Janssen Inc. v. Pharmascience Inc.

Date: 20220823

Docket: T-1441-20

T-558-22

Citation: 2022 FC 1218

Ottawa, Ontario, August 23, 2022

PRESENT: The Honourable Mr. Justice Manson

BETWEEN:

JANSSEN INC. and JANSSEN

PHARMACEUTICA N.V.

Plaintiffs

and

PHARMASCIENCE INC.

Defendant

PUBLIC JUDGMENT AND REASONS

(Confidential Judgment and Reasons issued August 23, 2022)

I.

Introduction

[1]

This proceeding involves two patent infringement actions – Court File Nos. T-1441-20

and T-558-22 – pursuant to subsection 6(1) of the Patented Medicines (Notice of Compliance)

Regulations, SOR/93-133 (the “Regulations”).

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II.

A.

Background

The Parties

[2]

The Plaintiffs are Janssen Inc., a corporation headquartered in Toronto, and Janssen

Pharmaceutica N.V., a corporation headquartered in Belgium (collectively, “Janssen”). Janssen

Inc. is a “first person” as defined in the Regulations, and Janssen Pharmaceutica N.V. is a party

to this action pursuant to subsection 6(2) of the Regulations as the registered owner of Canadian

Patent No. 2,655,335 (the “335 Patent”).

[3]

The Defendant, Pharmascience Inc. (“Pharmascience” or “PMS”), is a generic

pharmaceutical company headquartered in Montréal. Pharmascience is a “second person” in

accordance with the Regulations.

B.

Technical Background

(1)

Schizophrenia and Related Disorders

[4]

Schizophrenia is a debilitating, lifelong disease estimated to afflict over 300,000

Canadians. Symptom onset typically manifests as a psychotic breakdown, and often occurs when

the afflicted individual is in their early to mid-twenties.

[5]

Schizophrenia is characterized by “positive” symptoms (such as hallucinations,

delusions, and disorganized behaviour) and “negative” symptoms (such as apathy, lack of

motivation, and social withdrawal). Diagnosis takes place once symptoms persist for at least six

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months after onset and must include the presence of at least two characteristic symptoms for a

significant portion of time during a one-month period.

[6]

Schizophreniform disorder requires the presence of characteristic symptoms for at least

one month, but less than six months. Schizoaffective disorder requires similar diagnostic criteria

to schizophrenia with an additional mood element, such as major depressive episodes, manic

episodes, or both. Unless otherwise indicated, references to “schizophrenia” in these reasons

should be understood to mean schizophrenia, schizophreniform disorder, and schizoaffective

disorder.

[7]

The underlying mechanism causing schizophrenia symptoms is abnormal dopamine

functioning in certain parts of the brain. Since the 1970s, researchers have been aware that

effective antipsychotic medications act by blocking dopamine at the D2 receptor.

(2)

Treatment of Schizophrenia

[8]

Antipsychotic drugs are the cornerstone of schizophrenia treatment and management.

They can be broken down into two classes: (1) typical (first generation) antipsychotics; and (2)

atypical (second generation) antipsychotics.

[9]

Typical (first generation) antipsychotics block D2 receptors in the brain and work well

against positive symptoms of schizophrenia. However, they are also associated with a high

incidence of severe adverse side effects called extrapyramidal symptoms, which typically

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involve motor control issues (such as muscle spasms, muscle rigidity, restlessness, and jerky

movements).

[10] Atypical (second generation) antipsychotics entered the market in the 1990s, and act on

both dopamine and serotonin receptors. Atypical antipsychotics are associated with a far lower

incidence of extrapyramidal symptoms.

[11] As stated above, schizophrenia is incurable and requires life long management with

antipsychotic medications. Adherence to a treatment regimen is critical. Many schizophrenia

patients take oral antipsychotics and are responsible for administering their own medication. A

leading cause of relapse is non-adherence, where patients do no take their antipsychotic

medication as prescribed, or at all. Rates of non-adherence amongst individuals with

schizophrenia are very high.

[12] One strategy to ensure treatment adherence is the use of long-acting formulations of

antipsychotics. One type of long-acting formulation is intramuscular injections of antipsychotic

drugs, known as “depot formulations” or “long-acting injectables.” Once injected, the drug

releases from the injection site slowly, providing the patient with prolonged drug exposure.

C.

The Invention Story

[13] In the early 1990s, Janssen started working on a long-acting injectable paliperidone

formulation for the treatment of schizophrenia. Around 2003, a global research team to support

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this development was labelled the Paliperidone Palmitate Compound Development Team (PP

CDT).

[14] The primary goals of the PP CDT were to optimize the formulation of the paliperidone

palmitate injection for monthly delivery; evaluate the safety and efficacy of paliperidone

palmitate for the treatment of schizophrenia and other disorders; and to develop dosing regimens

for the drug that would achieve regulatory approval.

[15] Dr. An Vermeulen, a pharmacometrician at Janssen, was actively involved in the

development of the dosage regimen for paliperidone palmitate. Initial multi-dose studies

conducted at Janssen indicated that, among other things, once monthly injections patients would

only reach steady-state plasma concentrations of paliperidone after four to five months. In 1999,

Dr. Vermeulen designed a Phase I study, BEL-7, which compared two different loading dose

regimens: (1) administering a double dose on Day 1 with monthly dosing thereafter; and (2)

administering the same dose on Day 1 and Day 8 with monthly dosing thereafter. All doses were

administered intramuscularly in the gluteal muscle. The BEL-7 study showed that the second

loading dose regimen with fixed doses on Day 1 and Day 8 and monthly doses thereafter resulted

in steady-state plasma concentrations within the first month.

[16] Following Phase I clinical trials, Dr. Vermeulen developed a population pharmacokinetic

model to assist in making informed dosing decisions and support dosing regimen selections. In

2003, Janssen moved forward with the Phase II study SCH-201 based on the results of the BEL-

7 study and Dr. Vermeulen’s modeling. The SCH-201 study tested fixed doses of 50 and 100

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milligram equivalent (mg-eq.) administered in the gluteal muscle on Days 1, 8, and monthly

thereafter.

[17] Based on the success of SCH-201, Janssen designed two Phase III studies – PSY-3003

and PSY-3004 – to investigate fixed doses of 25, 50, 100, and 150 mg-eq. administered on Days

1, 8, and monthly thereafter into the gluteal muscle. These studies were conducted from

December 2004 to March 2006, and June 2005 to June 2006, respectively.

[18] In April 2006, Dr. Srihari Gopal joined Janssen as a Project Physician on the Clinical

Team subgroup of the PP CDT. He was assigned responsibility for ongoing paliperidone

palmitate Phase III clinical trials. At this time, the PSY-3003 and PSY-3004 studies were either

complete or nearing completion. The results of these studies were unexpectedly disappointing,

and led to the creation of a special task force, including Drs. Vermeulen and Gopal, to

troubleshoot problems identified following the Phase III studies and propose improvements to

the dosing regimen.

[19] To assist in revising the dosing regimen, Dr. Vermeulen developed a new population

pharmacokinetic model using clinical data from over 1,200 patients. She used this model to

evaluate several different dosing regimens by simulating the plasma concentrations of a virtual,

representative patient population.

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[20] The task force eventually identified a “treatment by country” interaction in patients from

the United States that was determined to be the result of high body mass index. The task force

then focused on adjusting the dose regimen for future trials to overcome the issue.

[21] In 2006, Dr. Vermeulen moved to a new position within Janssen. Dr. Mahesh Samtani

took over her role on the PP CDT in February 2007. He was tasked with developing a new

population pharmacokinetic model for Janssen’s long-acting injectable paliperidone palmitate

formulation.

[22] In February and December 2007, advisory board meetings were held with representatives

of Janssen (including Drs. Gopal (attended both meetings), Vermeulen (attended the February

meeting), and Samtani (attended the February meeting)) and external advisors (including Dr.

Ereshefsky (attended the December meeting)). The objectives of the meetings were to review

and obtain feedback on the clinical trial data and planned submissions to regulatory authorities.

At that time, the proposed dosing regimen included: 1) a 150 mg-eq. dose administered in the

deltoid muscle on Day 1 of treatment, 2) a second dose in the range of 25 to 150 mg-eq. in either

the deltoid or gluteal muscle starting on Day 8, and 3) monthly doses thereafter.

[23] The advisors were of the view that the use of a 150 mg-eq. dose for most of the patients

was a risk and a more acceptable regimen would be to start with 100 mg-eq. The reluctance to

accept a 150 mg-eq. starting dose was due to two concerns: 1) safety (overdosing) concerns and

2) the acceptability of regulatory authorities. In light of the feedback, Janssen went forward with

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an initial new drug application that had a 100 mg-eq. starting dose, including other refinements

to the regimen.

[24] Dr. Samtani built a new model using data from over 1,400 patients, comprising 15,000

samples from Phase I, II, and III studies. The development and validation took approximately six

months, and took into account a wide range of covariates and paliperidone palmitate’s absorption

and elimination process. Once complete, simulations were ran to guide optimization of the

paliperidone palmitate-dosing regimen.

[25] Dr. Samtani used his model to establish a dosing regimen comprised of loading doses of

150 mg-eq. on Day 1 and 100 mg-eq. on Day 8 injected into the deltoid muscle, and maintenance

doses of 75 mg-eq. monthly thereafter injected into either the deltoid or gluteal muscle. Based on

modeling, simulation, and the results of a further Phase III study PSY-3007, the team was

confident that this dosing regimen was safe and effective; did not require oral supplementation;

brought patients to steady-state plasma concentration within one week; and matched the plasma

concentrations of patients taking 6 mg dose of INVEGA®, an extended release oral tablet of

paliperidone.

[26] Dr. Samtani also used his model to develop recommended flexible tolerance intervals for

the timing of the second loading dose and subsequent maintenance dose injections, or “dosing

windows.” He determined that dosing windows of ± 2 days for the second loading dose and ± 7

days for the monthly maintenance doses would maintain therapeutic plasma concentrations

without affecting safety and efficacy. Based on modeling and clinical data, Dr. Samtani also

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determined the appropriate downward dose adjustments for renally impaired patients – a 100

mg-eq. dose on Day 1 followed by a 75 mg-eq. dose on Day 8, both in the deltoid, and monthly

doses thereafter of 50mg-eq. in either the deltoid or the gluteal muscle.

[27] While Janssen did not receive the results of the PSY-3007 study until after December 19,

2007 (the first priority date for the 353 Patent), Dr. Samtani had developed this regimen using his

population pharmacokinetic model and confirmed the safety and efficacy of the regimen (at least

in part) using the PSY-3007 results.

D.

The 335 Patent

[28] The 335 Patent is titled “Prolonged-Release Injectable Suspensions of Paliperidone

Palmitate and Dosage Forms and Delivery Systems Incorporating Same.”

