7147).

Lilly construes the word “it’s” as referring to the anticipation allegation, but it is equally possible to read it as referring to the issue of whether the anticipation analysis is done on a claim-by-claim basis or on the patent as a whole. On the basis of that ambiguity, I am unable to find that the anticipation allegation has unequivocally been dropped by Mylan.

[ 79 ] As for the argument that this allegation has not been put into play, I am also of the view that it is without merit. Mylan did not need to tender expert opinion evidence on the ultimate issue of whether an allegation is justified. This is a matter exclusively for the Court.

What Mylan was required to do was to give an “air of reality” to its allegation, and it did so as the facts that are relevant to the obviousness allegation are also relevant to the anticipation allegation. [ 80 ] Lilly also claims that it would be prejudiced if Mylan is permitted to raise arguments with respect to anticipation, as it has not had an opportunity to cross-examine Mylan’s witnesses and had not made submissions on the allegation. It is no doubt true that Mylan had Lilly’s Memorandum of Fact and Law for over 11 weeks, and could see that Lilly understood that anticipation was no longer an allegation.

Mylan could no doubt have tried to rectify the issue at that time. But Lilly could equally have raised the issue upon receiving Mylan’s original memorandum on August 22, 2014, at which point it ought to have known of Mylan’s position that anticipation is still a live issue.

Indeed, Lilly brought a motion to strike Mylan’s original memorandum for formatting irregularities on September 9, 2014, but remained silent about any intention to bring a motion to strike that same document on substantive grounds despite the Court asking whether any further motions would be brought before the hearing. [ 81 ] For all of the above reasons, the motion to strike from Lilly is dismissed and the allegation of anticipation ought to be addressed by this Court.

To ensure that Lilly will not suffer any prejudice as a result of that decision, I indicated at the hearing that the Court would be prepared to entertain any arguments that Lilly may wish to make orally with respect to anticipation. [ 82 ] The Court must therefore decide whether the following three allegations are justified:

(1) Is the allegation that the ‘684 Patent is invalid for lack of utility justified?

(2) Is the allegation that the claims are invalid for anticipation by the ‘784 Patent justified?

(3) Is the allegation that the claims are invalid for obviousness justified? V. Analysis [ 83 ] The parties are substantially in agreement as to the definition of the person skilled in the art. Indeed, the PSA was defined in much the same way by Dr. Goldstein, Dr. Brock and Dr. Melman. The ‘684 Patent is directed to a person or a drug development team having expertise in areas that are relevant to drug dosing, such as pharmacology and/or pharmacokinetics, physiology, dose ranging and safety assessment of candidate therapeutics, and with experience in the treatment of ED.

This team could include physicians, clinicians, research scientists, pharmacologists, toxicologists and statisticians, with at least a couple of years of experience working in a drug development environment in academia or in the pharmaceutical industry.

(1) Is the allegation that the ‘684 Patent is invalid for lack of utility justified? [ 84 ] The parties are in substantial agreement with respect to the law of utility, and there is no need to revisit the applicable principles as I have already canvassed them in the related case dealing with the ‘784 Patent (see 2015 FC 17 , at paras 70 ff). Because the Patent Act requires that every invention be new and useful (see the definition of “invention” at

section 2 of the Act), utility must either be demonstrated or soundly predicted as of the filing date where the gist of an invention is the new use of a compound: Apotex v Wellcome Foundation Ltd , 2002 SCC 77 , at para 56 , [2002] 4 SCR 153 [ AZT ]; Eli Lilly Canada v Novopharm Limited , 2010 FCA 197 , at para 74 [ Olanzapine ]. (

a) The Promise of the Patent [ 85 ] The promise of a patent is fundamental to the utility analysis and must be ascertained at its outset. As stated by the Federal Court of Appeal in Sanofi-Aventis v Apotex , 2013 FCA 186 , at para 47 , “[t]he promise of the patent is the standard against which the utility of the invention described in the patent is measured” . [ 86 ] If the parties agree on the relevant legal principles in the abstract, they differ on their application to the case at bar and diverge on the actual promise of the ‘684 Patent.

Lilly submits that the promise must be determined by focusing on the claims, and on that basis asserts that the promise of the ‘684 Patent is that the claimed doses are efficacious and, when administered to patients for the treatment of ED, will have a better side effect profile than sildenafil.

