Date: 20090319
Docket: T-1562-07
Citation: 2009 FC 235
Ottawa, Ontario, March 19, 2009
PRESENT: The Honourable Mr. Justice Hughes
BETWEEN:
ELI
LILLY CANADA INC.
Applicant
and
NOVOPHARM LIMITED and
THE MINISTER OF HEALTH
Respondents
and
ELI LILLY AND COMPANY
Respondent/Patentee
REASONS FOR JUDGMENT
[1]
This
is a proceeding brought under the provisions of the Patented Medicines
(Notice of Compliance) Regulations, SOR/93-133, as amended (NOC
Regulations). The Applicant is seeking to prohibit the Minister of Health
from issuing a Notice of Compliance to the Respondent Novopharm Limited for a
generic version of the Applicant’s raloxifene hydrochloride medicine until the
expiry of Canadian Letters Patent No. 2,250,191 (the ’191 patent).
[2]
In
a related proceeding heard at the same time (T-1561-07) the Applicant is
seeking to prohibit the Minister from issuing a Notice of Compliance to
Novopharm Limited in respect of its generic version of the same drug until the
expiry of Canadian Patent 2,150,399 (the ’399 patent).
[3]
A
third proceeding between these parties respecting the same medicine, Court file
No. T-1563-07 has been adjourned sine die by an Order of Prothonotary
Tabib dated January 6, 2009 and is not of any relevance to this present
proceeding. I am told that this proceeding relates to Canadian patent No.
2,101,356 which was the subject of my decision in another matter cited as 2008
FC 142 and is currently under appeal.
[4]
For
the Reasons that follow, I find that this application is dismissed with costs
to Novopharm. These Reasons were released on a confidential basis to the
parties on March 4, 2009. An opportunity was given to the parties to indicate
whether any changes should be made to the public version now released. They
indicated that no changes were required. I have made small spelling
corrections at paragraphs 22 and 25.
THE PARTIES
[5]
The
Applicant Eli Lilly Canada Inc. (Lilly Canada) has received from the
Minister of Health (Minister) a Notice of Compliance respecting a medicine
containing raloxifene hydrochloride in 60 mg tablet form which medicine the
Applicant markets in Canada under the brand name EVISTA under Drug
Identification Number (DIN) 02239028. This medicine is used in the treatment
and prevention of osteoporosis. The NOC Regulations refer to this
party as the “first person”.
[6]
The
Respondent Novopharm Limited (Novopharm) sent a Notice of Allegation to Lilly
Canada stating that it intends to market a generic version of such 60 mg
tablets containing raloxifene hydrochloride and is seeking to obtain a Notice
of Compliance from the Minister to do so by filing an Abbreviated New Drug
Submission (ANDS) in which Lilly Canada’s product has been referenced. The NOC
Regulations refer to this party as the “second person”.
[7]
The
Respondent Minister is charged with administering the NOC Regulations
and issuing Notice of Compliance where appropriate.
[8]
The
Respondent Eli Lilly and Company Limited (Lilly US) is the
patentee of the ’399 patent and has been made a party to these proceedings in
accordance with section 6(4) of the NOC Regulations.
THE PATENT AT ISSUE
[9]
At
issue is Canadian Letters Patent No. 2,250,191 (the ’191 patent). The
application for that patent was filed with the Canadian Patent Office under the
provisions of the Patent Co-Operation Treaty (PCT) effective March 10, 1997.
Thus the patent is governed by the provisions of the Patent Act, R.S.C.
1985, c. P-4, as they stand following amendments made after October 1, 1989.
These provisions may be referred to as the new Patent Act.
[10]
The
application for the ’191 patent was laid open for public inspection on October
2, 1997. This becomes an important date in construing the patent. The
application for the patent claims priority from applications filed in the
United States Patent Office on March 26, 1996 and April 4, 1996. The ’191
patent will expire 20 years from the date of filing the application in Canada, that is,
March 20, 2017. The ’191 patent was issued and granted on October 15, 2005.
That date is not particularly important in these proceedings save to indicate
that the patent has been issued and granted.
[11]
In
general, and subject to discussion later, the patent is directed to particle
size of a compound known as raloxifene and its salts such as raloxifene
hydrochloride (HCl). These compounds are directed, among other things, to the
treatment of osteoporosis. Well chosen particle size is said to benefit both
bioavailability and control of the manufacturing process.
THE EVIDENCE
[12]
The
evidence in this proceeding was provided, as is usual in applications before
this Court, by way of affidavits, exhibits to affidavits, transcripts of
cross-examination and exhibits to those cross-examinations. A Protective Order
was granted in this proceeding on October 15, 2007. I have issued a further Order
as to certain of the evidence that is to be maintained as confidential.
[13]
The
Applicant filed the affidavit evidence of the following witnesses:
·
Rubina
Luebke, a Regulatory Affairs Associate at the Applicant’s company. She
provided information as to approval of the Applicant’s EVISTA product and
exhibited certain product information submitted by the Applicant to Health Canada.
·
Dr.
Robert O. Williams III, professor of Pharmaceutics at the College of Pharmacy
at the University of Texas. He claimed
expertise in formulation development optimization and delivery of small organic
compounds, peptides and proteins by a variety of technologies. He gave
evidence directed to validity.
·
Dianne
Azzarello, pharmacist, experienced in the preparation and filing of new drug
submissions. She formed her own company and deals in the filing of New Drug
Submissions and Abbreviated New Drug Submissions with Health Canada. She
provided comments as to portions of Novopharm’s Notice of Allegation and the
Applicant’s New Drug Submission for its EVISTA product.
·
Mark
Feldstein, an American attorney admitted to practice before the US Patent and
Trademark Office, employed by the Washington law firm Fennegan
Henderson. That firm represents the Respondent Lilly US in
litigation in the United States Courts against a company known as Teva. Teva
is said to supply Novopharm with product samples of which were produced in the
context of the US litigation. Feldstein gave evidence in this
regard.
·
Amy
Ganden, Assistant Laboratory Manager of Particle Technology Labs Ltd. (PTL).
This lab analysed samples provided by Feldstein. She provided a report as to
the results.
·
Dr.
David E. Bugay, Managing Director of Aptuit Consulting. He specializes in the
analysis of materials in the solid state, particularly pharmaceutical drug
substances and dosage forms. He gave evidence on the infringement issue in his
affidavit in chief. He provided a further affidavit in reply addressing
matters raised by Novopharm’s witness Biggs on the infringement issue.
[14]
Each
of Williams, Ganden and Bugay were cross-examined.
[15]
The
Respondent Novopharm filed affidavits from the following witnesses:
·
A.
Louise McLean, a law clerk in the offices of Novopharm’s solicitors. She
provided a copy of the Notice of Allegation and copies of the documents
referenced in that Notice. She provided a second affidavit respecting the
delivery of certain Teva samples.
·
Dr.
(Professor) Isador Kanfer, a professor at the Faculty of Rhodes University,
South Africa, author and editor of texts related to drugs, all of which include
the areas of bioavailability, dissolution and absorption of drugs. He
addressed issues of validity.
·
Mali
Kadosh Project Manager of Teva, Israel. He testified as to
the dispatch of certain samples to Ms. McLean aforesaid.
·
Shirley
Zhao, analytical chemist at Dalton Pharma Services. She testified as to the
analysis of certain samples provided by Ms. McLean aforesaid.
·
Dr.
(Professor) Simon Biggs, professor of particle science and engineering at the
University of Leeds, U.K. His work includes particle size measurement,
characterization and analysis. He gave evidence as to the infringement issue.
Biggs provided a further affidavit in sur-reply.
[16]
Each
of Kanfer, Zhao and Biggs was cross-examined.
[17]
The
Minister did not file any evidence and did not participate actively in this
proceeding. Lilly US did not participate actively in this proceeding. I
assume that its interests were looked after by Lilly Canada.
[18]
I
endorse the sentiments expressed by Harrington J. of this Court in Lundbeck
Canada Inc. v. Canada (Minister of Health), 2009 FC 146 at paragraph 74,
where he wrote that we really do not have evidence by way of actual persons or
even “talking heads” in proceedings such as this: we simply have words on
pieces of paper. Other than in the most exceptional cases, a Court is not in a
position to come to any conclusions as to whether certain witnesses were
evasive, or acted as advocates or acted in other ways urged by counsel so as to
encourage the Court to take a dim view as to demeanour of any other party’s
witnesses. I add my voice to those crying in the wilderness for improvements
in the process.