[29] The 335 Patent issued from an application filed in Canada on December 17, 2008,

claiming priority from United States Patent Application No. 61/014,918, filed on December 19,

2007. The 335 Patent was laid open on June 19, 2009, issued on September 6, 2016, and has not

expired.

[30] The 335 Patent contains 63 claims – each of which is asserted in the two actions in this

proceeding. Claims 1, 2, 17, 18, 33, 34, 49, and 50 are independent claims.

[31] The 335 Patent relates to dosing regimens for long-acting injectable paliperidone

palmitate formulations for treatment of schizophrenia and related disorders, and teaches a dosing

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regimen that ensures an optimum plasma concentration-time profile for treating patients with

paliperidone. The inventors targeted a plasma concentration exposure range of 7.5 to 40 ng/mL

of paliperidone after injection to ensure efficacy and minimize adverse side effects.

[32] In order to rapidly achieve therapeutic blood plasma concentrations, the 335 Patent

teaches a “loading dose” regimen, wherein a specific dose is administered on Day 1 and a

different specific dose is administered on Day 8 – both in the deltoid muscle. The “loading dose”

regimen is followed by a “maintenance dose” regimen comprised of doses of paliperidone

palmitate administered monthly thereafter, in either the deltoid or the gluteal muscle.

[33] The dosing regimen incorporates “dosing windows” of ± 2 days for the second loading

dose, and ± 7 days for the monthly maintenance doses.

[34] The claims of the 335 Patent break down into four sets:

i. Claims 1 to 16 relate to prefilled syringes adapted for administration according

to the claimed dosing regimens;

ii. Claims 17 to 32 relate to a use of a “dosage form” according to the claimed

dosing regimens;

iii. Claims 33 to 48 relate to use of paliperidone as paliperidone palmitate in the

manufacture/preparation of a “medicament” adapted for administration

according to the claimed dosing regimen; and

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iv. Claims 49 to 63 relate to a “dosage form” adapted for administration according

to the claimed dosage regimens.

[35] The claimed dosing regimen for non-renally impaired psychiatric patients in need of

treatment for schizophrenia is defined in claims 1, 17, 33, and 49:

i. A first loading dose of 150 mg-eq. of paliperidone palmitate administered into

the deltoid muscle on Day 1 of treatment;

ii. A second loading dose of 100 mg-eq. of paliperidone palmitate administered into

the deltoid on Day 8 ± 2 days; and

iii. Maintenance doses of 75 mg-eq. of paliperidone palmitate administered into the

deltoid or gluteal muscle monthly ± 7 days after the second injection.

[36] The claimed dosing regimen for renally impaired patients, as defined in claims 2, 18, 34,

and 50 follows the same dosing schedule, dosing windows, and injection sites, but with loading

doses of 100 mg-eq. and 75 mg-eq., and maintenance doses of 50 mg-eq.

E.

INVEGA SUSTENNA®

[37] The 335 Patent is listed on the Patent Register maintained by the Minister of Health

pursuant to the Regulations in respect of Janssen’s paliperidone palmitate suspension, marketed

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under the brand name INVEGA SUSTENNA®, in dosage strengths of 50 mg/0.5 mL (i.e. 50

mg-eq.), 75 mg/0.75 mL, 100 mg/1 mL, and 150 mg/1.5 mL.

[38] The product monograph for INVEGA SUSTENNA® sets out dosing regimens falling

within the claims of the 335 Patent.

F.

Litigation History

(1)

Court File No. T-353-18: Janssen Inc. v. Teva Canada Ltd.

[39] Janssen has previously asserted claims 1 to 48 of the 335 Patent against Teva Canada Ltd.

in Court File No. T-353-18 (Janssen Inc. v. Teva Canada Ltd., 2020 FC 593 [Teva

Paliperidone]).

[40] In Teva Paliperidone, I determined, among other things, the Person of Ordinary Skill in

the Art (POSITA), the Common General Knowledge, and the construction of claims 1 to 48 of

the 335 Patent – the details of which will be set out in the relevant sections below.

[41] While the appeal of Teva Paliperidone is currently pending, the POSITA and

construction of claims 1 to 48 of the 335 Patent are not at issue in these proceedings.

(2)

Court File No. T-455-20: Janssen Inc. v. Pharmascience Inc.

[42] On February 28, 2020, Pharmascience served a Notice of Allegation and Detailed

Statement in respect of its Abbreviated New Drug Submission (ANDS) No. 236094 in regards to

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the 335 Patent and seeking approval to market and sell in Canada 50, 75, 100, and 150 mg-eq.

doses of a proposed pms-PALIPERIDONE PALMITATE product, a generic version of Janssen’s

INVEGA SUSTENNA® product.

[43] In response, Janssen commenced an infringement action under subsection 6(1) of the

Regulations on April 8, 2020 in Court File No. T-455-20. On October 2, 2020, the action in

respect to ANDS No. 236094 was discontinued on consent.

(3)

Court File No. T-1441-20: Janssen Inc. v. Pharmascience Inc.

[44] On October 16, 2020, Pharmascience served a Notice of Allegation and Detailed

Statement in respect of its ANDS No. 244641 in regards to the 335 Patent and seeking approval

to market and sell in Canada |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| doses of its proposed pms-

PALIPERIDONE PALMITATE, a generic version of Janssen’s INVEGA SUSTENNA®

product.

[45] Pharmascience alleges that the 335 Patent is invalid or void and would not be infringed

by the making, constructing, using, or selling of a proposed pms-PALIPERIDONE

PALMITATE as set out in ANDS No. 244641.

[46] In response, Janssen commenced an action (File No. T-1441-20) against Pharmascience

pursuant to subsection 6(1) of the Regulations on November 27, 2020. Janssen is seeking:

a. A declaration that the making, constructing, using, or selling of pms-

PALIPERIDONE PALMITATE by Pharmascience in accordance with ANDS

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No. 244641 would infringe claims 1 to 63 of the 335 Patent, directly and/or

indirectly;

b. A permanent injunction restraining Pharmascience (as well as its subsidiaries and

affiliates) from:

i. Making, constructing, using, or selling the pms-PALIPERIDONE

PALMITATE in Canada;

ii. Offering for sale, marketing, or having the pms-PALIPERIDONE

PALMITATE marketed in Canada;

iii. Importing, exporting, distributing, or having the pms-PALIPERIDONE

PALMITATE distributed in Canada; and

iv. Otherwise infringing or inducing others to infringe the 335 Patent.

c. If Pharmascience makes, constructs, uses, or sells the pms-PALIPERIDONE

PALMITATE before the expiry of the 335 Patent, damages or an accounting of

Pharmascience’s profits, as Janssen may elect, resulting from Pharmascience’s

infringing activities in respect of the 335 Patent;

d. Janssen’s costs of this action; and

e. Any other relief that this Honourable Court deems just.

[47] On January 26, 2021, Pharmascience brought a motion for summary trial on the grounds

that the pms-PALIPERIDONE PALMITATE, made in accordance with ANDS No. 244641,

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does not contain an essential element (i.e. the 75 mg-eq. dose) of any of the 63 claims of the 335

Patent and, therefore, cannot infringe the 335 Patent.

[48] In Janssen Inc. v. Pharmascience Inc., 2022 FC 62 [PMS Paliperidone], I found that

Janssen had shown, on a balance of probabilities, that Pharmascience’s proposed pms-

PALIPERIDONE PALMITATE in accordance with ANDS No. 244641 will induce infringement

of the 335 Patent. More specifically, based on the evidence, there appear to be several instances

in the product monograph of the proposed pms-PALIPERIDONE PALMITATE that would

influence prescribers to prescribe the claimed dosing regimen leading to direct infringement of

the 335 Patent.

[49] Thus, Janssen’s action was not dismissed and was allowed to proceed on

Pharmascience’s defence of alleged invalidity as described herein.

[50] The appeal of the PMS Paliperidone summary trial is currently pending.

[51] Since all 63 claims of the 335 Patent are at issue in Court File No. T-1441-20, claims 49

to 63 have been construed – the details of which will be set out in the relevant section below.

(4)

Court File No. T-553-22: Janssen Inv. v. Pharmascience Inc.

[52] On January 29, 2022, Pharmascience served a Notice of Allegation and Detailed

Statement in respect of its ANDS No. 251767 in regards to the 335 Patent and seeking approval

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to market and sell in Canada |||||||||||||||||||||||| of its proposed pms-PALIPERIDONE

PALMITATE, a generic version of Janssen’s INVEGA SUSTENNA® product.

[53] In the Statement of Claim, Janssen asserts that the letter served on them was not a proper

Notice of Allegation as Pharmascience failed to comply with the Regulations. However, this is

not an issue in these proceedings.

[54] Pharmascience alleges that the 335 Patent is invalid or void, but does not contest

infringement by the making, constructing, using, or selling of a proposed pms-PALIPERIDONE

PALMITATE as set out in ANDS No. 251767.

[55] In response, Janssen commenced an action (Court File No. T-558-22) against

Pharmascience pursuant to subsection 6(1) of the Regulations on March 14, 2022. Janssen is

seeking:

a. A declaration that the making, constructing, using, or selling of pms-

PALIPERIDONE PALMITATE by Pharmascience in accordance with ANDS

No. 251767 would infringe claims 1 to 63 of the 335 Patent, directly and/or

indirectly;

b. A permanent injunction restraining Pharmascience (as well as its subsidiaries and

affiliates) from:

i. Making, constructing, using, or selling the pms-PALIPERIDONE

PALMITATE in Canada;

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ii. Offering for sale, marketing, or having the pms-PALIPERIDONE

PALMITATE marketed in Canada;

iii. Importing, exporting, distributing, or having the pms-PALIPERIDONE

PALMITATE distributed in Canada; and

iv. Otherwise infringing or inducing others to infringe the 335 Patent.

c. If Pharmascience makes, constructs, uses, or sells the pms-PALIPERIDONE

PALMITATE before the expiry of the 335 Patent, damages or an accounting of

Pharmascience’s profits, as Janssen may elect, resulting from Pharmascience’s

infringing activities in respect of the 335 Patent;

d. Janssen’s costs of this action; and

e. Any other relief that this Honourable Court deems just.

III.

Issues

[56] As stated above, at the motion for summary trial dealing solely with the issue of

infringement, Janssen’s action was not dismissed, a finding of infringement was made, and this

action has proceeded on the basis Pharmascience’s defence of alleged invalidity of the 335

Patent.

[57] The Parties have filed a Joint Statement of Issues:

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i. Whether any of the claims of the 335 Patent are invalid on the basis of

obviousness, pursuant to section 28.3 of the Patent Act, RSC 1985, c P-4; and

ii. Whether any of the claims of the 335 Patent are invalid on the basis of lack of

patentable subject matter (i.e. as a method of medical treatment) under section 2

of the Patent Act.