While not disagreeing with that construction of the promise, Mylan is of the view that the ‘684 Patent goes much beyond it and promises that the selection of a unit dose of 1 to 20 mg of tadalafil provides an improvement over sildenafil by reducing three side effects (flushing, vision abnormalities, and the negative effects associated with co- administration with nitrates) to “clinically insignificant levels” , while higher dosages of tadalafil (i.e. greater than 20 mg) do not provide this improvement. [ 87 ] Lilly argued that Mylan has elevated its promise beyond the allegations in its NOA, wherein the promise of the ‘684 Patent was described as “the claimed dosage range of tadalafil (

a) provides an effective treatment for ED; and (

b) produces an improved side effect profile relative to sildenafil, including the ability to be co-administered with organic nitrates” (NOA, Potter affidavit, Exh “B”, AR Vol 1, p 113). According to Lilly, Mylan now refers to three specific side effects rather than to the side effect profile in general, and also states that the side effects will not only be better relative to sildenafil, but that they will be clinically insignificant. [ 88 ] I agree with Mylan that Lilly has misrepresented its allegations by quoting from a single sentence in the NOA.

A careful reading of the NOA reveals that Mylan provides additional details with respect to what it calls the “Improved Therapeutic Profile Concept” construction of the promise. On the very same page quoted by Lilly, we find the following additions: As set out above, the 684 Patent promises that the unit dosage selection results in an improved side effect profile that includes:

•Tadalafil can be co-administered with an organic nitrate; •Other side effects previously believed to be indicative of PDE5 inhibition, such as flushing and vision abnormalities, can be reduced to clinically insignificant levels; and •Accordingly, tadalafil can be administered to individuals who previously were untreatable or suffered from unacceptable side effects, including individuals having cardiovascular disease, such as in individuals requiring nitrate therapy, having suffered a myocardial infarction more than three months before the onset of sexual dysfunction therapy, and suffering from class 1 congestive heart failure, or individuals suffering from vision abnormalities. (NOA, Potter affidavit, Exh “B”, AR Vol 1, p 113) [ 89 ] On the basis of that extract, it is fair to say that the NOA does contain the factual basis upon which Mylan relies in support of its allegations, and it cannot be argued that Lilly is taken by surprise by the construction of the promise put forward by Mylan in its Memorandum of Fact and Law.

The Court must therefore turn to the divergent constructions of the promise offered by the parties and come to its own conclusion as to the proper

interpretation of the promise made by the patentee. [ 90 ] While sildenafil is associated with a number of adverse side effects, all the experts agree that the ‘684 Patent focuses on three side effects associated with sildenafil – flushing, vision abnormalities, and the negative effects associated with co-administration with nitrates. The first two are mild and transient, in the sense that the side effect will go away when the person stops taking the drug.

The third one is by far sildenafil’s most significant side effect, as the co-administration of sildenafil with nitrates can result in potentially life- threatening hypotension. As Dr. Brock conceded, “death trumps most other side effects” (Brock cross-examination, p 207, AR Vol 23, p 5064).

It is clear, therefore, that the promise of the ‘684 Patent is not just that the claimed doses will have a better side effect profile than sildenafil; the promise is more focused and targets specifically three side effects, one of which can be life-threatening. [ 91 ] As noted above, the parties strongly disagree not only as to the side effects to be considered but also as to the extent of the side effect reduction promised by the ‘684 Patent.

Despite the clear language of the Patent that the side effects previously believed to be associated with PDE5 inhibitors “can be reduced to clinically insignificant levels” by tadalafil at the selected dose, Lilly asserts that complete elimination of side effects is impossible and that the person skilled in the art would not believe the ‘684 Patent was promising to minimize or eliminate all adverse effects that were seen with sildenafil. In other words, as Dr.