ISSUES
[19]
There
are two issues raised in this proceeding: validity and infringement of the ’191
patent. As to validity there are two grounds raised:
a. Obviousness;
and
b. Lack of
utility
[20]
A
third ground raised by Novopharm as to validity was double patenting. Its
counsel advised at the hearing that this ground was dropped.
[21]
Novopharm
has also alleged that its product will not infringe the claims of the ’191
patent. On this issue certain evidence has been provided that will remain
confidential. It was conceded by all Counsel at the hearing that Lilly
Canada’s product came within the parameters of at least some of the claims of
the ’191 patent. It was also conceded by all Counsel at the hearing that claim
7, which deals with a particular use of the product, is not of concern in these
proceedings.
BURDEN OF PROOF
[22]
The
issue as to who bears the burden of proof in NOC proceedings, where the issue
of validity of a patent or infringement of a patent is an issue that I had
throught had been put to rest. Nonetheless the parties in such proceedings
continue to argue the point. It seems that my recent decision in Brystol-Myers
Squibb Canada Co. v. Apotex Inc., 2009 FC 137 has given fresh ammunition to
those continually wishing to stir the pot in this regard. Let me state
emphatically that I did not intend in Brystol-Myers to say or apply any
burden different than I had stated in previous decisions.
[23]
To
be perfectly clear, when I comes to the burden as to invalidity I canvassed the
law, in particular recent Federal Court of Appeal decisions, in Pfizer
Canada Inc. v. Canada (Minister of Health), (20008), 69 C.P.R. (4th)
191, 2008 FC 11 and concluded at paragraph 32:
32 I do not view the
reasoning of the two panels of the Federal Court of Appeal to be in substantial
disagreement. Justice Mosley of this Court reconciled these decisions in his
Reasons in Pfizer Canada Inc. v. Apotex Inc., [2007] F.C.J. No. 1271, 2007 FC 971 at paragraphs 44 to 51. What is required, when
issues of validity of a patent are raised:
1.
The second person, in its Notice of Allegation may raise one or more grounds
for alleging invalidity;
2.
The first person may in its Notice of Application filed with the Court join
issue on any one or more of those grounds;
3.
The second person may lead evidence in the Court proceeding to support the
grounds upon which issue has been joined;
4.
The first person may, at its peril, rely simply upon the presumption of
validity afforded by the Patent Act or, more prudently, adduce its own evidence
as to the grounds of invalidity put in issue.
5.
The Court will weigh the evidence; if the first person relies only on the
presumption, the Court will nonetheless weigh the strength of the evidence led
by the second person. If that evidence is weak or irrelevant the presumption
will prevail. If both parties lead evidence, the Court will weigh all the
evidence and determine the matter on the usual civil balance.
6.
If the evidence weighed in step 5 is evenly balanced (a rare event), the
Applicant (first person) will have failed to prove that the allegation of
invalidity is not justified and will not be entitled to the Order of
prohibition that it seeks.
[24]
I
stated the matter more succinctly in Pfizer Canada Inc. v. Canada (Minister of
Health),
2008 FC 500 at paragraph 12:
12 Here the only issue is
validity. Pharmascience has raised three arguments in that respect. Each of
Pfizer and Pharmascience have led evidence and made submissions as to those
matters. At the end of the day, I must decide the matter on the balance of
probabilities on the evidence that I have and the law as it presently stands.
If, on the evidence, I find that the matter is evenly balanced, I must conclude
that Pfizer has not demonstrated that Pharmascience's allegation is not
justified.
[25]
The
above cases state correctly in my view, the state of the law as to the burden
in NOC proceedings as to invalidity.
[26]
Turning
to infringement the law is well settled that where a generic has alleged
non-infringement, the statements that it makes in that regard in its Notice of
Allegation are presumed to be true. The Applicant (first party) bears the
burden of proof, on the balance of probabilities, to satisfy the Court that the
allegations of non-infringement are not justified; merely to raise the
possibility of infringement is insufficient. The Federal Court of Appeal made
these points quite clearly in its recent decision in Novopharm Limited v.
Pfizer Canada Inc. (2005), 42 C.P.R. (4th) 97, 2005 FCA 270 at
paragraphs 19, 20 and 24:
19 In Pharmacia Inc. v. Canada (Minister
of National Health and Welfare) (1995), 64 C.P.R. (3d) 450 (F.C.A.), Hugessen J.A.
addressed the evidentiary burden placed on a generic under the Regulations. He
adopted the reasons of the trial judge who described this burden as follows:
... the
grounds that the patentee has for challenging the generic's notice of
allegation should be advanced in the originating notice of motion filed
pursuant to s. 6(1) of the Regulations. ... The generic may then be informed as
to what vexes the patentee and why a prohibition order barring entry should be
issued. Initially, i.e., before the Minister, the generic has raised the issue
of non-infringement. At this stage, before the court, the generic now has the
opportunity to file evidence supporting its detailed statement. In essence,
this is the evidential burden on a respondent.
(see
Pharmacia Inc. v. Canada (Minister of National Health
and Welfare) (1995), 60 C.P.R. (3d) 328 at 339-40 (F.C.T.D.), per
Wetston J.)
20 In my view, this
statement remains good law. Where, as here, the NOA is found to be adequate,
the legal burden remains squarely on Pfizer to prove, on a balance of
probabilities, that the allegations in the NOA are unjustified. Novopharm has
no evidential burden to support the allegations in its NOA and detailed
statement (see AB Hassle 2 at paragraph 35). Therefore, Novopharm need only
file evidence supporting its detailed statement to counter evidence, if any,
submitted by Pfizer in the course of the prohibition proceedings.
…
24 For whatever reason,
Pfizer relies solely on Dr. Munson's speculations in this proceeding. The law
is well settled that in order to satisfy the legal burden placed on it under
section 6 proceedings, it is insufficient for Pfizer to merely raise the
possibility of infringement (see Glaxo Group Ltd. v. Canada (Minister of
National Health and Welfare) (1998), 80 C.P.R. (3d) 424 (F.C.T.D.) at paragraph 9). In
relying solely on Dr. Munson's evidence, Pfizer has failed to satisfy its legal
burden of proving that Novopharm's NOA is not justified.
CONSTRUCTION OF THE
CLAIMS
[27]
The
Supreme Court of Canada has instructed that the Court must first construe the
claims at issue before moving to consideration of issues such as validity and
infringement of those claims, the purpose in doing so is to identify what it is
in the claims that the inventor considered to be essential. This construction
is to be conducted in a purposive manner so as to endeavour to be fair to both
the patentee and the public of the decision of Binnie J. for the Court in Whirlpool
Inc. v. Camco Inc., [2000] 2 S.C.R. 1067:
43 The first step in a patent suit is
therefore to construe the claims. Claims construction is antecedent to
consideration of both validity and infringement issues.
…
45 The key to purposive
construction is therefore the identification by the court, with the assistance
of the skilled reader, of the particular words or phrases in the claims that
describe what the inventor considered to be the "essential" elements
of his invention.
[28]
The
relevant date for construction of the ’191 patent, being a “new” Patent Act
patent, is the date of its publication, October 2, 1997. Construction is to be
undertaken by the Court, viewing the claims as of that date through the eyes of
a person skilled in the art, assisted if needed by expert evidence as to the
meaning of special terms and the knowledge that such a person would bring to
bear. Regard is to be given to the whole of the disclosure of the patent and
the claims. Again, there are many authorities stating such propositions. One
is the Federal Court of Appeal, Sharlow JA. in Novopharm Ltd. v.
Janssen-Ortho Inc., 2007 FCA 217 at paragraph 4. (It is to be noted that
the patent there was an old Act patent therefore the date for consideration was
different.):
4 In any case in which
the validity or infringement of a patent claim is in issue, it is necessary to
construe the claim: Whirlpool Corp. v. Camco Inc., [2000] 2 S.C.R. 1067 at paragraph 43. The relevant date
for the construction of the 080 patent is the date of its issuance, June 23, 1992.