IV.

A.

Analysis

The Experts and Fact Witnesses

(1)

Janssen’s Fact Witnesses

(a)

An Vermeulen, PhD

[58] Dr. Vermeulen is a named co-inventor of the 335 Patent. She is currently the Clinical

Pharmacology and Pharmacometrics Therapeutic Area Head for Immunology at Janssen.

[59] Dr. Vermeulen received her PhD in Pharmaceutical Sciences from the University of

Ghent, with a focus on pharmacokinetics.

[60] Dr. Vermeulen was a credible witness and gave evidence on her work in the development

of pharmacokinetic models to guide decision-making, design clinical trials, and support dose

regimen selection and adaptation of the formulation and dosing regimens for Janssen’s

paliperidone palmitate injectable as described above in the invention story.

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(b)

Srihari Gopal, MD

[61] Dr. Gopal is a named co-inventor of the 335 Patent. Though no longer employed by or

associated with Janssen, at the time of signing his affidavit he was Senior Director (Head of

Development, Psychiatry) at Janssen Research & Development LLC.

[62] Dr. Gopal obtained his medical degree from Rutgers University before completing two

medical residencies: one in association with the Department of Surgery at the University of

Illinois, College of Medicine and the other in association with the Department of Family

Medicine at the Baylor College of Medicine in Texas. Dr. Gopal also has a Masters of Health

Science in association with the Clinical Research Training Program at Duke University in North

Carolina.

[63] Dr. Gopal was a credible witness and gave evidence about his role in the development of

the paliperidone palmitate one-month long-acting injectable formulation, as well as his

understanding of the studies completed before his employment at Janssen. Dr. Gopal became

involved with the PP CDT during the Phase III trials as described above in the invention story.

[64] On consent, the final paragraph of Dr. Gopal’s affidavit was removed in response to an

objection raised by Pharmascience.

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(c)

Mahesh Samtani, PhD

[65] Dr. Samtani is a named co-inventor of the 335 Patent. He is currently Senior Director, US

Pharmacometrics Head at Janssen.

[66] Dr. Samtani received his PhD in Pharmaceutical Science from the State University of

New York. A portion of his PhD thesis was on pharmacokinetic and pharmacodynamic modeling

of aqueous suspensions of a corticosteroid with long-acting properties.

[67] Dr. Samtani was a credible witness and gave evidence about his role in the development

of a population pharmacokinetic model that would be suitable for submissions to regulatory

authorities and would aid in optimizing the dosing regimen for paliperidone palmitate as

described above in the invention story.

(2)

Pharmascience’s Fact Witnesses

(a)

Horatiu Lazar

[68] Mr. Lazar is a Marketing and Sales Data Analyst at Pharmascience. He described how the

IGVIA (formerly, IMS) data (which provides pharmaceutical sales and prescription data for

paliperidone palmitate products from 2021) cited in Dr. Jeffries expert report was prepared.

[69] Mr. Lazar was not examined and his affidavit was entered into evidence as read.

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(b)

Nathaniel Frank-White

[70] Mr. Frank-White is a Records Request Processor at the Internet Archive, which provides

the Wayback Machine service. He provided screenshots of a Johnson & Johnson webpage that

linked to webcasts and documents of public conferences and events held by the company from

June 7, 2007 to January 22, 2008, including the Credit Suisse investors meeting transcript.

[71] Mr. Frank-White was not examined and his affidavit was entered into evidence as read.

(3)

Janssen’s Expert Witnesses

(a)

Dr. Pierre Chue

[72] Dr. Chue is a Medical Doctor with specialized training in the field of psychiatry. He

holds several clinical, research, and teaching positions with Alberta Health Services and the

University of Alberta. Dr. Chue’s practice focuses on the treatment of adult patients with mental

illness, including schizophrenia and schizoaffective disorder.

[73] Dr. Chue obtained his Bachelor of Medicine, Bachelor of Surgery (MBBCh) from the

Welsh National School of Medicine.

[74] Dr. Chue was qualified as an expert in the diagnosis and treatment of schizophrenia and

schizoaffective disorder. This expertise includes the clinical use of injectable depot medications,

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such as paliperidone palmitate (i.e. INVEGA SUSTENNA®), as well as oral antipsychotic

medications.

[75] Pharmascience raised a preliminary objection to portions of Dr. Chue’s testimony under

Rule 248 of the Federal Court Rules, SOR/98-106. Pharmascience objected to any testimony

regarding the prescribing practices of Canadian physicians because a Janssen corporate

representative had previously refused to answer whether they had any information about the

prescribing practices of Canadian physicians during discovery.

[76] As I have previously ruled in related proceedings, testimony regarding the practices and

knowledge of other physicians is hearsay, neither reliable nor necessary, and, as such, given little

to no weight (Teva Paliperidone at paragraph 52).

[77] Dr. Chue testified to the issues of obviousness and method of medical treatment. Dr.

Chue was somewhat obstructionist during cross-examination, and did not give straightforward

answers to many simple questions. Nevertheless, the weight of his evidence, when of value, is

considered below.

(b)

Larry Ereshefsky, PharmD

[78] Dr. Ereshefsky is a Clinical Pharmacologist and Certified Psychiatric Pharmacist with

over 40 years of experience as a clinician, scientist, and investigator in developing treatments

and clinical methodologies for neurodegenerative and psychiatric disorders, including

schizophrenia.

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[79] Dr. Ereshefsky obtained his PharmD from the University of Southern California and

completed his residency in psychiatric pharmacy/psychopharmacology at the University of

Southern California – Los Angeles County Medical Center. Now retired, he was a Professor of

Pharmacy, Psychiatry, and Pharmacology at the University of Texas, teaching courses in

psychiatric therapeutics and clinical pharmacology.

[80] As Associate Director of the Clinical Research Unit at San Antonio State Hospital, Dr.

Ereshefsky oversaw the clinical care and conduct of numerous clinical trials in the development

of atypical antipsychotics and new therapies for schizophrenia and other disorders.

[81] Dr. Ereshefsky was qualified as an expert in:

i. Clinical pharmacology, particularly in the clinical pharmacology of antipsychotic

drugs;

ii. Evaluating the pharmacokinetics, pharmacodynamics, bioequivalence, drug-drug

interactions, and pharmacogenetics of antipsychotic drugs, including long-acting

injectable (depot) antipsychotic drugs;

iii. The clinical use of antipsychotic drugs, including designing, implementing,

monitoring, and modifying treatment plans for patients using antipsychotic dugs

(including long-acting injectable antipsychotic drugs) for treatment pf psychiatric

disorders, including schizophrenia, schizoaffective disorder, and

schizophreniform disorder;

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iv. Clinical trial design and implementation, including clinical trials for drugs used in

the treatment of psychiatric disorders, including schizophrenia, schizoaffective

disorder, and schizophreniform disorder;

v. Translational psychopharmacology, including the evaluation of preclinical

(animal) data and models and the extrapolation of preclinical date to predict

pharmacokinetic and pharmacodynamic parameters in humans; and

vi. The evaluation of toxicology and safety signals, including in translating

preclinical and clinical trial data into design strategies incorporating patient

assessments/biomarkers and in exploring exposure limits.

[82] Dr. Ereshefsky testified to the issues of obviousness and method of medical treatment. He

suffered some credibility issues in providing several unreasonable opinions, related to evidence

on the issue of obviousness, as discussed in more detail below.

(4)

Pharmascience’s Expert Witnesses

(a)

Joel Jeffries, MD

[83] Dr. Jeffries was appointed as Staff Psychiatrist at the Centre for Addiction and Mental

Health from 1998 until May 2021, when he retired from active clinical practice. Among other

teaching roles, Dr. Jeffries has been an Associate Professor of Psychiatry and Pharmacy at the

University of Toronto since 1978, and claims more than 50 years of experience in psychiatry. Dr.

Jeffries received his medical degree from the University of Dublin.

Page: 25

[84] Dr. Jeffries was qualified as an expert in the field of psychiatry, including in the

diagnosis, monitoring, and treatment of patients with schizophrenia and related disorders,

including long-acting injectables and depot formulations. He is also an expert in the prescribing

practices of psychiatrists and the standard of practice of psychiatrists and physicians treating

patients with schizophrenia and related disorders.

[85] Dr. Jeffries provided his opinion on the issue of method of medical treatment. He

suffered some credibility issues, having provided inconsistent statements and sometimes seemed

confused or unable to follow relatively straight-forward questions. Dr. Jeffries has also never

prescribed INVEGA SUSTENNA®. As stated above for Dr. Chue’s testimony, any testimony

provided by Dr. Jeffries reflecting other physicians prescribing practices gathered from

discussions with colleagues is hearsay and is given little or no weight.

(b)

Pardeep Gupta, PhD

[86] Dr. Gupta is a Professor of Pharmaceutics and Burroughs Wellcome Chair in the

Department of Pharmaceutical Sciences at University of the Sciences in Philadelphia. He is also

the Director of Industrial Pharmacy Laboratory at Philadelphia College of Pharmacy, University

of the Sciences in Philadelphia. He teaches on the topics of injectable and non-injectable

pharmaceutical formulations, drug diffusion, controlled drug delivery, pharmaceutical rate

processes, drug stability, bioavailability and pharmacokinetics.

[87] Dr. Gupta received his PhD in Pharmaceutics and Physical Chemistry from the

University of Wisconsin – Madison. His research was focussed on study of the biological

Page: 26

variables that affect bioavailability of drugs and his graduate education in pharmaceutical

sciences involved extensive course work and research projects in the area of drug formulation,

chemical modifications of drugs and pharmacokinetics.

[88] Dr. Gupta was qualified as an expert in the field of drug dissolution, drug formulation,

and drug delivery systems, including nanoparticle-based injectables. He is also an expert in the

bioavailability and pharmacokinetic trials and is familiar with pharmacokinetic modelling.

[89] Dr. Gupta provided his opinion on the issue of obviousness. He suffered some credibility

issues in failing to agree to or admit simple, straightforward propositions. Dr. Gupta has also

never conducted or designed a clinical trial or pharmacokinetic trial in humans.

B.

Claim Construction

[90] Claim construction is a matter of law for the Court (Whirlpool Corp.v. Camco Inc., 2000

SCC 67 at paragraph 61). Where the judge can construe the patent as it would be understood by a

skilled person, expert evidence is not required (Pfizer Canada Inc. v. Canada (Minister of

Health), 2007 FC 446 at paragraphs 25, 35, and 36; Excalibre Oil Tools Ltd. v. Advantage

Products Inc., 2016 FC 1279 at paragraph 119).