Brock would have it, “the promise of the ‘684 Patent is the efficacy at a very low dose together with the lower incidences of adverse effects that these lower doses provide” (Brock affidavit, para 216, AR Vol 2, p 226; see also, to the same effect, Goldstein affidavit, paras 384-385 AR Vol 2, pp 335-336). [ 92 ] Having carefully read the ‘684 Patent and the affidavits of the experts, I am unable to read down the promise of that Patent as Lilly would construct it. Such an

interpretation would fly in the face of the clear language of the ‘684 Patent, which explicitly promises much more than a marginal improvement over sildenafil. [ 93 ] As previously mentioned, the very first paragraph of the ‘684 Patent states that the unit dosage form described therein provides a benefit in therapeutic areas where inhibition of PDE5 is desired, “with minimization or elimination of adverse side effects resulting from inhibition of other phosphodiesterase enzymes” .

It then goes on to state that the product can be administered with “clinically insignificant” side effects associated with the combined effects of a PDE5 inhibitor and an organic nitrate.

While this may plausibly be characterized as a mere observation drawn from clinical studies, as Lilly argued, the next sentence goes much further and clearly reads as a promise: “[t]hus, the contraindication once believed necessary for a product containing a PDE5 inhibitor is unnecessary …” (emphasis added). [ 94 ] The Patent further reiterates (at p 10, line 29 to p 11, line 5) that the selection of a unit dosage form of 1 to 20 mg of tadalafil minimizes undesirable side effects previously believed unavoidable, including facial flushing, vision abnormalities, and a significant decrease in blood pressure when a PDE5 inhibitor is administered in combination with nitrates.

Read in conjunction with the previous sentence, according to which the present invention is based on detailed experiments and clinical trials showing that side effects can be reduced to “clinically insignificant levels” by the selection of a compound and unit dose, it is a fair assumption that the minimization of the undesirable side effects with the selected doses of tadalafil is more than marginal.

The language of elimination or minimization of adverse side effects also finds its way into the penultimate paragraph, both for vision abnormalities, flushing and the negative effects for individuals undergoing nitrate therapy. [ 95 ] On the basis of these ambitious and explicit statements throughout the Patent, I agree with Mylan that the promise is not merely a de minimis improvement over sildenafil; the language of the disclosure makes it clear that the promised improvement when it comes to adverse side effects is not just marginal but significant.

In this respect, I prefer the opinions of Mylan’s experts to those of Lilly’s experts on the construction of the promise, because they are more in line with the wording of the Patent. Accordingly, I would adopt the following characterization of the promise offered by Dr.

Melman in his affidavit: In my opinion, based on a complete reading of the ‘684 Patent, a Skilled Person would understand the patentee to be promising that the claimed unit dose of tadalafil (1 to 20 mg) will reduce all three of the adverse effects associated with sildenafil (flushing, vision abnormalities, and the negative effects associated with nitrate interactions) to clinically insignificant levels.

In my opinion, reducing adverse events to “clinically insignificant levels” would mean that the adverse effects would occur with sufficient rarity, and/or would be sufficiently mild, such that they would not affect a clinician’s judgment when prescribing a treatment for erectile dysfunction. (Melman affidavit, para 88, AR Vol 18, p 4233.

See also, to the same effect, Siegel affidavit, para 152, AR Vol 18, p 4299) [ 96 ] As Mylan points out, Lilly’s experts read down the promise based on irrelevant considerations: they find that the ‘684 Patent did not promise “clinically insignificant” nitrate interaction because, at the time, Lilly knew that this had not been achieved. When asked about how a skilled person would interpret specific statements in the ‘684 Patent, both Dr. Brock and Dr.

Goldstein referred to the data that Lilly actually had in hand at the filing date rather than to the language of the Patent itself (see for example Brock cross-examination, AR Vol 26, pp 5987-5988, 5992-5994, 5996-5999; Goldstein cross-examination, pp 133-136, AR Vol 24, pp 5363-5366). Such an approach is clearly unacceptable: a clear promise cannot be narrowed down to fit what has been demonstrated, otherwise utility would

never be an issue. As this Court stated in AstraZeneca v Apotex, 2014 FC 638, at para 128: First, AstraZeneca’s approach to utility is tautological. On a high level, the promise is the yardstick against which utility is measured forthe purpose of demonstration. Yet, AstraZeneca proposes a backwards approach that establishes that benchmark based on what canultimately be demonstrated in the patent. To circumscribe the scope of the promise based on what is demonstrated in the patent makes itimpossible to ever conclude that a patent is invalid for lack of utility.