The patent must be understood as being addressed to a person skilled in the
art, taking into consideration the knowledge that such a person is expected to
possess on that date. The construction of a patent claim is a task for the
Court and must be based on the whole of the disclosure and the claim, assisted
by expert evidence as to the meaning of certain terms and the knowledge that a
person skilled in the art is expected to possess on the relevant date.
PERSON SKILLED IN THE
ART
[29]
The
parties spent little time in argument defining the person or persons who
represented those skilled in the art to whom the ’191 patent was addressed.
Novopharm, through its witness Dr. Kanfer at paragraph 18 of his affidavit
stated that such a person was:
“…a person with a degree in
science, focused on the physical sciences and preferably in the field of
pharmacy, with at least several years experience in pharmaceutical formulation
in an academic or industry setting.”
[30]
Applicant’s
counsel in oral argument accepted that definition. I accept it as well.
THE ’191
PATENT-DESCRIPTION
[31]
The
’191 patent begins at page 1 in stating that the invention is directed to a
particle size range of a class of pharmaceutical compounds known as
benzothiophenes, which size range enhances bioavailability and allows control
during manufacturing:
This invention relates to the
fields of pharmaceutical and organic chemistry and provides a benzothiophene
compound, in particulate form, which is useful for the treatment of various
medical indications, including osteoporosis and lipid lowering. More
particularly, the benzothiophene is of a particle size range which allows
enhanced bioavailability and control during the manufacturing process.
[32]
Later
on page 1 and over to page 2, the patent restricts the discussion to one
benzothiophene, raloxifene, useful in treating osteoporosis, but states that
raloxifene has solubility problems that affect both its bioavailability and
manufacturing:
The advancement of raloxifene
has been somewhat hampered by its physical characteristics, both as to
bioavailability and in manufacturing. For example, it is generally insoluble,
and this can adversely affect the bioavailability. Clearly, any improvement in
the physical characteristics of raloxifene, would potentially offer a more
beneficial therapy and enhanced manufacturing capability.
[33]
At
page 2 a general description of the invention of the patent is given.
Raloxifene is depicted in its chemical diagrammatic form:
This invention provides a
compound of formula I
and pharmaceutically
acceptable salts and solvates thereof, characterized in that the compound in
its particulate form, said particles having a mean particle size of less than
about 25 microns, and preferably between about 5 and about 20 microns.
[34]
Thus
the invention is stated to be the provision of raloxifene in particulate size
less than about 25 microns and preferably between about 5 and about 20
microns. Further statements are made as to at least 90% of the particles being
less than 50 microns, preferably less than 35 microns. It is pointed out that
this raloxifene can be formulated with pharmaceutical compounds for treatment
of osteoporosis and other conditions.
[35]
The
benefits of bringing the particle sizes within the specified narrow range are
said to be in respect of dissolution, bioavailability and improved
manufacturing capabilities. At pages 2 and 3 the patent says:
It has now been found that by
processing compounds of formula I, to bring their particle sizes within a
specified narrow range, pharmaceutical compositions may be prepared which
exhibit for their active ingredient both a consistent in vitro dissolution
profile and in vivo bioavailability. In addition to bringing about these
desired dissolution/bioavailability characteristics, the control of particle
size to narrow range has also resulted in significant improvements in
manufacturing capabilities.
[36]
The
particle size and range is again set out at page 3:
The mean particle size of
compounds of formula I, as set out by the invention, is less than about 25
microns, preferably between about 5 and about 20 microns. Further, the
invention encompasses formula I compounds with at least 90% of the particles
having a particle size of less than about 50 microns, preferably less than
about 35 microns. More preferably, the mean particle size range is between
about 5 and about 20 microns, with at least 90% of the particles having a size
of less than about 35 microns.
[37]
Pages
4 and 5 of the patent discuss conventional wisdom, that poor solubility can be
improved by reducing particle size but reduced particle size gives rise to
manufacturing problems such as heating of the ingredients and caking in the
machinery. There must be a compromise between the two:
Often, compounds which have
poor solubility profiles can have their bioavailability enhanced by increasing
the surface area of the formulated particles. The surface area generally
increases per unit volume as the particle size decreases. Various techniques
for grinding or milling a drug substance are well known in the art…very finely
divided material presents difficulties and cost in capsule filling or tablet
preparation, because the material will not flow, but becomes caked in finishing
machinery. Such finishing difficulties generate non-homogeneity in the final
product, which is not acceptable for a drug substance. Additionally, the
milling process physically generates heat and pressure on the material, such
conditions lead to chemical degradation of the compound, thus such milling
techniques are usually kept to a minimum.
Therefore, there is always
dynamic between the properties which yield the maximum bioavailability
(particle surface area) are the practical limits of manufacture. The point of
compromise which marks this “best solution” is unique to each situation and
unique as to its determination.
[38]
At
page 5 the patent tells the reader that, in the raw state, raloxifene has a
broad size distribution with a volume diameter of about 110-200 microns. That
size is measured by a Horiba LA900 device. At page 7 the particle size
measurement technique is more fully described in respect of raloxifene whose
particle size has been reduced:
The particle size of the
reduced raloxifene HCl was measured as follows. The laser scattering particle
sizes distribution analysis was effected on a small sample of the reduced
material which is suspended in approximately 180 ml of dispersant solution.
Sample is added to the dispersant until an acceptable level of laser light
obscuration achieved at which point the particle sizes distribution is
measured. Prior to the sample suspension the dispersant solution was prepared
by adding 20 drops of Coulter 1A dispersant to a saturated aqueous solution of
raloxifene HCl. The dispersant solution was filtered through a 0.2 micron
microporous membrane filter to provide the necessary particle-free suspending
dispersant.
Within five minutes of the
preparation of the dispersion, triplicate particle size measurements were
performed.
[39]
At
page 8 there begins a discussion as to the rate of dissolution of raloxifene
and its absorption into the gastrointestinal tract, thus the effect upon
bioavailability:
Given the low solubility, the
rate at which the dosage form dissolves in the gastrointestinal tract can
potentially impact the rate and extent of absorption of the active compound.
Two related physical properties of the bulk drug which can alter the
dissolution rate of the dosage form are particle size and surface area.
[40]
There
follows at pages 9 to 12 a description of in vitro and in vivo
testing of raloxifene of various particle sizes obtained through
recrystallization (said to be a control batch), micronizing and two forms of
milling. As stated at page 9:
To ascertain the effect of
particle size/surface area of raloxifene HCl on in vitro dissolution, lots with
varying particle size distribution were obtained via recrystallization and
further modified through various milling technologies.
[41]
Tables
showing the surface area and particle size and rate of dissolution of the
samples are provided as Tabs 1, 2 and 3. At page 11, the patent postulates
that the surface area of the particles as measured by a certain technique does
not predict its dissolution:
It is postulated that the
surface area as measured by nitrogen adsorption for the various types of milled
raloxifene does not predict the effective surface area accessible to the
dissolution medium.
[42]
At
page 12 the patent states that, as a result, a decision was made to pursue
particle size as a parameter for drug performance:
Based upon these findings, the
decision was made to pursue particle size distribution as a control parameter
to ensure consistent performance of the drug product with regards to release of
the drug component.
[43]
A
study was conducted, as set out in pages 12 to 15 of the patent, where it
states that monkeys were fed from two batches of raloxifene, one with a mean
particle size of 48.1 microns (Lot 5A) and one with a mean particle size of 9.0
microns (Lot 5B).
[44]
At
page 15 the patent states that particle size is critical and that the study
confirms that in vitro testing can confirm the in vivo
absorption:
This data is further evidence
of the critical nature of the particle sizes distribution on its impact on
bioavailability. The study also confirms the discriminating ability of the in
vitro dissolution method and its relationship to in vivo absorption. Once
again, the differences observed in the in vitro dissolution profiles translated
into in vivo absorption differences.
[45]
Based
on this work, certain particle size specifications were established and work
was undertaken to justify the range established. At page 15 and at page 17 the
reader was told that bulk lots of raloxifene were milled and formulated into
tablets which were then studied:
Based upon the above work and
physical property data generated, a particle size specification was
established. The invention provides that the mean particle sizes, as
determined by laser light diffraction, should be less than about 25 microns.