[91] The principles of claim construction were summarized by the Federal Court of Appeal in

Tearlab Corporation v. I-Med Pharma Inc., 2019 FCA 179 at paragraphs 30 to 34:

[30] The general principles of claim construction are now well

established and were set out by the Supreme Court in three cases

(Whirlpool at paras. 49-55; Free World Trust v. Électro Santé Inc.,

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2000 SCC 66, [2000] 2 S.C.R. 1024 at paras. 31-67 [Free World

Trust]; Consolboard Inc. v. MacMillan Bloedel (Sask.) Ltd., 1981

15 (SCC), [1981] 1 S.C.R. 504 at p. 520 [Consolboard]).

These principles can be summarized as follows.

[31] The Patent Act promotes adherence to the language of the

claims, which in turn promotes fairness and predictability (Free

World Trust at paras. 31(a), (b) and 41). The words of the claims

must, however, be read in an informed and purposive way (at para.

31(c)), with a mind willing to understand (at para. 44). On a

purposive construction, it will be apparent that some elements of the

claimed invention are essential while others are non-essential (at

para. 31(e)). The interpretative task of the court, in claim

construction, is to separate and distinguish between the essential and

the non-essential elements, and to give the legal protection to which

the holder of a valid patent is entitled only to the essential elements

(at para. 15).

[32] To identify these elements, the claim language must be read

through the eyes of a POSITA, in light of the latter’s common

general knowledge (Free World Trust at paras. 44-45; see also Frac

Shack at para. 60; Whirlpool at para. 53). As noted in Free World

Trust:

[51] …The words chosen by the inventor will be read

in the sense the inventor is presumed to have

intended, and in a way that is sympathetic to

accomplishment of the inventor’s purpose expressed

or implicit in the text of the claims. However, if the

inventor has misspoken or otherwise created an

unnecessary or troublesome limitation in the claims,

it is a self-inflicted wound. The public is entitled to

rely on the words used provided the words used are

interpreted fairly and knowledgeably. [Emphasis in

the original.]

[33] Claim construction requires that the disclosure and the claims

be looked at as a whole “to ascertain the nature of the invention and

methods of its performance, … being neither benevolent nor harsh,

but rather seeking a construction which is reasonable and fair to both

patentee and public” (Consolboard at p. 520; see also Teva Canada

Ltd. v. Pfizer Canada Inc., 2012 SCC 60, [2012] 3 S.C.R. 625 at

para. 50). Consideration can thus be given to the patent

specifications to understand what was meant by the words in the

claims. One must be wary, however, not to use these so as “to

enlarge or contract the scope of the claim as written and …

understood” (Whirlpool at para. 52; see also Free World Trust at

Page: 28

para. 32). The Supreme Court recently emphasized that the focus of

the validity analysis will be on the claims; specifications will be

relevant where there is ambiguity in the claims (AstraZeneca

Canada Inc. v. Apotex Inc., 2017 SCC 36, [2017] 1 S.C.R. 943 at

para. 31; see also Ciba at paras. 74-75).

[34] Finally, it is important to stress that claim construction must be

the same for the purpose of validity and for the purpose of

infringement (Whirlpool at para. 49(b)).

[92] The relevant date for construing the claims is the publication date: June 19, 2009.

[93] As stated above, the construction of all 63 claims of the 335 Patent and the POSITA have

been previously determined and are not at issue in these proceedings.

[94] The essential elements of claim 1 are (Teva Paliperidone at paragraph 145):

i. Prefilled syringes containing a depot formulation of paliperidone as paliperidone

palmitate formulated as an aqueous nanoparticle suspension;

ii. For administration by intramuscular injection to a psychiatric patient in need of

treatment for schizophrenia, schizoaffective disorder, or schizophreniform

disorder;

iii. Wherein the prefilled syringes are adapted for administration in accordance with

the following dosing regimen:

a. A first loading dose of about 150 mg-eq. of paliperidone injected into the

deltoid on treatment Day 1;

Page: 29

b. A second loading dose of about 100 mg-eq. of paliperidone injected into

the deltoid on treatment Day 8 ± 2 days;

c. Continuous maintenance doses of 75 mg-eq. of paliperidone injected into

the deltoid or gluteal monthly ± 7 days thereafter.

[95] The essential elements of claim 2 are the same, except that the patient in need of

treatment must have renal impairment, and the claimed dose amounts are about 100 mg-eq., 75

mg-eq., and 50 mg-eq., respectively (Teva Paliperidone at paragraph 146).

[96] The essential elements of the claims are conjunctive. The first claim set requires the

combination of multiple prefilled syringes of varying dosage amounts adapted for administration

in accordance with the claimed dosing schedule and injection sites. The claimed invention is a

dosing regimen, not simply dosage forms (Teva Paliperidone at paragraphs 147).

[97] Claims 3 through 14 depend from claims 1 and 2, and include further specific

formulation limitations. Claims 3 through 14 incorporate the dose amounts, dosing windows, and

injection sites from independent claims 1 and 2 (Teva Paliperidone at paragraph 128).

[98] Claim 15 further limits any of claims 1 to 14 to administration to a psychiatric patient in

need of treatment for schizophrenia only. Claim 16 is similar, but limited to psychiatric patients

in need of treatment for schizoaffective disorder only (Teva Paliperidone at paragraph 129).

[99] Claims 1 to 16 comprise “product” claims (Teva Paliperidone at paragraphs 145 to 147).

Page: 30

[100] Claims 17 to 32 effectively mirror claims 1 to 16, except that they are directed towards

“use of a dosage form of paliperidone as paliperidone palmitate” rather than prefilled syringes

(Teva Paliperidone at paragraph 148).

[101] Claims 17 and 18 claim the same dosing regimen as claims 1 and 2. Claims 19 to 30

include the same formulation limitations as claims 3 to 14. Claims 31 and 32 are identical to

claims 15 and 16 except for the claims upon which they depend (Teva Paliperidone at paragraph

149).

[102] Where the same terms are used in claims 17 to 32, they have the same meaning as

defined above for claims 1 to 16. The only additional claim term in need of construction in this

claim set is “use of a dosage form” (Teva Paliperidone at paragraph 150).

[103] The POSITA would understand “use of a dosage form” in claims 17 and 18 to mean the

use of a syringe containing a depot formulation of paliperidone as paliperidone palmitate to

administer the formulation by intramuscular injection according to the dosing and administration

schedule in the claims (Teva Paliperidone at paragraph 152).

[104] Claims 17 to 32 comprise “use” claims (Teva Paliperidone at paragraph 153).

[105] Claims 33 to 48 also mirror claims 1 to 16, except that they are directed towards “use of

paliperidone as paliperidone palmitate for the preparation [or manufacture] of a medicament”

(Teva Paliperidone at paragraph 154).

Page: 31

[106] Claims 33 and 34 claim the same dosing regimen as claims 1 and 2. Claims 35 to 46

include the same formulation limitations as claims 3 to 14. Claims 47 and 48 are identical to

claims 15 and 16 except for the claims upon which they depend (Teva Paliperidone at paragraph

155).

[107] Where previously used terms are repeated in claims 33 to 48, they have the same

meaning as defined above for claims 1 to 16. The only additional claim term in need of

construction in this claim set is “preparation [or manufacture] of a medicament” and

“medicament form” (Teva Paliperidone at paragraph 156).

[108] “Medicament” means a medicine, and is distinguishable from the term “dosage form” as

used in claims 33 and 34 in that a medicament does not require a delivery means for the

formulation. The “medicament” must be suitable for the depot formulation to be administered

intramuscularly. Examples of a “medicament” in this context include vials containing the depot

formulation. Prefilled syringes and “dosage forms” as used in the earlier claims fall within the

meaning of medicament (Teva Paliperidone at paragraphs 157 and 158).

[109] Claims 33 to 48 comprise Swiss-type claims and are “product” claims (Teva Paliperidone

at paragraph 162 to 163).

[110] Claims 49 to 63 were found to be nearly identical to the earlier claims. In addition, the

Court did not require further expert evidence since these claims can be construed by their plain

and ordinary meaning (PMS Paliperidone at paragraph 85).

Page: 32

[111] Claims 49 to 63 comprise “product” claims (PMS Paliperidone at paragraph 85; Teva

Paliperidone at paragraph 125).

C.

Person of Ordinary Skill in the Art (POSITA)

[112] The POSITA is a worker of ordinary skill in the art, to which the invention relates, and

who possesses the ordinary amount of knowledge incidental to that particular trade (Consolboard

Inc. v. MacMillan Bloedel (Saskatchewan) Ltd., [1981] 1 SCR 504 (SCC) at paragraph 523). The

POSITA may be a team of persons with different skills (Teva Canada Limited v. Janssen Inc.,

2018 FC 754 [Teva Canada] at paragraph 66, aff'd 2019 FCA 273).

[113] As stated above, the POSITA is not at issue in this proceeding and the Parties agree that

the POSITA consists of a team comprised of a clinician, a pharmaceutical formulator, a

pharmacometrician, and a pharmacokineticist (Teva Paliperidone at paragraphs 98 to 108).

D.

Common General Knowledge

[114] Common general knowledge is the knowledge generally known at the relevant time by

the person skilled in the field of art or science to which the patent relates. It does not include all

information in the public domain (Sanofi-Synthelabo Canada Inc. v. Apotex Inc., 2008 SCC 61

[Sanofi] at paragraph 37; Eurocopter c. Bell Helicopter Textron Canada Ltée, 2013 FCA 219 at

paragraphs 63 to 65).

Page: 33

[115] At the relevant dates, the POSITA would have had the following common general

knowledge (Teva Paliperidone at paragraphs 109 to 123):

i.

Schizophrenia is a lifelong disease with no cure. The POSITA would have had

knowledge of typical and atypical antipsychotics for treating schizophrenia.

ii.

Depot formulations are designed for intramuscular injection of a relatively large

dose of a long-acting drug. In the case of paliperidone palmitate, hydrolyzation of

the palmitate ester provides the active compound paliperidone.

iii.

Depot formulations could be oil- or aqueous-based and prefilled syringes had

been designed for ease of administration.

iv.

v.

Dosing of depot formulations varied from drug to drug.

Population pharmacokinetic modeling could be used to assist in designing dosing

regimens.

vi.

The risk of serious adverse effects was a concern with depot formulations due to

their long-acting nature.

vii.

A risperidone depot formulation, RISPERDAL CONSTA®, was on the market.

viii. Paliperidone is a metabolite of risperidone.

ix.

An extended release oral formulation of paliperidone, INVEGA®, was on the

market.

x.

Aqueous nanoparticle suspensions of paliperidone palmitate had been developed.

