Date: 20051017
Docket: T‑1937‑03
Citation: 2005 FC
1421
Ottawa,
Ontario, this 17th day of
October, 2005
Present: The Honourable Mr. Justice Richard G. Mosley
BETWEEN:
PFIZER CANADA INC.
and PFIZER INC.
Applicants
and
APOTEX INC.
and THE MINISTER OF HEALTH
Respondents
REASONS FOR ORDER AND ORDER
[1] This application by Pfizer Canada Inc. and Pfizer Inc.
(hereafter collectively "Pfizer") under section 6 of the Patented
Medicines (Notice of Compliance) Regulations, SOR/93-133, as amended by
SOR/98‑166 and SOR/99‑379, is for an order of prohibition against
the Minister of Health to prevent the issuance of a notice of compliance to Apotex
Inc. ("Apotex") until after the expiry of Canadian Letters Patent
2,148,071. The application is in response to a notice of allegation made by Apotex
in a letter dated August 29, 2003. Pfizer’s notice of application was served on
the Minister on October, 17, 2003.
Background
[2] The
application addresses Apotex’ submission for a notice of compliance with
respect to its apo‑azithromycin tablets. Pfizer’s azithromycin tablets
are marketed in North
America under
the brand name ZITHROMAX. Apotex proposes to market tablets for oral
administration comprising azithromycin isopropanolate monohydrate in a strength
equivalent to 250 mg azithromycin. The ZITHROMAX formulation is azithromycin dihydrate.
[3] There
is nothing novel about azithromycin itself. It was invented in the early 1980's
in Europe and has long been approved for use in Canada. Azithromycin is the first macrolide antibiotic of the azalide
group. Other macrolides include erythromycin, from which azithromycin was
derived, and clarithromycin. Azithromycin is commonly used in the treatment of
upper and lower respiratory infections, pneumonia, strep throat, and
genitourinary infections such as chlamydia.
[4] Azithromycin
has unique properties that make it a valuable instrument in treating microbial
infections. While it has low oral bioavailability (absorption of the drug into
the bloodstream for therapeutic effect) producing low blood serum
concentrations, azithromycin goes directly to the site of the infection, has a
long half‑life and does not need to be administered
as
long or as often as other antibiotics. In contrast to erythromycin, it is acid stable,
has decreased gastrointestinal tolerance and increased absorption capability.
[5] ZITHROMAX
was initially marketed in North America in a capsule dosage form, beginning in
the early 1990's. Tablets were not approved. It appears to have been available
also in suspension form, at least to researchers, and to have been prescribed
by physicians in tablet, powder and suspension forms in Europe. In the capsule form, the
oral bioavailability of azithromycin was found to be adversely affected by the
presence of food in the patient’s system. For that reason, ZITHROMAX product labelling
required that the capsules should be taken at least one hour before or two
hours after a meal. Compliance with the dosage instructions presented
difficulties for some patients, particularly the young. Failure to follow them
reduced the therapeutic effectiveness of the drug.
[6] Conducting
research into the other dosage forms, Pfizer scientists found that azithromycin
in tablets, powders or suspensions, could be taken with food without losing
approximately 50% of its bioavailability. Pfizer sought protection for this
claimed discovery. A patent application was filed in Canada on April 27, 1995 and the
‘071 patent was issued on October 17, 2000. The priority date, based on the U.S. filing, is April 29, 1994.
[7] The
‘071 Patent has 33 claims. Certain of the claims are limited to tablets made by
wet granulation, a formulation Apotex says it does not use. Others are limited
to dosages in the form of powders for oral suspension, or unit doses in packets
or sachets, which again Apotex says it does not employ. The claims are set out
in full in the attached Annex "A".
[8]
The parties are agreed that the only claim at issue in this litigation is
number 23 which reads:
Use of a therapeutically effective
amount of azithromycin for the preparation of a pharmaceutical dosage form
which does not exhibit an adverse food effect for administration, in the
treatment of an antimicrobial infection, to a patient that has eaten.