In addition, 90% of the particles by volume should be under 50 microns, which
allows for characterization of the distribution. Preferably, the size between
about 5 and about 20 microns, and 90% of the particles have a size of less than
about 35 microns. To justify this range, bulk lots were produced by pin
milling and samples of the available extremes were manufactures into formulated
tablets and in vitro dissolution testing. In one study, six bulk lots of
raloxifene hydrochloride (ca. 1 kg) were received and manufactured into
formulated 60 mg raloxifene HCl tablets representative of the tablets being
utilized in Phase III clinical testing.
…
Another similar study was
performed with 7 different particle size distribution of bulk drug, with each
again being formulated into 60 mg tablets.
[46]
Data
respecting these studies is presented, including tables. A conclusion is set
out at page 18. This conclusion, the Applicant argues, is the inventive step
of the patent: namely, that within the stated particle size range, the in
vivo absorption/bioavailability characteristics are surprisingly
consistent:
Given the relationship shown
between in vitro dissolution and in vivo absorption, it follows that the
particle size distribution range claimed in this patent will provide
surprisingly consistent in vivo absorption/bioavailability characteristics.
[47]
There
follows at pages 18 and 19 a discussion as to particle sizes and
manufacturing. Too fine a particle size results in poor flow and poor control
of the process. Thus the particle size constraints of the patent result in
more amenable processing. At page 19:
Too fine a granulation
distribution can lead to poor granulation flow and poor control of individual
table weight during the compression step. Thus the narrow particle size
constraints previously mentioned have also resulted in making the process more
amenable to automation by reducing the variations in water required during the
granulation step and producing dry milled granules of the appropriate
distribution to prevent the rejection of tablets during compression due to
unacceptable tablet weight.
[48]
From
page 19 to page 36 various formulas for manufacturing tablets containing
raloxifene are provided together with the added ingredients (excipients). The
patent ends with 8 claims.
THE CLAIMS OF THE ’191
PATENT
[49]
The
8 claims of the ’191 patent are as follows:
1. A compound of formula I
and pharmaceutically acceptable salts
thereof, characterized in that
the compound is in particulate form, said particles having a mean
particle size of less than 25 microns, at least 90% of said
particles have a size of less than 50 microns.
2. The compound of claim 1 wherein said particles have a
mean particle size of between 5 and 20 microns.
3. The compound of claim 1 or 2 wherein at least 90% of said
particles have a size of less than 35 microns.
4. A pharmaceutical composition comprising or formulated
using a compound according to any one of claim 1, 2 or 3, or a
pharmaceutically acceptable salt thereof, in combination with one or
more pharmaceutically acceptable carrier, diluent or excipient.
5. A compound of any one of claim 1, 2 or 3 which is non-
solvated crystalline 6-hydroxy-2- (4-hydroxy-phenyl) -3-[4-(2-
piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride.
6. The use of a compound of claim 5 or a pharmaceutically
acceptable salt thereof for inhibiting osteoporosis in a person in
need thereof.
7. The use of a compound of claim 5 or a pharmaceutically
acceptable salt thereof for preventing breast cancer in a woman in
need thereof.
8. A pharmaceutical composition
comprising or formulated
using the compound of claim 5 and one or more pharmaceutically
acceptable carrier, diluent or excipient.
[50]
The
compound as depicted in Formula I of claim 1 is the same as that as written in
claim 5 and can be simply stated as raloxifene. The pharmaceutically
acceptable salt can be described for the purposes of this proceeding as
hydrochloride. Thus the claims can be more briefly be rewritten as:
a. Raloxifene
hydrochloride in particulate form having a mean particle size of less than 25
microns, at least 90% of which particles have a size less than 50 microns.
b. As per claim
1 with a mean particle size of between 5 and 20 microns.
c. As per claims
1 and 2 in which 90% of the particle size is less than 35 microns.
d. A
pharmaceutical composition using the compound of any of claims 1, 2 or 3.
e. A compound of
any of claims 1, 2 or 3 comprising raloxifene hydrochloride.
f.
Use
of the claim 5 compound to inhibit osteoporosis.
g. (Not at
issue). Use of the compound in preventing breast cancer.
h. A
pharmaceutical composition of claim 5.
[51]
The
parties are agreed as to the essential elements of the claims and that for
purposes of these proceedings, we need only to look at claims 1, 2 and 3. The
essential elements of those claims are:
Claim 1: -Raloxifene
hydrochloride
i.
in
particulate form
ii.
such
particles having a mean particle size of less than 25 microns, at least 90% of
which particles have a size of less than 50 microns
Claim
2:
The compound of claim 1 where the mean particle size is between 5 and 20
microns.
Claim
3: The
compound of claim 1 and 2 wherein at least 90% of the particles have a size of
less than 35 microns.
INFRINGEMENT
[52]
It
is agreed that, for purposes of considering Novopharm’s allegations as to
non-infringement, only claim 1 needs to be considered. It is assumed that
Novopharm will be formulating its raloxifene hydrochloride into pharmaceutical
compositions for use directed to osteoporosis. The only issue is as to the
particle size of the raloxifene hydrochloride. The broadest parameters for
particle size are those found in claim 1 which requires the particle size to be
less than about 25 microns, and at least 90% of the particles to have a size of
less than 50 microns.
[53]
Novopharm’s
Notice of Allegations at pages 36 and 37 addresses its non-infringement
allegation and states, inter alia:
Novopharm’s Tablets will not
infringe any of the claims of the ’191 Patent. Novopharm’s Tablets will not
contain raloxifene or a pharmaceutically acceptable salt thereof with a
particle sizes of less than about 25 microns, and at least 90% of the particles
having a size of less than 50 microns, as claimed and required in the ’191
Patent. The particles of raloxifene that Novopharm will use and incorporate
into its Novopharm Tablets will have a mean particle size significantly greater
than 25 microns, and the raloxifene (or a pharmaceutically acceptable salt
thereof) particles used by Novopharm will not have at least 90% of the
particles with a sizes of less than 50 microns.
[54]
Novopharm
relies on two things in support of its allegation. First, the information that
it supplied to Health Canada in support of its own Abbrieviated New
Drug Submission (ANDS). Second it relied on testing conducted by an outside
laboratory known as Dalton and its employee Ms. Zhao who provided an
affidavit and was cross-examined. Comments were provided thereon by
Novopharm’s expert Dr. Biggs.
[55]
The
Applicant relied on testing of samples provided by Teva, an organization
related to Novopharm, in the context of certain United States litigation.
It was agreed by the parties that the results of such testing may be introduced
into this proceeding as if the samples had been provided by Novopharm in the
context of these proceedings. The testing was conducted by an outside
laboratory, PTL, under the supervision of Ms. Ganden, who provided an affidavit
and was cross-examined in these proceedings. The Applicant’s expert, Dr.
Bugay, commented on this testing and the results.
[56]
Each
of Drs. Biggs and Bugay also provided comments as to the testing done by the
other parties and conclusions that might be drawn as to the evidence of each
other.
[57]
I
have no reason to doubt that all of the testing was performed as reported and
that the results were accurately reported. I also have no reason to be
critical of the evidence given by any of Ganden, Zhao, Biggs or Bugay or their
independence or credibility.
[58]
The
critical issue is directed to how the particle size of the raloxifene is
measured. I accept the evidence of Dr. Bugay in cross-examination found at
pages 40 to 42 of the transcript, pages 1569 to 1570 of the Record, that in
measuring particle size one must be careful not to cause the particles to
dissolve, to be sure that the particles are not agglomerated, and to ensure
that particles are not fractured during the course of measurement. I also
accept the evidence of Zhao at paragraph 6 of her affidavit that bubbles in the
sample may cause problems with measurement.
[59]
The
information given in the ‘191 patent as to how measurements of particle size
were made is set out at pages 5 and 7:
The efficiency of the milling
is checked by sampling using a Horiba LA900 Laser Scattering Particle Size
Distribution Analyzer and the final particle size is checked in a similar
manner.