Page: 34

[116] During the trial, the experts provided evidence of the following additional common

general knowledge at the relevant time:

i.

9-hydroxyrisperidone is an active and equipotent metabolite of risperidone;

ii.

Four milligrams per day of oral risperidone therapy reached median plasma levels

of approximately 20 to 65 ng/mL at steady-state;

iii.

iv.

v.

Risperidone is metabolized extensively in the liver into paliperidone;

Paliperidone is equipotent to risperidone;

The pharmacological profile of paliperidone closely resembles that of risperidone;

Paliperidone shares a receptor binding profile similar to risperidone;

Paliperidone has a half-life of about one day;

vi.

vii.

viii. Paliperidone is eliminated by the kidneys;

ix.

RISPERDAL CONSTA®, a long-acting injectable of risperidone, requires dose

adjustment for patients with renal impairment;

x.

INVEGA®, an extended release oral tablet of paliperidone, require dose

adjustment for patients with renal impairment;

xi.

Body weight is a covariate on the pharmacokinetics that can have an effect on the

efficacy of a drug; and

Page: 35

xii.

A loading dose can take the form of a higher initial dose, more frequent dosing, or

both.

E.

Obviousness

[117] As a starting point, the 335 Patent is presumed to be valid (subsection 43(2) of the Patent

Act). Pharmascience bears the burden of establishing obviousness on a balance of probabilities.

[118] The relevant date for assessing obviousness is the first priority date of the 335 Patent:

December 19, 2007.

[119] The four part obviousness framework was laid out by the Supreme Court of Canada in

Sanofi at paragraph 67:

i. Identify the notional “person skilled in the art” and the relevant common general

knowledge of that person;

ii. Identify the inventive concept of the claim in question or if that cannot readily be

done, construe it;

iii. Identify what, if any, differences exist between the matter cited as forming part of

the “state of the art” and the inventive concept of the claim or the claim as

construed;

Page: 36

iv. Viewed without any knowledge of the alleged invention as claimed, do those

differences constitute steps which would have been obvious to the person skilled

in the art or do they require any degree of invention?

[120] In areas of invention where advances are often achieved by experimentation, such as the

pharmaceutical industry, an “obvious to try” test might be appropriate (Sanofi at paragraph 68).

In such situations, the following non-exhaustive factors should be taken into account at the

fourth step of the obviousness inquiry (Sanofi at paragraphs 69 to 71):

i. Is it more or less self-evident that what is being tried ought to work? Are there a

finite number of identified predictable solutions known to persons skilled in the

art?

ii. What is the extent, nature and amount of effort required to achieve the invention?

Are routine trials carried out or is the experimentation prolonged and arduous,

such that the trials would not be considered routine?

iii. Is there a motive provided in the prior art to find the solution the patent addresses?

iv. What was the actual course of conduct which culminated in the making of the

invention?

[121] This Court has considered the “actual course of conduct” factor as part of the “extent,

nature and amount of effort required to achieve the invention” factor (Teva Canada at paragraph

85; Tensar Technologies, Limited v. Enviro-Pro Geosynthetics Ltd., 2019 FC 277 at paragraph

Page: 37

157). This approach is not inconsistent with the Supreme Court of Canada’s guidance in Sanofi

that obviousness is largely concerned with how a skilled worker would have acted in light of the

prior art, but this is no reason to exclude evidence of the history of the invention (Sanofi at

paragraph 70).

[122] The Federal Court of Appeal has referred to the actual course of conduct factor as “an

elaboration of the second factor” (Bristol-Myers Squibb Canada Co .v Teva Canada Ltd, 2017

FCA 76 [Bristol-Myers Squibb FCA] at paragraph 44).

[123] The Court must be wary of hindsight bias from expert witnesses. It is not fair to a party

claiming to have invented a combination invention to break the combination down into its parts

and find that, because each part is known, the combination is therefore obvious (Bridgeview

Manufacturing Inc .v 931409 Alberta Ltd. (Central Alberta Hay Centre), 2010 FCA 188

[Bridgeview] at paragraph 51). The question to ask is whether the POSITA, in light of the state

of the art and their common general knowledge, would have come directly and without difficulty

to the solution taught by the patent (Beloit Canada Ltd v. Valmet Oy, (1986) 8 CPR (3d) 289

(FCA) at 294).

[124] The obviousness inquiry should be undertaken on a claim-by-claim basis (Zero Spill

Systems (International) Inc. v. Heide, 2015 FCA 115 at paragraph 85).

[125] As I found previously in Teva Paliperidone at paragraphs 172 to 175 in regards to claims

1 to 48, which is now extended to all of the claims of the 335 Patent, the validity of dependent

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claims 3 to 16, 19 to 32, 35 to 48, and 51 to 63 rises or falls with the inventiveness of the dosing

regimens in independent claims 1, 2, 17, 18, 33, 34, 49, and 50. This is because, considering

Janssen’s Canadian Patent Nos. 2,309,629 and 2,236, 691 (the “629 Patent” and the “691

Patent”, respectively) in light of the common general knowledge, a skilled formulator would

have arrived at aqueous depot formulations containing nanoparticles of paliperidone palmitate

with an average particle size of 1600 nm to 400 nm, with surfactants, buffering agents,

suspending agents, and preservatives in the claimed amounts, without any degree of

inventiveness. There has been no evidence or argument in this proceeding to the contrary.

[126] The POSITA and common general knowledge have been described in detail above.

[127] In addition, in Teva Paliperidone at paragraphs 176 to 188, I found that the inventive

concept is a safe and effective dosing regimen using a depot formulation of paliperidone as

paliperidone palmitate, formulated as an aqueous nanosuspension for treatment of schizophrenia

patients, designed to reach the therapeutic range of plasma concentrations quickly, and maintain

patients within that range. For non-renally impaired patients, the dosing regimen is as detailed in

claims 1, 17, 33, and 49:

i. 150 mg-eq. of paliperidone as paliperidone palmitate injected into the deltoid on

Day 1;

ii. 100 mg-eq. of paliperidone as paliperidone palmitate injected into the deltoid on

Day 8 ± 2 days;

Page: 39

iii. 75 mg-eq. of paliperidone as paliperidone palmitate injected into the deltoid or

gluteal monthly ± 7 days thereafter.

[128] For renally impaired patients, the dose amounts are adjusted downwards to loading doses

of 100 and 75 mg-eq., and maintenance doses of 50 mg-eq., as detailed in claims 2, 18, 34, and

50.

[129] Pharmascience argues that Janssen’s experts, Drs. Chue and Ereshefsky, both improperly

expanded the inventive concept. I agree that to the extent they both refer to the claims being in

respect of a “standardized” dosing regimen, they overstate the inventive concept. As stated

previously in Teva Peliperidone at paragraph 184, I found that the claims are not “standardized”

and that this concept overstates and contradicts the plain language of the claims.

(1)

Differences between the state of the art and the inventive concept

[130] As of December 19, 2007, it was known that pharmacokinetic profiles of depot

antipsychotics dictate their dosing. There were a number of first-generation depot antipsychotics

on the market (some examples below) and one second-generation antipsychotic:

i. Fluphenazine decanoate: Patients had to be gradually switched from oral to the

depot injection only after the patient was stabilized on oral medication. A loading

dose could not be used to initiate treatment because of an initial spike during a

rapid release phase in the first 24 hours following injection and thus adding a

loading dose would cause toxic levels of fluphenazine in the body.

Page: 40

ii. Zuclopenthixol decanoate: Like many of the other depot antipsychotics, this

medication was only used for patients stabilized on oral medication using dose

conversion from the patient’s individual oral dose. Oral supplementation was also

used to avoid diminished therapeutic response.

iii. Haloperidol decanoate: While the haloperidol papers, such as those authored by

Dr. Ereshefsky, studied loading doses of haloperidol decanoate for “very ill

patients”, this dosing was individualized based on the patient’s prior dose of oral

haloperidol. Dr. Chue testified that use of loading doses of haloperidol depot

injection was not common clinical practice amongst Canadian physicians.

iv. RISPERDAL CONSTA®: Because essentially no drug releases from the depot

for the first three weeks, this formulation was not suitable for use with a loading

dose; rather, it required oral supplementation over that period.

[131] While the prior art (Goodman & Gilman’s The Pharmacological Basis of Therapeutics,

10^thed. (McGaw-Hill: New York, 2001) did state that generally injections of aqueous solutions

into the deltoid muscle result in faster absorption, it would be understood that this does not

necessarily apply to depot formulations in oil or suspensions, and in any case, it would not be

known whether faster absorption would result in a clinically meaningful and beneficial effect.

Pharmascience’s expert Dr. Gupta admitted that deltoid injections would not be helpful for

certain formulations like RISPERDAL CONSTA®, and further agreed that without an

understanding of the drug’s pharmacokinetics, it would be possible that deltoid injections might

result in a high blood plasma concentration level that could result in adverse effects.

Page: 41

[132] As of December 19, 2007, the prior art disclosed the following information regarding a

depot paliperidone palmitate injection:

i.

Citrome (2007): This review paper disclosed limited information from

clinicaltrials.gov regarding seven planned and ongoing clinical trials for a depot

of paliperidone palmitate, but does not disclose results, including no efficacy,

safety, or pharmacokinetic data from these trials. It also did not provide any

details of the paliperidone palmitate depot formulation used in any of the trials.

Pharmascience’s experts referred to only two (NCT00210548 and NCT00210717)

of the seven studies which are discussed below.

ii.

Clinicaltrials.gov NCT00210548: relates to a clinical trial of paliperidone

palmitate that looked to investigate fixed doses of 50 mg-eq., 100 mg-eq., or 150

mg-eq. on days 1, 8, 36, and 64. “Fixed doses” in this context means that the same

dose was given on each day. This is the only trial investigating the use of a

loading dose with paliperidone palmitate. All injections were in the gluteal. No

safety, efficacy, or pharmacokinetic data are disclosed.

iii.

Clinicaltrials.gov NCT00210717: relates to a clinical trial investigating monthly

injections of paliperidone palmitate depot “flexibly” dosed (i.e. determined by

physicians rather than the amounts being pre-set) with 25-100 mg-eq. doses, all of

which are to be injected into the gluteal muscle. No safety, efficacy, or

pharmacokinetic data are disclosed.

iv.

NCT00101634 was to study doses of 25, 5,0 or 100 mg-eq. versus placebo. No

dosing schedule is provided in Citrome and site of injection is not disclosed.

Page: 42

v.

NCT00147173 was to study doses of 50, 100 and 150 mg-eq. versus placebo. No

dosing schedule is provided in Citrome and site of injection is not disclosed.

vi.

NCT00073320 was described in Citrome as an “open-label pharmacokinetic study

of injections in the arm or buttock”. No dosage strengths or dosing schedule is

provided.

vii.