[9] Apotex
asserts in its notice of allegations and detailed statement that its product,
Apo‑azithromycin, won’t infringe this claim because 1) its tablets are
made in accordance with the prior art and thus satisfy the defence set out in Gillette
Safety Razor Company v. Anglo‑American Trading Company Ltd., (1913)
R.P.C. 465; and 2), that if claim 23 is found to be valid and to cover its
tablets, they undertake not to market them as intended for administration to a
patient that has eaten.
[10] Apotex
further alleges that the invention claimed in the ‘071 Patent is obvious,
anticipated, a method of treatment claim, ambiguous, overbroad, lacking in
utility, and improperly on the patent register. Consequently, Apotex asks that
I find that the ‘071 patent is invalid, that it is improperly listed on the
register (either in addition to or alternatively to its invalidity), and that
there is no bar to the Minister issuing a notice of compliance in respect of
its apo‑azithromycin product.
Onus
and Burden of Proof
[11] As
recently reiterated by the Federal Court of Appeal in Pfizer Canada Inc v. Novopharm
Limited [2005] F.C.J. No. 1318, 2005 FCA 270 at paragraph 20, Apotex has no
evidentiary burden to support the allegations in its notice of allegations and
detailed statement.
[12] The
legal burden in these proceedings is on Pfizer to prove, on a balance of
probabilities, that the allegations in Apotex’ notice were not justified; AB
Hassle v.Canada (Minister of National Health and Welfare (2002), 22 C.P.R.
(4th) 1, 2002 FCA 421 at paragraph 35 (AB Hassle 2) .
[13] In
establishing that the allegations of invalidity are not justified, Pfizer is
entitled to rely upon the statutory presumption of validity found in subsection
43(2) of the Patent Act R.S.C. 1985, c. P-4; Eli Lilly and Co. v. Apotex
Inc. (1995), 60 C.P.R. (3d) 206 at 216 91 F.T.R. 181 at 216 (F.C.T.D.), aff’d
(1996), 66 C.P.R. (3d) 329, 195 N.R. 378 (F.C.A.); Bayer Inc. v. Canada
(Minister of National Health and Welfare) (2000), 6 C.P.R. (4th) 285, N.R.
238 (F.C.A.). Apotex has the evidentiary burden, on a balance of probabilities,
to prove that the patent is invalid; Procter & Gamble Pharmaceuticals
Canada Inc. v. Canada (Minister of Health) [2005] 2 F.C.R.269, 2004 FCA
393. If the allegations are not justified, the prohibition order is granted.
The
Evidence
Pfizer’s
principal witnesses
[14] Dr.
Robert A. Rapp is a Professor of Pharmacy and Professor of Surgery at the
University of Kentucky Colleges of Pharmacy and Surgery. He was tendered as an
expert witness to provide opinion evidence as a person skilled in the art of
clinical pharmacy. Dr. Rapp has experience in studying azithromycin in a
clinical context, and has published papers related to its therapeutic
applications. He is also familiar with food‑drug interactions and co‑authored
his university hospital’s food‑drug interaction guidelines. He has no
direct experience in pharmaceutical formulation but has served as an advisor to
drug companies particularly Pfizer.
[15] His
opinion is that the subject matter of claim 23 was neither anticipated nor
obvious based on the general state of the knowledge among clinicians and
researchers as of the priority date. In Dr. Rapp’s view the knowledge shared by
most persons skilled in the art was that azithromycin in any dosage form
exhibited a food effect. Consequently, the fact that it did not in tablets and
suspensions was a surprising result.
[16] Dr.
Vincent Andriole is a specialist in internal medicine and infectious
diseases and Professor of Medicine at Yale University, New
Haven, Connecticut.