…
The particle size of the
reduced raloxifene HCl was measured as follows. The laser scattering particle
size distribution analysis was effected on a small sample of the reduced
material which is suspended in approximately 180 ml of dispersant solution.
Sample is added to the dispersant until an acceptable level of laser light
obscuration achieved at which point the particle size distribution is
measured. Prior to the sample suspension the dispersant solution was prepared
by adding 20 drops of Coulter 1A dispersant to a saturated aqueous solution of
raloxifene HCl. The dispersant solution was filtered through a 0.2 micron
microporous membrane filter to provide the necessary particle-free suspending
dispersant.
Within five minutes of the
preparation of the dispersion, triplicate particle size measurements were
performed. Triplicate measurements are effected as a minimum check a) to
produce more reliable measurements and b) to check the equivalent sampling of
the suspended material has been reproducible i.e., the suspension has not
settled.
The results were automatically
recorded and displayed graphically to give a frequency percentage vs. undersize
and a cumulative percentage vs. undersize characteristics curves for the
sample.
[60]
It
appears that in the testing provided to the Court a device known as a Malvern
Mastersizer was used rather than a Horiba LA900 but Counsel for the parties
were agreed that these devices may be considered as equivalent for the purposes
of this proceeding.
[61]
Two
matters should be noted in respect of the procedure for particle size
measurement set out in the ’191 patent. First, a dispersant identified as
Coulter 1A was used. Second, the procedure is silent as to agglomeration and
if any were noticed, how, if at all, it is to be dealt with. It is noted that
measurements are taken within five minutes of treating the sample with the
dispersant.
[62]
I
accept the evidence of the Applicant’s expert Dr. Bugay as to the manner in
which a sample would be prepared and handled as set out in paragraph 27 of his
affidavit:
27. It is important to note
that all particle size measurements are designed to measure representative
samples of the individual fine particles of the material of interest as opposed
to clumps of those particles such as aggregates or agglomerates. Consequently,
regardless of the measuring apparatus used, the accuracy of a particle size
measurement is highly dependent on ensuring that the measured material is in
fine particles and not clumps. This is achieved through proper sample
preparation and handling which include: (1) de-aggregating the original sample
such that the individual fine particles are being measured; (2) selecting the
medium to suspend the individual particles within for the subsequent
measurement; (3) utilizing a dispersing agent to prevent aggregation; and (4)
concentrating the particles within the suspension matrix in order to achieve
the proper obscuration.
[63]
I
accept, and no party challenged, that this procedure would have been one known
to and followed by the relevant person skilled in the art as of the date of
publication of the ’191 patent application, October 2, 1997.
[64]
Turning
then to Novopharm’s submissions as to the evidence of non-infringement. First
Novopharm relies on its submission to Health Canada in support
of its Abbreviated New Drug Submission found as Exhibit D to the affidavit of
Dr. Bugay. Data is given in respect of two pilot batches of its raloxifene
hydrochloride. Particle size measurements on a Malvern Mastersizer were given
as having a mean particle size for one batch as 37.4 microns and the other as
39.4 microns which is well above the value of 25 microns given in claim 1. A
90% particle size value for the first batch is given as 92.0 microns and the
second as 97.2 microns, again well above the value of 50 microns establishes in
claim 1. Novopharm argues that its submissions to Health Canada must be
taken very seriously and any deviation from such values may well result in
serious consequences. I agree that, if there were no other evidence, then such
evidence as found in the submission may possibly be taken as determinative.
Here, however, there is other evidence, all of which must be evaluated.
[65]
The
method by which these samples were measured is set out at Exhibit B of the Dr.
Biggs affidavit, pages 607 and 608 of the Record and commented upon by him at
paragraphs 50 to 52 of his affidavit. There are two matters of note. First
the dispersant used was isopropyl alcohol (IPA) not the Coulter 1A of the
patent. Second, the sample was subjected to vortex mixing for 30 seconds
(described in the evidence as attaching a suction cup to the vessel containing
the sample and shaking it) and to sonification for five seconds (described in
the evidence as the application of ultrasonic energy waves to the sample). It must
be remembered that the patent is silent as to how, if at all, the sample is
mixed or shaken or whether sonification is used.
[66]
The
Applicant criticized this method (called the Teva method) on two grounds. The
first is the use of IPA as the dispersant and not Coulter 1A. The second
ground was that there was insufficient shaking or mixing of the sample so as to
get rid of agglomeration.
[67]
Novopharm
ran another set of tests, this time through an independent laboratory known as Dalton, by one of
its employees Ms. Zhao. Zhao’s affidavit testifies that two sets of tests were
run in accordance with a protocol provided by a lawyer in the firm acting for
Novopharm. The first tests were suspected of being influenced by the presence
of bubbles so a second set of tests was run. At the hearing, relying on
questioning of Dr. Biggs found at page 44 of the transcript of his
cross-examination (page 1788 of the Record), Applicants counsel argued that the
lawyer devised the protocol. I am satisfied in reading the questions and
answers that while the lawyer wrote the protocol, the protocol was devised by
Dr. Biggs, not the lawyer. The protocol is said to follow that set out in the
’191 patent to the extent that it can be done.
[68]
Coulter
1A is used as a dispersant (not IPA). The sample was shaken by hand briefly.
The Applicants Counsel argues that this was insufficient to get rid of
agglomeration. Ms. Zhao was clear in her cross-examination that sonification
would not be recommended for particle size analysis. She said in answer to
questions 186 to 192 as to sonification that it is not recommended for particle
size analysis:
186. Q.
So when we talked about the short mixing, that was the hand-mixing that we were
talking about?
A. Yes
187. Q. And it says:
“...No sonification should be used…”
A. Yes.
188. Q. What is
sonification used for?
A. The sonification, you are
asking what is sonification used, right?
189. Q. Yes.
A. The sonification when we
use in general lab…in general term, in lab, we use the gassing purpose, for the
dissolving purpose.
190. Q. For dissolving
purpose?
A. Yes. You put your solid in
there and then you have your solution in there but some time you want to de-gas
because there is some gas in there, you put in sonification…and then start it.
That’s the sonification works.
191. Q. So sonification
can get rid of gas that is in the solution?
A. Yes.
That’s the sonification works for.
192. Q.
can it also be used for agglomerates if a particle is agglomerated?
A. We use for in the lab, we
use this for dissolving purpose. Some sample takes time dissolve, that helps
dissolve. But this…in particle sizes, sonification is not recommended.
193. Q. It is not
recommended?
A. No. It is for general lab
purpose but not for particle size analysis.
[69]
The
second set of tests run by Zhao shows that in the two samples tested the mean
particle size were 43.7 microns and 40.4 microns, well above the 25 microns of
Claim 1 and the 90% criterion was 108.0 microns and 100.3 microns, again well
above the 50 micron requirement of claim 1 (see Exhibit B to Zhao, page 556 of
the Record). The first test (Exhibit A to Zhao, page 548) gave results equally
above the limits of claim 1.
[70]
The
Applicant relies on testing conducted by PTL, supervised by Ms. Ganden. PTL in
2004 had, at the request of Mark Feldstein, a lawyer in the United
States
law firm of Finnegan Henderson, prepared a protocol for the testing of
raloxifene hydrochloride particle sizes. This protocol (found as Exhibit H to
the affidavit of Feldstein, pages 80 to 93 of the Record) was submitted by
Lilly US to the United States Food and Drug Authority as part of its
submissions as to its raloxifene hydrochloride drug. In this regard it is on a
footing similar to Novopharm’s ANDS submission. At page 80 of the Record,
first page of the submission, it is stated that three dispersants were
investigated, hexane, isopropyl alcohol (IPA) and water, and that in water
containing 20 drops per litre of Coulter 1A the particles dispersed rapidly.
The others, hexane and IPA, caused particles to clump together and form
agglomerates. It is not stated whether sonification was used. Stir rates and
agitation rates are mentioned.