For NCT00111189, no doses or dosing schedule is provided, and site of injection

is not disclosed.

viii. NCT00119756 looked to investigate “safety and tolerability comparing injection

in shoulder vs. buttock muscles”. No dosage strengths or dosing schedule is

provided in Citrome.

ix.

Credit Suisse: This is a transcript of an investor meeting disclosing that Janssen

filed a submission to the FDA for a monthly depot of paliperidone palmitate

available for deltoid and gluteal injections. Credit Suisse makes several

comparisons to RISPERDAL CONSTA® (including differences in frequency of

dosing, storage needs, needle sizes, and administration sites), but does not make

any comparison to RISPERDAL CONSTA®’s initiation strategy (i.e. oral

supplementation). Dr. Chue opined that the skilled person would believe that like

RISPERDAL CONSTA®, the paliperidone palmitate product does not use

loading doses. Dr. Ereshefsky stated that, even if the skilled person considered the

possibility that it utilized loading doses, they would have no appreciation for the

necessity of these doses to be administered into the deltoid, given that Credit

Suisse indicates that injections are interchangeable for both sites.

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The product label for INVEGA®, an oral paliperidone extended-release tablet,

x.

provided some pharmacokinetic information about paliperidone based on that

formulation. Dr. Chue opined that the skilled person would not extrapolate this

information to a paliperidone palmitate intramuscular depot given the formulation

differences. It is necessary to conduct pharmacokinetic studies and clinical trials

for safety and efficacy with the paliperidone palmitate depot formulation of

interest, which was unknown in the prior art. The prior art included patents and

patent applications relating to formulations of paliperidone palmitate, including

the 629 Patent, the 691 Patent, and WO 2006/114384.105.

xi.

Both INVEGA® and RISPERDAL CONSTA® require lower doses of

paliperidone for patients with renal impairment.

[133] In light of the 629 and 691 Patents, the Citrome review article, and applicable data from

the clinicaltrials.gov, in Teva Paliperidone at paragraphs 190 to 197, I found that the differences

between the state of the art and the inventive concept are:

i. A depot antipsychotic dosing regimen designed to quickly and safely reach

therapeutic plasma concentrations without the need for oral run in, oral

supplementation, or dose titration;

ii. The specified dose amounts of paliperidone palmitate of the claimed regimens;

iii. A loading dose regimen administered into the deltoid muscle;

iv. Maintenance doses administered interchangeably in the deltoid or gluteal muscle;

Page: 44

v. Dosing windows of ± 2 days (second loading dose) and ± 7 days (maintenance

doses); and

vi. An adjusted regimen of paliperidone palmitate for patients with renal impairment.

[134] I find that the differences between the state of the art and the inventive concept in this

proceeding consistent with those found in Teva Paliperidone. The information described in the

Credit Suisse transcript is broad and does not disclose details of the claims of the 335 Patent that

would modify the analysis of the prior art previously examined.

(2)

Do the differences constitute steps that would have been obvious to the POSITA?

[135] While Janssen argues that the evidence in this case is entirely consistent with the findings

regarding non-obviousness in Teva Paliperidone, Pharmascience argues that there are a number

of critical differences in the evidence in this proceeding than that heard in the Teva Paliperidone

proceeding, including:

i. The POSITA would know the safe and effective plasma concentration range of

paliperidone to target from the INVEGA® product and that no further studies

were needed; and

ii. The Credit Suisse transcript discloses that Janssen had submitted a new drug

application to the FDA, including deltoid and gluteal injections, from which the

POSITA would understand that such a product was safe and effective.

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[136] Viewed without any knowledge of the invention claimed in the 335 Patent, the

differences between the state of the art and the inventive concept constitute steps would not have

been obvious to the skilled person. The evidence in this case is consistent with the findings

regarding non-obviousness in Teva Paliperidone.

[137] The state of the art did not set out safety, efficacy, pharmacokinetic, or

pharmacodynamics. In order to determine a suitable dosing regimen for paliperidone palmitate

long-acting depot injection, at the very least pharmacokinetic information and results from

clinical trials both with paliperidone palmitate would be required. As was shown above in the

invention story, the skilled person would first have needed to run clinical studies to determine the

pharmacokinetic profile of paliperidone injection as this information is crucial in dosing regimen

design. As admitted by Pharmascience’s expert Dr. Gupta, even if the skilled person chose to

investigate a loading dose regimen, studies would be required to determine what loading dose

regimen was required to rapidly achieve therapeutic plasma concentrations; and, in any case the

prior art did not disclose any safety, efficacy, or pharmacokinetic data for a paliperidone

palmitate depot formulation.

[138] It appears that Dr. Gupta’s analysis was driven by hindsight. Pharmascience’s argument

breaks down the dosing regimen into its parts and asserts that each part is well known and, thus,

the combination is obvious. This argument ignores several key differences between the state of

the art and the regimens claimed in the 335 Patent, including the lack of disclosure regarding

formulations of paliperidone palmitate used in the clinical trials listed in Citrome and the NCT

documents, the dosing windows of paliperidone palmitate, and a loading dose regimen utilizing

Page: 46

injection into the deltoid; and the fact that no prior antipsychotic depot injection was approved

for injection into the deltoid muscle and that loading doses of antipsychotic depot formulations

were not commonly used in clinical practice.

[139] The claims are inventive:

i. The dose amount for each injection: the prior art did not disclose a dosing

regimen with doses of 150 mg-eq. followed by 100 mg-eq. followed by 75 mg-eq.

for paliperidone palmitate. The art disclosed trials with fixed dose amounts

whereby each dose was the same amount and one flexible dose study. None of the

art pointed to three different pre-set dose amounts used in a specific sequence and

specific injection sites to rapidly attain and maintain therapeutic plasma

concentrations. Arriving at these dose amounts for each dose was inventive.

ii. Loading doses: while NCT548128 had a Day 1, 8, 36, 64 regimen for

paliperidone palmitate, which would be understood as a loading strategy, all doses

in that study were fixed (meaning patients received the same dose on each day).

The prior art did not disclose two loading doses whereby the amount for each

dose was specified regardless of a patient’s prior treatment or any patient specific

factor (other than renal impairment). The only other long-acting antipsychotic

disclosed in the art that had explored use of loading doses in clinical studies was

haloperidol decanoate, which determined the loading dose based on the amount of

oral haloperidol the patient had been receiving, rather than one regimen designed

to safely and effectively achieve and maintain therapeutic plasma concentrations.

All other drugs in the prior art utilized either oral supplementation or titration,

Page: 47

including RISPERDAL CONSTA®, which is directly contrasted against

Janssen’s proposed paliperidone palmitate product in Credit Suisse, without any

mention of the proposed product being improved because it used loading doses

and did not require oral supplementation. Furthermore, the prior art did not

disclose a loading dose regimen whereby a loading dose of 150 mg-eq. followed

by a second loading dose of 100 mg-eq. is administered on days 1 and 8. The

loading dose regimen of the 335 Patent claims was arrived at following significant

clinical investigations as well as population pharmacokinetic analyses. This aspect

of the claims was inventive.

iii. Deltoid injections: No long-acting depot antipsychotic in the prior art was

approved for injections into the deltoid muscle, and no clinical trial of

paliperidone palmitate in the prior art even investigated loading doses into the

deltoid muscle, let alone a study that required two loading doses of unequal

amounts of paliperidone palmitate to be administered into the deltoid muscle. The

prior art disclosed gluteal injections to be the preferred injection site. Although

Credit Suisse discloses that both deltoid and gluteal will be available for the

planned monthly product (which at that stage might or might not have been

approved), this does not provide any information as to requiring loading doses to

be in the deltoid (particularly since Credit Suisse does not even mention loading

doses and only refers to monthly administration). Without pharmacokinetic

information, the skilled person would not know whether administration of a depot

antipsychotic drug into the deltoid would result in a clinical difference. Further,

without pharmacokinetic data, the skilled person would not know if

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administration of a depot antipsychotic into the deltoid leads to “toxic” levels of

drug in the body. Requiring administration of the first two doses into the deltoid

muscle as part of a loading dose regimen was inventive.

iv. The dosing schedule: the prior art disclosed that at least two dosing regimens were

being investigated with paliperidone palmitate depot, including dosing once a

month, dosing the same dose on Days 1, 8, 36, and 64 into the gluteal muscle, as

well as several investigations with unspecified dosing regimens. Without clinical

trial results, the skilled person would not know which, if any, dosing schedule was

preferred. The skilled person would know that clinical trials fail and without

results would have nothing to guide them. Indeed, although not known to the

skilled person, the NCT548 trial (the only trial in the prior art that disclosed a

loading dose regimen with paliperidone palmitate) failed, proving that phase III

trials do indeed fail. Based on Credit Suisse, the skilled person would also be led

to assume a monthly injection was to be used without a loading regimen. A dosing

schedule whereby pre-set doses of paliperidone in three different amounts were

administered on Days 1, 8, and monthly thereafter was inventive.

v. The dosing windows: the prior art did not disclose or mention any dosing

windows, including dosing windows for the second loading dose or for the

monthly maintenance dose. This dosing windows element was inventive.

vi. Dosing for renally impaired patients: the prior art did not disclose or mention

dosing of paliperidone palmitate in patients with renal impairment. Without

knowing the dosing regimen for patients without renal impairment, the skilled

Page: 49

person could not apply an adjustment. Further, there was no information in the

prior art as to the degree of adjustment required for patient with renal impairment

being administered paliperidone palmitate; in fact, Dr. Gupta stated that it could

be true that no dosing adjustment for the loading doses would need to be made.

The dosing regimen for patients with renal impairment was inventive. However,

the common general knowledge, as stated above, does include that paliperidone is

eliminated by the kidneys, and both RISPERDOL CONSTA® and INVEGA®

both required adjustments for renally impaired patients.

vii. Dosing regimen as a whole: The evidence shows that the specific combination of

the dosing regimen elements as claimed in the 335 Patent was not obvious.

(a)

Is it more or less self-evident that what is being tried ought to work? Are there a finite

number of identified predictable solutions known to persons skilled in the art?

[140] In a pharmaceutical invention such as this, where the advance in the art was made as a

result of experimentation, this question is best answered by an application of the “obvious to try”

test outlined in Sanofi at paragraphs 69 to71.

[141] The obvious to try analysis must be approached cautiously; it is not a panacea for alleged

infringers (Sanofi at paragraph 64). The factors to be considered are those laid out by the

Supreme Court of Canada in Sanofi.