He has been the editor, served on the editorial boards, and acted as a reviewer
for a large number of medical journals. He has also served on many advisory
committees for pharmaceutical companies, including one related to azithromycin
for Pfizer from 1989 until the early 1990s. Dr. Andriole provided opinion
evidence on a fairly narrow question regarding the construction of claim 23.
That is whether it suffers from overbreadth because, on its face, the claim is
not limited to tablets but to all formulations of azithromycin that can be
taken with food.
[17] Madelaine
Pesant is an employee of Pfizer Canada and attaches to her affidavit
documents related to the litigation, with a view to establishing that the ‘071
patent is properly listed on the register in connection with the 250 and 500 mg
tablets. She also attests to the commercial success of the ZITHROMAX 250 mg
tablets. She was not cross‑examined on her affidavit but was asked to
respond to written interrogatories.
Apotex’s
principal witnesses
[18] Dr.
Robert S. Langer is a Professor of Chemical and Biomedical Engineering at
MIT, the Department of Chemical Engineering, Whitaker College of Health
Sciences, Technology and Management, and the Harvard‑MIT Division of
Health Sciences and Technology. He is tendered as an expert in pharmaceutics
and pharmaceutical formulation technology. He has been awarded a great number
of honours including many of the highest awards in medicine, such as the
highest Canadian prize in that field. He has published over 700 articles and is
a named inventor of hundreds of patents.
[19] In
Dr. Langer’s opinion, the Apotex azithromycin tablets made by non‑wet
granulation will not infringe the ‘071 claims. He attests that the azithromycin
tablets made by Apotex are in accordance with the prior art and will not
infringe because of the Gillette defence. Even if claim 23 is valid, the
tablets will not be identified as administrable to a patient who has eaten. He
also supports Apotex’ position that the ‘071 patent is anticipated and that it
was also obvious in light of the state of the knowledge in 1994. He also
believes that claim 23 is ambiguous, overbroad, and lacks utility.
[20] Professor
Jonathan S. Dordick is a Professor of Chemical and Biological Engineering
at Rensselaer Polytechnic Institute in Troy, New York. He has conducted research on the delivery of drugs in the body,
serves as a consultant to numerous companies in the pharmaceutical and chemical
industries and is tendered as an expert in pharmaceutical formulations,
biosynthetic chemistry and bioanalytical chemistry.
[21] Dr.
Dordick states the opinion that claim 23 is anticipated by the prior art
because formulations prepared according to the prior art meet the requirements
of claim 23. He discusses dissolution tests and asserts that the formulations
tested were anticipated by several north american and european patents. He
refers in particular to the Canadian 2,101, 466 patent (the ‘466 or Catania
patent) which taught the use of azithromycin in a taste‑masked form by
grinding up a tablet or using a powder to sprinkle on food. He thinks that the
‘071 patent was obvious as well, in light of the ‘466 patent.
[22] Dr.
Michael Mayersohn is Professor of Pharmaceutical Sciences in the College of Pharmacy at the
University of Arizonan and a former member of the Pharmaceutical Sciences
Advisory Committee to the US Federal Drug Administration. Dr. Mayersohn has
prior but not recent experience as a pharmacist advising patients. He is
tendered as an expert in pharmacokinetics, biopharmaceutics and pharmaceutics.
[23] Dr.
Mayersohn also reviewed the results of dissolution tests. He concludes that the
‘071 patent is anticipated, so does not deal with any of the other allegations.
In his view, formulations disclosed in prior art patents anticipate the very
same rapid dissolution formulations that are described in the ‘071 patent. He
is also of the opinion that the ‘466 patent discloses the taking of azithromycin
with food.
[24] Dr.