[71]
In
2006 PTL, at the request of Feldstein, conducted particle size analysis on the
two Teva samples agreed to be relevant in respect of the Novopharm product at
issue here. A report was provided, Exhibit A to the Ganden affidavit, Exhibit
F to the Feldstein affidavit, pages 65 to 78D of the Record. The results of
the testing of the two samples appear at page 67 of the Record. The mean
particle size of the first sample was 25.18 microns, very near the 25 micron
limit of claim 1 and of the second sample was 21.71 microns, within the 25
micron limit of claim 1. The 90% figure for the first sample was 56.55 microns
thus it was above the 50 microns limit of claim 1 and for the second sample was
45.27 microns thus within the 50 micron limit of claim 1. In sum, the first
sample was outside the two parameters of claim 1, the second sample was within.
[72]
It
appears that the protocol used by PTL in its testing is that which it developed
in 2004. Although not entirely clear from that protocol, it appears, for
instance as set out in paragraph 5 of the Reply affidavit of Dr. Bugay, pages
147-148 of the Record that, after the dispersant was added to the sample, the
sample was subjected to hand shaking followed by at least 15 seconds of
sonification. At paragraph 6 and 7 of the same affidavit at page 148 of the
Record, Dr. Bugay refers to a chart, found at page 1490 of the Record, showing
particle size measured as against ultrasonification time showing a visible
reduction in particle size over the first fifteen seconds, a relatively stable
period, then a more gradual drop after three minutes.
[73]
Drs.
Bugay and Biggs have a clear difference of views as to the effect of
sonification. Dr. Bugay says that sonification for fifteen seconds serves
merely to break down agglomeration. Dr. Biggs says that sonification would not
be used at all unless agglomeration was visually detected, and that any
sonification would result in some fracture of some particles thus reducing the
overall particle size of the entire sample. The exchanges of views are best
set out in their second affidavits. The differences between them cannot be resolved
on the basis of credibility, I have not seen the witnesses, I have only
affidavits and transcripts. No exchange in cross-examination is so striking as
to enable a credibility assessment to be made. Thus, they both are credible.
[74]
We
are left with this. Novopharm has in its ANDS told Health Canada that its
particle size will be outside the range claimed in the ’191 patent. However
this data appears to have been created by testing using a dispersant (IPA) that
Lilly told the United States Authorities, would lead to agglomeration,
therefore readings according to Lilly that are too high. Novopharm therefore
had an independent lab test its material using the dispersant called for in the
patent, Coulter 1A. The tests again showed both samples outside the range
claimed in the patent. Lilly criticised this second test for not shaking the
sample sufficiently including applying it to sonification so as to ensure there
was no agglomeration.
[75]
Lilly
ran its own tests on two samples. One was found to be inside the claimed
range, one outside. Lilly used the dispersant described in the ’191 patent and
subjected the sample to shaking for one minute followed by fifteen seconds of
sonification.
[76]
The
patent is silent as to shaking or sonification or any other such manipulation
of the material to be tested.
[77]
I
take note of what Ms. Zhao of Dalton said as to the testing that she did on
behalf of Novopharm. She said that did she not observe any agglomeration of
the sample to be tested. In the exchange set out in earlier in these Reasons
it is to be noted that she said that for testing of particle size sonification
is not normally used.
[78]
The
point of shaking or sonification is to ensure that there is no agglomeration.
The evidence satisfies me that, as of the publication date of the patent
application, October 1997, a person skilled in the art in measuring particle
size would want to get rid of agglomeration and that if any agglomeration was
detected it would be by visual inspection and that shaking would be the usual
remedy. I am satisfied, particularly having regard to the Affidavit Reply
Affidavit of Dr. Biggs, that sonification creates substantial energy in the
sample and that some fracture, that is, reduction in size of some particles, is
likely to occur.
[79]
The
patent is silent as to de-agglomeration techniques, if needed. I agree with
the opinion expressed by Dr. Biggs at paragraph 63 of his first Affidavit,
pages 601 and 602 of the record, that if agglomeration were a problem requiring
the application of techniques in applying energy such as sonification, then the
patent would have said so.
[80]
What
is to be determined is the measurement of particle size as it would have been
understood and done as of October, 1997. The Dalton technique
more nearly resembles what would have been understood at that time. The Dalton technique
results in both samples tested being measured as clearly outside the parameters
of claim 1 of the ’191 patent. The more aggressive PTL technique utilizing
energy supplied by sonification results in only one of two samples being within
those parameters. Therefore, I find, on a balance of probabilities, that
Novopharm’s allegation of non-infringement, is justified.
VALIDITY - GENERALLY
[81]
Novopharm
has attacked the validity of the ’191 patent claims on two grounds, obviousness
and utility.
[82]
As
a first step, the claims have already been construed. The essential elements
of claim 1 are:
Raloxifene
hydrochloride
i.
in
particulate form
ii.
such
particles having a mean particle size of less than 25 microns at least 90% of
which are less than 50 microns.
of claim 2
are:
- The
compound of claim 1 where the mean particle sizes is between 5 and 20 microns.
of claim 3:
iii.
The
compound of claim 1 and claim 2 wherein at least 90% of the particles have a
size of less than 35 microns.
[83]
The
balance of the claims are directed to compounds and pharmaceutical compositions
and uses. Counsel have agreed that it is unnecessary to consider them here,
for if any of claims 1, 2 or 3 are valid, so are claims 4 to 8; conversely if
claims 1, 2 and 3 are invalid, so are claims 4 to 8; if one or more only of
claims 1, 2 or 3 are valid, then to the extent that claims 4 to 8 depend on a
valid claim, they too are valid.
[84]
The
’191 patent acknowledges at pages 1 and 2 previously set out in these reasons
that raloxifene hydrochloride was a known compound useful in treating
osteoporosis and other health conditions, but that it was generally insoluble
and that can affect bioavailability. At page 5 of the ’191 patent we are told
that “raw” raloxifene hydrochloride comprises particles with a volume diameter
of about 110-200 microns and a broad size distribution.
[85]
At
pages 4 and 5 of the ’191 patent it is acknowledged that it is known that often
compounds with poor solubility can have bioavailability enhanced by decreasing
particle size. However, we are told that it was known in the prior art that a
reduction of particle size brings with it associated problems presented by
manufacturing difficulties such as overheating and caking in the machinery.
The experts put forward by the parties, Williams for the Applicants at
paragraph 25 to 28 of his affidavit and pages 37 to 42 of the transcript of his
cross-examination, and Kanfer for Novopharm at paragraph 53 to 67 of his
affidavit and questions 16 to 48 of the transcript of his cross-examination,
both agreed.
[86]
The
’191 patent states the problem at page 5 which is to find the “best solution”
for the particular drug in question:
Therefore, there is always
dynamic between the properties which yield the maximum bioavailability
(particle surface area) and the practical limits of manufacture. The point of
compromise which marks the “best solution” is unique to each situation and
unique as to its determination.
[87]
Dr.
Williams in paragraph 28 of his affidavit states that each pharmaceutical
ingredient is different. Consequently a pharmaceutical scientist must
determine what particular factors to focus upon and design experiments and
analyse their effects before arriving at a best solution. Dr. Kanfer at paragraphs
63 to 68 of his affidavit appears to agree with this proposition but states
that such an assessment was part of the standard approach in the production of
pilot plant batches. In answering Question 35 on cross-examination Dr. Kanfer
said:
35. Q.
Okay, and for a person skilled in the art, the choice and design and
interpretation of this is complex. You have to weigh the factors, see what the
effect of them is to try and get to your ultimate objective?
A. As I mentioned, that is the
area which is known biopharmaceutics, which in the pharmaceutical course an
undergraduate student would be well aware of these kind of things.
[88]
Dr.
Williams, in the course of his cross-examination, particularly at pages 38 to
43 agrees that it was known that bioavailability is improved by increasing the
surface area of particles and that manufacturing capability would decrease as a
result.
[89]
To
this point therefore, there is nothing disclosed by the patent that would not
have been known to a person skilled in the art as to the problem and how to
address it and that any person skilled in the art could resolve the problems
routinely to arrive at a “best solution”. Nothing so far is unobvious, nor is
any further disclosure needed to show utility.
[90]
The
’191 patent at page 3 states a particle size and range. As previously
discussed, this is the expected result that would be achieved by a person
skilled in the art, even an undergraduate:
The mean particle size of the
compounds of formula I, as set out by the invention, is less than about 25
microns, preferably between 5 and about 20 microns. Further, the invention
encompasses formula I compounds with at least 90% of the particles having a
particle size of less than about 50 microns, preferably less than about 35
microns. More preferably, the mean particle size range is between about 5 and
about 20 microns, with at least 90% of the particles having a size of less than
about 35 microns.