[142] In order to satisfy the test there “must be evidence to convince a judge on a balance of

probabilities that it was more or less self-evident to try to obtain the invention. Mere possibility

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that something might turn up is not enough” (Sanofi at paragraph 66; see also Pfizer Canada Inc.

v. Apotex Inc., 2009 FCA 8 [Pfizer]; Hospira Healthcare Corporation v. Kennedy Trust for

Rheumatology Research, 2020 FCA 30 [Hospira FCA] at paragraph 88). A high degree of

motivation to find a solution to a problem does not transform any discovered solution into an

obvious solution (Pfizer at paragraph 44). Evidence of tests being required indicates the

invention was not self-evident (Allergan Inc. v. Canada (Minister of Health), 2014 FC 567 at

paragraphs 34-35, aff’d 2015 FCA 137).

[143] Considering the factors of the Sanofi obvious to try test, the evidence shows that the

invention of the 335 Patent was not more or less self-evident to the skilled person, given that

there were numerous potential paths that the skilled person could have pursued without ever

arriving at the dosing regimens claimed in the 335 Patent. There was not a finite number of

identified predictable solutions. Indeed Dr. Gupta does not propose a finite number of identified

solutions, let alone any predictable solutions. A significant amount of skill, effort, and non-

routine work, as well as inventiveness would be required to arrive at the subject matter claimed

in the 335 patent, particularly given the lack of any human pharmacokinetic, safety, or efficacy

results for paliperidone palmitate.

[144] While Pharmascience argues that the target therapeutic plasma concentration would have

been known from the prior art, the questions of whether a depot formulation of paliperidone

palmitate administered intramuscularly using the claimed dosing regimens would have reached

and maintained the therapeutic plasma concentration safely and effectively was not known and

required significant skill and effort as set out above in the invention story.

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[145] The evidence of Dr. Gupta is that further experimentation was required, including

determining the pharmacokinetic profile of paliperidone palmitate depot. As explained by

Janssen’s experts, further clinical trials also would be needed to investigate different dosing

regimens. As Drs. Ereshefsky and Chue explained, clinical trials are not routine, often fail, and

require a great amount of arduous effort. Moreover, Dr. Gupta’s own testimony reveals the result

of his proposed further studies was not predictable to him. When suggesting a loading dose

would be investigated he stated “If the loading dose determined to be required…exceeds 150

mg…”, and agreed that he is saying “if” because “you don’t know” what loading dose would be

determined to be required to rapidly attain therapeutic plasma concentrations based on the prior

art, you have to do studies to figure that out.

[146] Similarly, the Citrome (2007) paper concludes that “The depot intramuscular preparation

holds greater promise if it can be demonstrated that it can be administered less frequently than

risperidone intramuscular microspheres and that there is little lag time prior to the development

of adequate blood level (emphasis added)” it is because even to the author it was unknown

whether paliperidone palmitate depot could be administered less frequently without little lag time

prior reaching adequate blood levels.

[147] The evidence of an expert must not be conclusory and must provide supporting analysis

(Bridgeview at paragraph 53). As stated above, it appears that Dr. Gupta approached the analysis

with hindsight (Bristol-Myers Squibb Canada Co. v. Teva Canada Ltd., 2016 FC 580 at

paragraph 165, aff’d Bristol-Myers Squibb FCA; GlaxoSmithKline Inc. v. Pharmascience Inc.,

2011 FC 239 at paragraph 70).

Page: 52

[148] Dr. Gupta offers an opinion from the perspective of a formulator/pharmacokineticist. On

cross-examination, Dr. Gupta admitted he does not have experience performing pharmacokinetic

trials on humans and he did not do any analysis and does not offer any opinion on the clinical

aspects of the 335 Patent.

[149] Dr. Gupta did not provide evidence on how a skilled person could have arrived at the

specific dosing regimen taught by the 335 Patent in light of the prior art. He also did not address

the claimed dosing windows.

(3)

What is the extent, nature and amount of effort required to achieve the invention?

Are routine trials carried out or is the experimentation prolonged and arduous,

such that the trials would not be considered routine?

[150] The POSITA need not be capable of conducting the same experiments that the inventors

did to reach the claimed invention (Hospira FCA at paragraph 94). As stated above, the fourth

factor, the actual course of conduct, is inherently tied to the second factor, and sheds light on the

amount of effort required to reach the claimed invention (Sanofi at para 71; Bristol-Myers Squibb

FCA at paragraph 44).

[151] Although “obviousness is largely concerned with how a skilled worker would have acted

in the light of the prior art” an “important factor may arise from considering the actual course of

conduct which culminated in the making of the invention” (Sanofi at paragraph 70).

[152] Further, “Where those involved … were highly skilled in the particular technology

involved, the evidence may suggest that the skilled person would have done a lot worse and

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would not likely have managed to find the invention. It would not have been obvious to [them] to

try the course that led to the invention” (Sanofi at para 71; see also Bayer Inc. v. Cobalt

Pharmaceuticals Co., 2016 FC 1031 at paragraph 138).

[153] Dr. Ereshefsky’s opinion is that the inventors’ course of conduct was complex, time and

resource consuming, and non-routine. The inventors encountered unexpected set-backs in phase

III of development; had to revise the dosing regimens several times, including because they

encountered unsuccessful phase III studies; and as a result of their “complex and non-routine”

work were able to develop a regimen which quickly and safely achieves therapeutic

concentrations of paliperidone in patients regardless of BMI. The work of the inventors,

including use of population pharmacokinetic modelling, resulted in a dosing regimen which

contains several completely novel and inventive features, and ensures a consistent plasma

concentration profile without the need for conversion, oral supplementation, oral run-in, or

titration, something which was previously not seen with any other depot antipsychotic drug.

[154] As stated above, Dr. Gupta’s opinion that only routine work was needed is weakened by

his lack of experience in conducting pharmacokinetic of clinical trials in humans – the experts

and witnesses with first hand knowledge of the events spoke to the issues encountered, and skill

and effort needed to overcome them to arrive at the invention.

(4)

Is there a motive provided in the prior art to find the solution the patent

addresses?

Page: 54

[155] As found in Teva Paliperidone at paragraph 219, the experts agreed that there would

have been a general motivation to develop a depot formulation of paliperidone, but not

necessarily a specific motivation to develop the dosing regimens contained in the 335 Patent.

The POSITA would have known of the benefits of depot formulations over oral treatments for

patients with compliance issues. However, at the time, depot formulations were indicated for

maintenance treatment, not for patients experiencing acute symptoms, and known dosing

regimens required oral run in, oral supplementation, or dose titration.

(5)

Conclusion on obviousness

[156] Having considered all of the expert evidence and the prior art, I am not satisfied that

Pharmascience has met its burden. While the added formulation elements in the dependent

claims may not be inventive, each of the independent claims of the 335 Patent incorporates one

of the dosing regimens as essential elements, which results in all of the claims being non-

obvious.

[157] Pharmascience primarily relies on Dr. Gupta’s expert opinion evidence that the claims

are obvious. However, Dr. Gupta suffered some credibility issues in failing to agree to or admit

to simple propositions, and never conducted or designed a clinical trial or pharmacokinetic trial

in humans. As stated above, Dr. Gupta’s evidence is conclusory and driven by hindsight. He

broke the dosing regimen down into its component parts and concluded that the claimed

combination was therefore obvious (Bridgeview at paragraph 51).

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[158] Recognizing that the obvious to try factors laid out in Sanofi are not exhaustive, after

reviewing the above factors, I am satisfied that the difference between the state of the art and the

inventive concept of the 335 Patent claims would not have been obvious to the POSITA.

[159] I find that the combination of the claimed dosing regimen elements in the claims of the

335 Patent is inventive, and the claims of the 335 Patent are not obvious.

F.

Method of Medical Treatment

[160] Section 2 of the Patent Act defines patentable subject matter. An “invention” is “any new

and useful art, process, machine, manufacture or composition of matter, or any new and useful

improvement in any art, process, machine, manufacture or composition of matter.” The

prohibition on methods of medical treatment is rooted in the Supreme Court of Canada’s

decision in Tennessee Eastman Co. et al. v. Commissioner of Patents (1972), [1974] SCR 111.

[161] As I have previously discussed, there are inconsistencies in Canadian law on what

constitutes a method of medical treatment which has been highlighted by judges of this Court

and the Federal Court of Appeal (Teva Paliperidone at paragraph 143). However, the common

starting point is to examine the language and substance of the claims: “what do the claims say?”

(Bayer Inc. v. Cobalt Pharmaceuticals Company, 2013 FC 1061 [Bayer] at paragraph 162).

[162] Pharmascience argues that, in accordance with Teva Paliperidone, the selection of the

maintenance doss – from within the range of 25 to 150 mg-eq. as available in the product

monographs for INVEGA SUSTENNA® and the proposed pms-PALIPERIDONE

Page: 56

PALMITATE – depends upon individual characteristics. The experts agreed that a particular

maintenance dose may not work for every patient and the physician, alongside the patient, would

need to determine the most safe and efficacious maintenance dose depending on various factors,

including adverse side effects, other medications, comorbidities, etc. As such, the choice of a

maintenance dose within the range in accordance with the product monographs would require

skill and judgment on the part of the prescriber (Teva Paliperidone at paragraph 290; PMS

Paliperidone at paragraph 137).

[163] However, there appears to be no question in the case law that claims to a vendible

product are patentable as not being methods of medical treatment (see for example, Apotex Inc.

v. Wellcome Foundation Ltd., 79 CPR (3d) 193 (FC) at paragraph 74, aff’d 10 CPR (4th) 66

(FCA) at paragraph 74, aff’d 2002 SCC 77 at paragraph 50; Merck & Co Inc. v. Pharmascience

Inc., 2010 FC 510 at paragraph 110 [Merck 2010]; Novartis Pharmaceuticals Canada Inc. v.

Cobalt Pharmaceuticals Co., 2013 FC 985 [Novartis] at paragraph 78, aff’d 2014 FCA at

paragraph 3; Biogen Canada Inc. v. Taro Pharmaceutical Inc., 2020 FC 621 [Biogen] at

paragraph 22). As stated above, claims 1 to 16, and 33 to 63 are “product” claims (Teva

Paliperidone at paragraphs 145 to 147 and 162 to 163; PMS Paliperidone at paragraph 85) and

are not “methods” of medical treatment. Therefore, the method of medical treatment analysis is

only relevant in respect of claims 17 to 32, which are “use” claims (Teva Paliperidone at

paragraph 153; Merck 2010 at paragraph 111).