Eli Shefter is a Doctor of Pharmaceutics and Professor of Pharmacy at the University of Colorado and Adjunct
Professor at the University of California at San Diego. He is the Chief Scientific
Director for IriSys Research and Development LLC and also works as a consultant
to pharmaceutical and biotech companies on matters pertaining to formulation,
stability and regulatory issues. He too was a consultant to the FDA for over
five years and also served on the USP Committee of Experts. He has experience
in formulating antimicrobial dosage forms. Dr. Shefter’s evidence was similar
to that of Dr. Mayersohn.
[25] Stephen
Levine is a formulation scientist at Emerson Pharma Services. He prepared
three formulations based on the US
4,963,531 (Remington) patent for azithromycin suspension
and
two weights of tablets. He contracted an analytical laboratory (Chemir Pharma
Services) to conduct dissolution tests (as described in the ‘071 patent)
comparing the formulations. The tests showed that for each dosage form, at
least 90% of the azithromycin dissolved within 30 minutes and also within 15
minutes. He includes as Exhibit 4 the results of the tests. Lev Fridman
is the employee of Chemir Pharma Services who conducted the dissolution tests.
He also attaches the results of the tests. He attests that the instructions he
followed were the same as those in the ‘071 patent. Neither Mr. Levine nor Mr.
Fridman were cross‑examined.
[26]
Pfizer’s experts, Dr’s Rapp and Andriole, have expertise in the clinical
applications of drugs such as azithromycin and both were involved in its
development in a consultative capacity.They do not have expertise in drug
formulation. Pfizer submits that their evidence, as that of a practising
pharmacist and physician with direct experience with the drug should be given
greater weight than that of the Apotex witnesses. Apotex claims, in turn, that
the opinions of pharmaceutical scientists such as Dr. Mayersohn and drug
formulation experts such as Drs Langer and Dordick should be preferred over
that of clinicians, however eminent they may be.
[27] While
all of the experts tendered by the parties in this case have impressive
qualifications, I do have reservations about Dr. Rapp’s evidence. It is clear
from his evidence that, despite his long experience with the therapeutic
applications of azithromycin, he did not become fully aware of the revised
dosing instructions until he was instructed for this litigation in 2003. His
university’s drug interaction guidelines, of which he is co‑author, did
not reflect the change until that year. As stated by Justice Binnie in Camco
Inc.et al v. Whirlpool Corp.et al,
[2000]
2 S.C.R. 1067, (2000) 9 C.P.R. (4th) 129 at paragraph 74 [Camco],,
the skilled worker is thought to be reasonably diligent in keeping up with
advances in the field to which the patent relates. It is open to question how
diligent Dr. Rapp was in keeping up with advances in the field.
[28] On
cross‑examination, it emerged that Dr. Rapp has significant ties to
Pfizer, including owning stock in the company, doing promotional talks for it,
serving on consulting boards and receiving research grants that, indirectly at
least, contribute to the level of compensation he receives from the university.
He stated that this is typical of those in his position, at least at his
university. While that may be the case, in my view such close links to one of
the parties compromises the independence expected of a witness tendered as an
expert by that party in litigation. I have also concluded from reviewing his
cross‑examination that Dr. Rapp seemed defensive and appeared to cross
the line at times from independent expert to advocate for the Pfizer position.
[29] I
had no difficulty with the manner in which Dr. Andriole and the Apotex experts
provided their evidence. While Pfizer counsel took me to several portions of the
transcript of Dr. Langer’s cross‑examination where he stated a lack of
knowledge or that he would need to review the evidence in question, I was
satisfied that was entirely consistent with what is to be expected from an
independent and objective expert.
[30] Having
carefully reviewed the experts’ affidavits and cross‑examinations, where
there is a conflict between Dr. Rapp’s evidence and that of the Apotex experts,
I generally preferred the latter as appearing to be more thorough, objective
and grounded in the scientific literature.
Issues
[31] At
issue in these proceedings is whether the Court should grant an order
prohibiting the Minister from issuing a notice of compliance to Apotex. That
requires a determination of whether the allegations of invalidity and non‑infringement
set out in Apotex’ notice of allegation and detailed statement are justified.