[91]
The
’191 patent describes a number of tests conducted which, the Applicant states,
led to a surprising conclusion, namely, that within the range determined for
particle size there is surprisingly consistent in vivo
absorption/bioavailability characteristics. At page 18 the ’191 patent says:
As with the previous set of
particle size distribution, the comparable dissolution profiles obtained with
these particle size distributions support the range of particle size given in
this invention. Given the relationship shown between in vitro dissolution and
in vivo absorption, it follows that the particle size distribution range
claimed in this patent will provide surprisingly consistent in vivo
absorption/bioavailability characteristics.
[92]
In
other words, the Applicant is saying that while the optimization of the range
of particle size may have been routine work within the skill of a person
skilled in the art, it lead to surprising results, namely that, within that
range the in vivo absorption/bioavailability characteristics of the
raloxifene hydrochloride was surprisingly consistent. Thus, within the range,
large particles or small, the in vivo absorption/bioavailability of the
compound would be about the same. That, says the Applicant, is the inventive
concept.
[93]
Novopharm
attacks the validity of the claims on two basis:
1. Obviousness –
that is, a person skilled in the art would have known to optimize particle size
range
2. Utility – if
one says that the inventive concept is that within the particle size range
there is surprising in vivo absorption/bioavailability consistency, then
one has not demonstrated that by the data provided in the patent nor could this
have been soundly predicted as of October 1997 based on the data which is
presented.
[94]
These
arguments are interrelated. I will turn first to the obviousness.
OBVIOUSNESS
[95]
The
Supreme Court of Canada has recently, in Apotex Inc. v. Sanofi-Synthelabo
Canada Inc., 2008 SCC 61 provided a review and restatement of the law as to
obviousness in Canada. The Federal Court of Appeal carried the matter further
in Apotex Inc. v. Pfizer Canada Inv., 2009 FCA 8. In Sanofi
Rothstein J. for the Court endorsed the English “restated” Windsurfing
test as a proper approach to obviousness. At paragraph 67 he wrote:
67 It will be useful in an
obviousness inquiry to follow the four-step approach first outlined by Oliver L.J.
in Windsurfing International Inc. v. Tabur Marine (Great Britain) Ltd., [1985]
R.P.C. 59 (C.A.). This approach should bring better structure to the
obviousness inquiry and more objectivity and clarity to the analysis. The Windsurfing
approach was recently updated by Jacob L.J. in Pozzoli SPA v. BDMO SA, [2007]
F.S.R. 37, [2007] EWCA Civ 588, at para. 23:
In the
result I would restate the Windsurfing questions thus:
(1)
(a) Identify the notional "person skilled in the art";
(b)
Identify the relevant common general knowledge of that person;
(2)
Identify the inventive concept of the claim in question or if that cannot
readily be done, construe it;
(3)
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;
(4)
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? [Emphasis
added.]
It will be
at the fourth step of the Windsurfing/Pozzoli approach to obviousness that the
issue of "obvious to try" will arise.
[96]
If
we look at the ’191 patent with the aid of these criteria it can be seen that
while optimization of particle size range would have been a known task, which
could be accomplished routinely by a person skilled in the art, the result, as
stated in the patent, as being consistent in vivo
absorption/bioavailability characteristics, was according to the patent,
surprising.
[97]
There
is ample law to support the proposition that new compositions that could be
arrived at by a person skilled in the art are not in themselves inventive.
However if they are found to possess unexpected utility, then they could be
elevated to the status of an invention. I quote from Thurlow J. (as he then
was) in Société des Usines Chimiques Rhone-Poulenc v. Jules R. Gilbert Ltd. (1968),
55 C.P.R. 207 (ExQ), aff’d [1968] S.C.R. 950, at page 227:
The invention as claimed in
claim 18 is one for a process which includes the reacting of certain known
chemical substances with certain other known chemical substances in a
well-known type of chemical reaction for the purpose of producing a result
which any skilled chemist would have expected. All this is admitted…and from
it it follows, notwithstanding the further fact that no one had previously
carried out the reaction using the particular starting substances, that there
could have been no invention in the process unless it has been found to produce
substances possessing utility which on the basis of previous knowledge could
not have been expected from them. As mere new chemical substances they would
not constitute inventions unless they were found to possess unexpected utility
but if they were found to possess such utility, for example, as drugs or as
paints or dyes, or for any practical purpose, they might both constitute
inventions of new and useful substances and at the same time supply the utility
necessary to elevate the well-known method as applied to the materials that
would produce them to the status of an invention as well. This, as I
understand, is the effect of the reasoning of Jenkins, J., in Re May &
Baker Ltd. and Ciba Ltd. (1948), 65 R.P.C. 255, which was adopted and approved
by the Supreme Court of Canada in Commissioner of Patents v.
Ciba Ltd., 30 C.P.R. 135, 19 Fox Pat. C. 18, 18 D.L.R. (2d) 375, [1959] S.C.R.
378.
[98]
Thus,
as long as the requirement of utility is satisfied, the subject matter of the
claim can be said to be inventive. For this reason I must pass on to the
allegation as to lack of utility.
UTILITY
[99]
The
Patent Act, section 2 in defining an “invention” requires that the
invention be “new and useful”. As stated by Thorson P. in Minerals
Separation North American Corp. v. Noranda Mines Ltd. [1947] Ex.C.R. 306 at
page 317, there is a requirement that the description of the patent set out all
the information known to the inventor, without leaving the matter to chance, so
as to enable the invention to be put into practice:
The description must also give
all information that is necessary for successful operation or use of the
invention, without leaving such result to the chance of successful experiment,
and if warnings are required in order to avert failure such warnings must be
given. Moreover, the inventor must act uberrima fide and give all information
known to him that will enable the invention to be carried out to its best
effect as contemplated by him.
[100] It is clear
that unexpected utility can support an otherwise obvious invention. However
that utility must be clearly stated in the description. Merely to state that
there are advantages is insufficient. I reviewed this law in Eli Lilly
Canada Inc. v. Novopharm Ltd., [2008] 2 F.C.R. 749 (appeal dismissed for
mootness [2008] 3 F.C.R. 449, leave to appeal to Supreme Court of Canada
refused) at paragraphs 135 and 136:
135 The invention thus lies
in the determination that a compound that lies within a previously disclosed
class of compounds and which possesses a previously undisclosed advantage, an
advantage that "cannot be predicted with any confidence," one that a
person skilled in the art would not "expect to find in a large number of
the previously defined class" can be the subject of a valid patent. That
"advantage" was stated by the Federal Court of Appeal in Pfizer
Canada Inc. v. Canada (Minister of Health), [2007] 2 F.C.R. 137, at paragraph 31 to include a
disadvantage to be avoided:
To meet
the statutory requirement in subsection 34(1) of the Patent Act, R.S.C., 1985,
c. P-4 (old Act) that a patent be "useful", the selected species must
have an advantage over the [page809] class as a whole (see Consolboard Inc. v.
MacMillan Bloedel (Sask.) [Ltd.], [1981] 1 S.C.R. 504, at pages 525-526), That case broadly
defined the utility required for valid patent as discussed in Halsbury's Laws
of England (3rd ed.), Vol. 29, at page 59:
... it is
sufficient utility to support a patent that the invention gives either a new
article, or a better article or a cheaper article, or affords the public a
useful choice.
However,
there are no special legal requirements regarding what particular type of
advantage is required. The test for advantage is understood to include a
disadvantage to be avoided, as is the case here (see I.G. Farbenindustrie at
page 322).
136 The advantage, however,
must be stated in the specification. A patentee cannot merely state that the
selected compound or group has advantages. The patentee must state clearly what
the invention is, namely the specific advantages; as Maugham J. said at pages
321 and 323 of In re I.G. Farbenindustrie A.G.'s Patents (1930), 47 R.P.C. 239
(Ch. D.) case referred to by the Federal Court of Appeal in Sanofi-Synthelabo
Canada Inc. v. Apotex Inc. (2006), 282 D.L.R. (4th) 179. In the matter of Farbenindustrie,
Maugham J. states at pages 322 and 323:
It is
clear, for example, that mere verification is not invention. (See Sharpe &
Dohme Inc. v. Boots Pure Drug Co. Ld., (1928) 45 R.P.C., 153.) Where the method
of manufacture is laid down in the originating patent, the selection patent
must not be an exact repetition of the same process coupled with a statement of
the properties possessed by the selected bodies. No man can have a patent
merely for ascertaining the properties of a known substance.