[164] For use claims, the analysis is on the essential claim elements to determine whether

professional skill and judgment is required to practice the invention as claimed. A claim for

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“use” of a medicine to treat a patient is not an unpatentable method of medical treatment if it

includes a specific dosage amount and/or specific administration interval. With respect to dosing

elements, the law has evolved such that claims restricted to particular dosages and specific

administration schedules have been found to be patentable subject matter, where the amounts and

timing are fixed (see for example, Merck & Co Inc. v. Apotex Inc., 2005 FC 755 at paragraph

136; Merck 2010 at paragraph 111; AbbVie Biotechnology Ltd. v. Canada (Attorney General),

2014 FC 1251 at paragraph 121; Bayer at paragraph 162; Hospira FCA at paragraphs 52 to 53;

Biogen at paragraphs 211 and 213; Hoffmann-La Roche Limited v. Sandoz Canada Inc., 2021 FC

384 at paragraphs 197 and 202 (distinguished from the claims of the 335 Patent in Teva

Paliperidone at paragraph 103)), whereas claims to dosages or schedules with ranges within

which the physician must exercise skill and judgment have been found to not be a vendible

product and thus not patentable (Janssen Inc. v. Mylan Pharmaceuticals ULC, 2010 FC 1123 at

paragraphs 52 to 53; Bayer at paragraph 162; Novartis at paragraphs 98 to 99).

[165] While this dichotomy, between specific dosages and administration intervals contrasted

with ranges of dosages and schedules, has led to a series of cases wherein the former has been

held to be patentable, vendible products and the latter, at least in some cases, as being

unpatentable as requiring skill and judgment amounting to methods of medical treatment, seems

to have a questionable underpinning in resulting judgments based on this dichotomy,

nevertheless that is where we are under the current state of decisions up to and including

decisions in the Federal Court of Appeal.

[166] As stated by Justice Locke in Hospira FCA at paragraph 52:

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This state of the jurisprudence has a tempting simplicity. However,

it is not clear to me that the decisions of the Supreme Court of

Canada that form the basis of the principle that methods of medical

treatment are not patentable justify a distinction between a fixed

dosage (or interval of administration) and a range of dosages (or

intervals). It would seem that a medical professional will be

constrained in their exercise of skill in either case. Also, a drug is

arguably no less a vendible product simply because its dosage or

interval of administration is not fixed.

[167] As Pharmascience’s expert Dr. Jeffries agreed, claims 17-32 do not prevent physicians

from practicing in a manner they had previously “because they weren’t doing anything before”

the 335 Patent with paliperidone palmitate to treat schizophrenia.

[168] In addition, claims 17 to 32 do not require professional skill and judgment; there are no

choices in respect of possible ranges for the dosage amounts, which are fixed at loading doses of

150 mg-eq. on Day 1, 100 mg-eq. on Day 8, and 75 mg-eq. thereafter as the maintenance dose

for non-renally impaired patients, and loading doses of 150 mg-eq. on Day 1, 100 mg-eq. on Day

8, and 75 mg-eq thereafter as the maintenance dose for non-renally impaired patients, and

loading doses of 100 mg-eq. on Day 1, 75 mg-eq. on Day 8, and 50 mg-eq. thereafter as the

maintenance dose for renally impaired patients.

[169] The use claims provide for two possible dosing regimens, one for non-renally impaired

patients and another for renally impaired patients. Once a physician chooses to use the products

for the purpose claimed, each of the claims teaches fixed dose amounts, fixed intervals, and fixed

injection sites.

Page: 59

[170] While there are elements where there are choices (dosing windows around the Day 8 and

monthly doses, and injection sites for the maintenance dose), those choices do not have clinical

implications. The experts explained the dosing windows are incorporated into the regimen to

allow flexibility in order to avoid a missed dose without significant clinical difference, and the

maintenance dose injection site is clinically interchangeable. Therefore, no skill and judgment is

required that would interfere with or restrict a physician’s skill or judgment in deciding to

prescribe the dosing regiment within the claimed invention.

[171] The claims are a guide for the treatment of schizophrenia, providing specific dosing

regimens expected to produce a plasma concentration of paliperidone within the therapeutic

range necessary for safe and effective treatment of patients. A physician can choose to

implement a claimed specific dosing regimen or not; however, skill and judgment are not

required to implement the claimed dosing regimens. To the extent a physician chooses a

maintenance dose other than 75 mg-eq. (as is contained in the product monograph and which

much cross-examination and testimony were focused), or decides to stop treatment with

paliperidone palmitate and switch therapies, they would no longer be practicing the claimed

invention. Thus, the claimed subject matter does not require the exercise of skill and judgment

and is not a method of medical treatment.

[172] I find that the 335 Patent discloses patentable subject matter.

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V.

Conclusion

[173] In conclusion, Pharmascience has not established that the claims of the 335 Patent are

invalid on the basis of either obviousness or lack of patentable subject matter (i.e. as a method of

medical treatment).

[174] As previously found in the motion for summary trial on the sole issue of infringement in

Court file No. T-1441-20, the proposed pms-PALIPERIDONE PALMITATE product made,

constructed, used, or sold as set out in ANDS No. 244641 will infringe the claims of the 335

Patent.

[175] As stated above, the Notice of Allegation in accordance with ANDS No. 251767 does not

contest infringement of the claims of the 335 Patent by the making, constructing, using, or

selling of a proposed pms-PALIPERIDONE PALMITATE as set out in ANDS No. 251767.

VI.

Costs

[176] The Plaintiffs submit that the Court should consider a reasonable costs award to the

successful party on the validity phase of both actions before the Court, (excluding costs for the

previous summary trial), and should be calculated according to one of three scenarios:

i. a lump sum award of $1.5 million, inclusive of all legal fees, disbursements and

taxes; or

Page: 61

ii. a lump sum award of 25% of all legal fees plus all disbursements and taxes; and

any dispute about reasonableness of fees and disbursements to be determined by

an assessment officer; or

iii. costs to be assessed at the top of column IV of Tariff B of the Federal Court

Rules;

iv. post-judgment interest of 3.5%.

[177] The Defendant submits that if the Plaintiffs are successful, they should be awarded costs:

i. in T-1441-20, in accordance with the middle of column III of Tariff B;

ii. in T-558-22, costs should be limited to preparation of pleadings and assessed in

accordance with the middle of column III of Tariff B, in a separate order;

iii. fees of Dr. Chue should be reduced by 33% given that he provided unhelpful and

unnecessary evidence dealing with obviousness and on issues (decided in Janssen

Inc. v Tera Canada Ltd., 2020 FC 593) (Teva Paliperidone), and

iv. fees of Dr. Ereshefsky should be reduced by 50%, given he provided unhelpful

and unnecessary evidence on obviousness and issues in the Teva Paliperidone

matter and he used recycled evidence on the same patent in the Teva Paliperidone

matter;

v. legal fees and costs should be awarded to Pharmascience with respect to the

failure of the Plaintiffs to call Dr. Gobburu, on a solicitor-client basis;

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vi. no costs or fees should be awarded for the fact affidavits of the inventors, Dr.

Gopal, Dr. Vermeulen and Dr. Samtani, given their evidence is substantially the

same as was used in the Teva Paliperidone matter;

[178] Having carefully considered the parties’ written representations and relevant case law,

and the nature of the evidence tendered by the witnesses at trial, as well as the conduct of the

witnesses during the trial, I find as follows:

The Plaintiffs are hereby awarded a lump sum of 25% of all reasonable legal fees plus

100% of all reasonable disbursements and taxes, and any dispute about

reasonableness of those fees and disbursements shall be determined by an assessment

officer if no agreement is reached within 45 days from the issuance of this decision,

with the following limitations to be accounted for:

i. The fees of Dr. Ereshefsky and Dr. Chue are reduced by 25%. As stated in

my reasons above, there was inconsistent evidence given by each of these

witnesses having regard to their previous testimony in related proceedings and

at times their testimony was not forthcoming when it should have been.

ii. No fees are awarded for Dr. Gobburu, and costs are awarded to

Pharmascience for all reasonable costs thrown away given the last minute

failure to call him as a witness at the trial;

iii. Post-judgment interest shall be calculated at 2.5%;

Page: 63

JUDGMENT in T-1441-20 & T-558-22

THIS COURT’S JUDGMENT is that:

1. The claims of the 335 Patent are not obvious, and are valid.

2. The claims of the 335 Patent are not methods of medical treatment, are patentable

subject matter, and are valid.

3. The making, constructing, using, or selling of pms-PALIPERIDONE

PALMITATE by Pharmascience in accordance with ANDS Nos. 244641 and

251767 will infringe the claims of the 335 Patent.

4. An injunction is granted until the expiry of the 335 Patent on December 17, 2028,

restraining Pharmascience, as well as its subsidiary and affiliated companies,

officers, directors, employees, agents, licensees, successors, assigns, and any

others over whom it exercises lawful authority, from:

a. Making, constructing, using or selling pms-PALIPERIDONE

PALMITATE in Canada in accordance with ANDS Nos. 244641 and

251767;

b. Offering for sale, marketing or having pms-PALIPERIDONE

PALMITATE marketed in Canada in accordance with ANDS No. 244641

and 251767; and

c. Importing, exporting, distributing or having pms-PALIPERIDONE

PALMITATE distributed in Canada in accordance with ANDS Nos.

244641 and 251767.

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5. Janssen is awarded 25% of reasonable legal fees and 100% of reasonable

disbursements, exclusive of any motions for which costs have been fixed

including the motion for summary trial in Court file no. T-1441-20, with the

following limitations:

a) the fees of Dr. Ereshefsky and Dr. Chue are reduced by 25%;

b) No fees are awarded for Dr. Gobburu, and costs are awarded to

Pharmascience for all reasonable costs thrown away given the last minute

failure to call him as a witness at the trial.

6. Within 45 days of receiving this decision, the Parties will endeavour to agree on a

reasonable costs quantum in accordance with the foregoing parameters, failing

which the costs shall be assessed by an assessment officer in accordance with

these reasons and judgment.

“Michael D. Manson”

Judge

FEDERAL COURT

SOLICITORS OF RECORD

T-1441-20 & T-558-22

DOCKET:

JANSSEN INC. AND JANSSEN PHARMACEUTICA

N.V. v. PHARMASCIENCE INC.

STYLE OF CAUSE:

TORONTO, ONTARIO

JULY 4-8, 12, & 15, 2022

MANSON J.

PLACE OF HEARING:

DATE OF HEARING:

PUBLIC JUDGMENT AND

REASONS:

AUGUST 23, 2022

DATED:

APPEARANCES:

Peter Wilcox

FOR THE PLAINTIFFS

FOR THE DEFENDANT

Marian Wolanski

Megan Pocalyuko

Juliette Sakran

Marcus Klee

Scott Beeser

Jessica Sudbury

Yaseen Manan

SOLICITORS OF RECORD:

Belmore Neidrauer LLP

Barristers and Solicitors

Toronto, Ontario

FOR THE PLAINTIFFS

FOR THE DEFENDANT

Aitken Klee LLP

Barristers and Solicitors

Ottawa, Ontario