Following construction of the claim at issue, the specific questions I will
address are whether the ‘071 Patent is invalid on the grounds that the invention
claimed was anticipated or obvious by reason of the prior art, whether claim 23
is ambiguous or overbroad, whether the claimed invention is not properly the
subject of a patent and, as further alleged by the respondent, whether the
patent was improperly listed and whether the Apotex product will not infringe.
Claim
Construction
[32] The
first step before addressing the issues is to construe the claims through eyes
educated by a person or persons skilled in the art. In conducting my analysis,
I have had regard to the principles enunciated by the Supreme Court of Canada
decisions in Free World Trust v. Électro-Santé Inc., [2000] 2 S.C.R.
1024, 2000 SCC 66 [ Free World Trust] and Camco, supra.
[33] The
object of claim construction is to fairly and reasonably define the purpose of
the invention. The assistance of experts may be necessary, but is not
determinative. I am not bound by the suggested constructions put forward by the
parties or their experts. The words of the claims themselves are to be the focus
of the analysis: Novartis Pharmaceuticals Canada Inc. v. RhoxalPharma Inc. (2005)
38 C.P.R. (4th) 193, 2005 FCA 11 at para. 45, 53.
[34] As
noted above, Claim 23 is the contentious portion of the ‘071 patent. It reads
as follows:
Use of a therapeutically effective
amount of azithromycin for the preparation of a pharmaceutical dosage form
which does not exhibit an adverse food effect for administration, in the
treatment of an antimicrobial infection, to a patient that has eaten.
[35] Claims
1‑22 are claims to dosage forms, that is tablets, powders for oral
suspension and unit dose packets. Claims 24 to 27 are formulation claims for
specific tablets. Claims 28 and 32 are a therapeutic package claim. Claims 29‑31
refer to powders, 32 to a unit dose packet. The claims are set out in full in
Annex "A" to these reasons.
[36] There
is some common ground between the parties as to the appropriate construction of
Claim 23. For instance, they agree that the reference to
"antimicrobial" infections is simply a typographical error and is of
no moment. Clearly, the intended wording was "microbial". There is
also no serious argument about the meaning of the words "a patient that
has eaten." These words are understood by the skilled person to be a
patient who has eaten in the hour prior to taking the dose of oral azithromycin
or who will eat in the two hours following taking that dose. There is also
general agreement that none of the dosage forms contain a significant amount of
an alkaline earth oxide or hydroxide (referred to in the claims), and, finally,
that capsules are excluded from the claim.
[37] I
interpret the words "a therapeutically effective amount of azithromycin"
in claim 23 to mean simply, as several of the experts suggested, "enough
of the drug to treat the infection". Nothing of importance in these
proceedings turns on this in my view.
[38] Pfizer’s
position is that claim 23 is a "use to treat" claim. Pfizer’s reading
emphasises the following parts of the claim:
Use of a therapeutically effective
amount of azithromycin for the preparation of a pharmaceutical dosage
form which does not exhibit an adverse food effect for administration, in
the treatment of an antimicrobial infection, to a patient that has eaten.
[Emphasis added]
[39] In
other words, Pfizer’s position is that the claim is for a new use of azithromycin
(in particular dosage forms) in a particular manner – the treatment of
microbial infections in a patient who has eaten. In its submission, the
essential elements in claim 23 are:
(I) the
oral administration of a dosage form of azithromycin;
(ii) to
treat a microbial infection;
(iii) where the oral
dosage form does not exhibit an adverse food effect in a patient who has eaten.
[40] Apotex
criticises this reading of claim 23 because it says it ignores a large part of
the language of the claim. Apotex emphasises the importance of the words
underlined below:
Use of a therapeutically effective
amount of azithromycin for the preparation of a pharmaceutical dosage form which
does not exhibit an adverse food effect for administration, in the
treatment of an antimicrobial infection, to a patient that has eaten.