...
I must add
a word on the subject of the drafting of the specification of such a patent. It
should be obvious, after what I have said as to the essence of the inventive
step, that it is necessary for the patentee to define in clear terms the nature
of the characteristic which he alleges to be possessed by the selection for
which he claims a monopoly. He has in truth disclosed no invention whatever if
he merely says that the [page810] selected group possesses advantages. Apart
altogether from the question of what is called sufficiency, he must disclose an
invention; he fails to do this in the case of a selection for special
characteristics, if he does not adequately define them. The cautions repeatedly
expressed in the House of Lords as regards ambiguity have, I think, special
weight in relation to selection patents. (Natural Colour etc. Ld. v. Bioschemes
Ld., (1915) 32 R.P.C. 256, at p. 266; and see British Ore etc. Ld. v. Minerals
Separation Ld., (1910) 27 R.P.C. 33, at p. 47.)
[101] In what has
become known as the AZT case, Apotex Inc. v. Wellcome Foundation Ltd.,
[2002] 4 S.C.R. 153 the question of adequacy of disclosure in respect of
utility was canvassed first by the Trial Judge and ultimately by the Supreme
Court of Canada. The principles established by the Supreme Court must,
therefore, be those from which guidance is obtained the Reasons and not of the
Trial Judge. The Supreme Court determined that if there was not a fulsome disclosure
in the patent itself from which a person skilled in the art could conclude that
there was utility, the disclosure could nonetheless be considered to be
adequate for that purpose if a person skilled in the art could “soundly
predict” that there would be utility. Binnie J. in his Reasons for the court
set out three components for sound prediction: first, a factual basis; second
an articulable and sound line of reasoning; and third, proper disclosure. He
said at paragraph 70:
70 The doctrine of sound
prediction has three components. Firstly, as here, there must be a factual
basis for the prediction. In Monsanto and Burton Parsons, the
factual basis was supplied by the tested compounds, but other factual
underpinnings, depending on the nature of the invention, may suffice. Secondly,
the inventor must have at the date of the patent application an articulable and
"sound" line of reasoning from which the desired result can be
inferred from the factual basis. In Monsanto and Burton Parsons, the line
of reasoning was grounded in the known "architecture of chemical
compounds" (Monsanto, at p. 1119), but other lines of reasoning, again
depending on the subject matter, may be legitimate. Thirdly, there must be
proper disclosure. Normally, it is sufficient if the specification provides a
full, clear and exact description of the nature of the invention and the manner
in which it can be practised: H. G. Fox, The Canadian Law and Practice Relating
to Letters Patent for Inventions (4th ed. 1969), at p. 167. It is generally not
necessary for an inventor to provide a theory of why the invention works.
Practical readers merely want to know that it does work and how to work it. In
this sort of case, however, the sound prediction is to some extent the quid pro
quo the applicant offers in exchange for the patent monopoly. Precise
disclosure requirements in this regard do not arise for decision in this case
because both the underlying facts (the test data) and the line of reasoning
(the chain terminator effect) were in fact disclosed, and disclosure in this
respect did not become an issue between the parties. I therefore say no more
about it.
[102] What then is
the disclosure for utility in the ’191 patent which is said to support the
claimed monopoly to particle sizes? Is that disclosure sufficient in itself to
support the claim to utility and, if not, is there enough set out in the
description in the patent so as to enable a sound prediction that all that
which is claimed as to particle size will have the utility?
[103] I return to
page 18 of the ’191 patent which asserts surprising consistency within the
“particle size distribution range”. Looking at the claims, only claim 2
addresses a range of sizes, between 5 and 20 microns. Claims 1 and 3 only
address the maximum size, a mean particle size of less than 25 microns,
at least 90% of which are less than 50 (in claim 3-35) microns.
Novopharm did not allege or argue ambiguity. I will proceed on the basis that
a person skilled in the art would read claims 1 and 3 as defining a range with
reference to what is called a “Gaussian distribution” as illustrated by Dr.
Bugay at paragraph 20 of his affidavit:
[104] Thus the
“range” of claims 1 and 3, in the absence of an allegation from Novopharm as to
vagueness or ambiguity can be said to be that which is reasonably established
by the Gaussian distribution.
[105] What
information then is disclosed in the ’191 patent to establish that within the
range there is surprising consistency respecting in vivo
absorption/bioavailability?
[106] The only
pertinent data respecting in vivo absorption/bioavailability in the ’191
patent is that set out in Tables 4 to 6 together with the discussion at pages
12 to 15. In these Tables and the discussion only two samples are
investigated. One, Lot 5A, is well outside the claimed range, a mean particle
size of 48.1 microns (vs. 25 microns) and 90% under 90 microns (vs. 50
microns). The other, Lot 5B is within, a mean particle sizes of 9.0
microns (vs. 25 microns) and 90% under 15.1 microns (vs. 50 microns). One, Lot
5A is well outside the range, the other, Lot 5B, is well inside.
[107] A single
point cannot define a range. There is no data at or near the limits of the
range nor is there provided data as to a number of points within the stated
range so as to establish that in the range there is surprising consistency. A
single point within the range does not demonstrate consistency throughout the
range.
[108] Therefore the
question becomes whether there is sufficient information provided in the ’191
patent to enable a person skilled in the art to “soundly predict” consistency
within the range. Novopharm’s expert, Dr. Kanfer at paragraphs 82-95 of his
affidavit, sets out that there is no basis for “sound prediction” set out in
the ’191 patent. His opinions were not shaken on cross-examination. The
Applicant’s expert Dr. Williams does not clearly address in his affidavit
whether the patent contains sufficient description so as to enable consistency
within the range to be soundly predicted. I have carefully reviewed Dr.
Williams’ cross-examination transcript, particularly at pages 37 to 69 and I
find that he cannot provide any basis for which a sound prediction could be
made; instead it appears to be unsure and perhaps even confused in respect of
this matter.
[109] As a result,
I find that the claims 1, 2 and 3, hence 4 to 8 also in the ’191 patent are
invalid in that the description contained in the patent fails to establish that
the claimed particle size range has the promised utility, namely consistent in
vivo absorption/bioavailability. Novopharm’s allegation as to invalidity
for lack of utility is justified.
IN SUMMARY
[110] In summary, I
have found that, on a balance of probabilities, Novopharm’s allegation as to
non-infringement is justified. I have further found that Novopharm’s
allegation as to invalidity of the claims of the ’191 patent is justified on
the basis that the utility of the promised invention, in vivo
consistency of absorption/bioavailability, within the claimed particle size
range has not been described and could not have been soundly predicted based on
what was described. The application is therefore dismissed with costs to
Novopharm.
COSTS
[111] Novopharm is
the successful party. It is entitled to its costs which may be taxed, as is
usual in these cases, at the middle of Column IV.
[112] Costs for two
counsel, one senior, one junior, at the hearing may be taxed. Two counsel, if
present, one senior, one junior, in conducting cross-examination, may be
taxed. Only one counsel, a senior, is allowed in defending a
cross-examination. No costs are allowed for other lawyers, in house or out
house, students, paralegals or clerical persons.
[113] As in
previous cases of this kind, I remain concerned that fees allowed for experts
may be excessive. Here Novopharm may tax the fees of Drs. Kanfer and Biggs and
may tax the reasonable costs of the experiments conducted by Dalton that were
disclosed in the Zhao affidavits. Those fees shall not be disproportionately
large having regard to fees charged to the Applicant by its witnesses Drs.
Williams and Bugay or in the testing conducted by PTL. I may be spoken to
should a dispute arise in this regard however I expert that counsel can resolve
a quantum among themselves. Nothing is allowed for any other expert or other
person who may have assisted Novopharm or its witnesses.
"Roger
T. Hughes"
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