No matter how broad a promise (e.g. this drug cures cancer), itwould always be read down to a narrower promise based on what was demonstrated. Such an approach would run contrary to the policyobjectives of patent law which serve to create consistency and clarity in the bargain struck between innovators and the public.

Instead,unequivocal promises in patents could in no way be relied upon and would be subordinate to more complex questions of demonstrationwithin the patent. [97] With respect to the issue relating to nitrates, Lilly focused on the package insert language and on the use of the word“preferably” in the following quotation found at page 8 of the Patent: Significantly, the package insert supports the use of the product to treat sexual dysfunction in patients suffering from a retinal disease,for example, diabetic retinopathy or retinitis pigmentosa, or in patients who are using organic nitrates.

Thus, the package insertpreferably is free of contraindications associated with these conditions, and particularly the administration of the dosage form with anorganic nitrate. [98] Dr. Brock emphasized in his affidavit that warnings and contraindications imposed by drug regulatory policies do notnecessarily define actual risk or utility, and that it is up to the FDA, Health Canada and the European Medicines Board to determinewhether or not there should be contraindication for the use of tadalafil with nitrates.

According to Lilly, this is precisely why the Patentspeaks in terms of preference, and does not rule out the possibility of a contraindication. [99] It is no doubt true that contraindications are regulatory matters, and I accept Lilly’s argument that a patentee cannot promisethat which it has no control over. Yet, the language of a patent cannot be ignored and a patentee can make an explicit promise that acontraindication is unnecessary even if, at the end of the day, this is a matter primarily for regulators. This is precisely what was donehere.

As previously mentioned, there is an explicit promise that tadalafil can be safely co-administered with nitrates such that acontraindication is “unnecessary” (see the quotation at para 93). This statement cannot simply be ignored when construing the promiseof the Patent, as Lilly’s experts seem to be doing. Having made an explicit promise of a specific result in the Patent, the patentee hasmade the contraindication not only a regulatory issue, but also a patent issue. Indeed, there is nothing wrong with such a promise ascontraindications are not the sole purview of regulators.

Clinicians and independent organizations do recommend contraindications basedon experimental evidence, and Dr. Goldstein himself was apparently part of an expert panel that reviewed the available evidence andpublished practical guidelines for doctors who treat ED (Goldstein cross-examination, pp 156-165, AR Vol 24, pp 5386-5395). [100] On the basis of the foregoing, I am therefore prepared to hold that the promise of the ‘684 Patent is not merely to lower theincidence of adverse side effects as compared to sildenafil, but to minimize them significantly or even to eliminate them.

This is true forall three side effects that are the focus of the ‘684 Patent, but more particularly with respect to the co-administration of tadalafil withnitrates; this is the inescapable conclusion that one must draw from the statement that a contraindication is unnecessary when tadalafil isadministered as a unit dose of about 1 to about 20 mg. [101] Counsel for Lilly tried to argue that the promise should be construed by focusing on the claims rather than the specification, andrelies for that proposition on the decision of this Court in Fournier Pharma v Canada (Health), 2012 FC 741 [Fournier] (subsequentlyfollowed by the decision of Justice Kane in Alcon Canada v Apotex, 2014 FC 699).

In Fournier, Justice Zinn wrote (at paras 126-127): The Federal Court of Appeal in Eli Lilly Canada Inc v Novopharm Limited, 2010 FCA 197, citing Consolboard Inc v MacMillan Bloedel(Sask) Ltd, (SCC), [1981] 1 SCR 504, stated at para 76 that “where the specification sets out an explicit ‘promise’,utility will be measured against that promise [emphasis added]”. The promise of a patent, as that term is used in patent law, is nothingmore than the utility the inventor claims for his invention.

Where that promise – that claimed utility – is clearly and unequivocallyexpressed by the inventor in the claims of the patent, then that expression ought to be viewed as the promise of the patent. Any statementfound elsewhere should be presumed to be a mere statement of advantage unless the inventor clearly and unequivocally states that it ispart of the promised utility. […] The

interpretation should be focused on the claims because an inventor is not obliged to claim a monopoly on everything new, ingenious,and useful disclosed in the specification. If, as here, the claims are certain and unambiguous in stating the promise, then the disclosureshould not be examined microscopically to find additional promises that are outside t

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