[41] The
words regarding the preparation of the dosage form should not have been
included if their meaning was simply going to be ignored, Apotex contends.
Experts cannot read in words, and neither should they be able to read them out
of a claim: GlaxoSmithKline Inc. v. Canada (Attorney General) (2005) 40 C.P.R.(4th) 93, 2005
FCA 197 at paragraph 13.
[42] Apotex’s
position on claim construction, therefore, is that the emphasis in construing
the essential elements of claim 23 must be placed on the formulation of azithromycin
dosage forms (that can then be used in a particular way) rather than for the
use of the dosage form itself.
[43] Apotex
finds support for this position in the terms of claim 27:
A tablet as defined in any one of
claims 22 to 26, which is coated with a film of hydroxypropylmethylcellulose, hydroxypropylcellulose
or acrylate‑methacrylate copolymer.
If claim 23 defines a tablet (rather than the use of a tablet), as
suggested by claim 27, this gives some support to Apotex’s theory that claim 23
is a formulation claim. However, I do not find this to be conclusive.
[44] Pfizer
submits that the experts also read claim 23 as a use to treat claim. Its
witness, Dr. Rapp, deposes that a person skilled in the art would understand
that the invention described in claim 23 is to administer a pharmaceutical form
of azithromycin to a patient who has eaten in a way to overcome the adverse
food effect observed with capsules. Dr. Andriole provided a similar opinion.
[45] Pfizer
also finds support for its interpretation in the evidence of Apotex’
witnesses. In Dr. Dordick’s affidavit, at paragraph 40, he states that the key
issue in respect of Claim 23 is "...the use of an azithromycin
formulation which does not exhibit an adverse food effect and administration of
such to a mammal that has eaten" (emphasis added). Further, at paragraph
41 where he breaks down the elements of claim 23 for an anticipation analysis,
his description is similar to that urged on the court by Pfizer.
[46] While
Dr. Mayersohn initially stated that one of ordinary skill in the art would have
no way of interpreting what was disclosed in claim 23, the scope of the claim
or the invention that it reflects, he agreed on cross‑examination that
one aspect disclosed was a method of treating a microbial infection.
[47] On
the other hand, Pfizer’ s witness Dr. Andriole, at paragraph 47 of his
affidavit, seems to have agreed with Apotex’ position in stating that
"...what was claimed in claim 23 is the use of ‘pharmaceutical
formulations’ ..." Dr. Rapp also, at paragraph 61 of his affidavit, seems
to put the emphasis in construing claim 23 on the making of the dosage form.
[48] Dr.
Langer, Apotex’ expert pharmaceutical chemist, was clear in his evidence at
paragraphs 11 and 64 that he reads claim 23 as claiming the use of azithromycin
in pharmaceutical dosage forms that do not exhibit an adverse food effect upon
administration to fed patients.
[49] Notwithstanding
the assistance of the experts, I do not find that the correct reading of claim
23 is plain on its face, as argued by both Pfizer and Apotex. A purposive
construction thus requires that it be interpreted in light of the whole of the
disclosure: Schmeiser v.Monsanto Canada Inc., [2004] 1 S.C.R. 902, 2004
SCC 34 at paragraph 18.
[50]
The title of the Patent is "Method of Administering Azithromycin".
The first paragraph of the disclosure section reads:
This invention relates to a
dosage form of azithromycin, and also to a method of treating a
microbial infection which involves administering azithromycin in the fed state
to a mammal, including a human patient, in need of such treatment. [emphasis
added]
Thus, it is reasonable to expect that the individual claims of the
patent will apply to either the dosage form of azithromycin or the
administration of azithromycin as a method of treatment.
[51] The
"Summary of the Invention" section of the patent disclosure provides
for four aspects of the invention: an oral dosage form of azithromycin that
does not exhibit an adverse food
effect,
specific oral azithromycin dosage forms (i.e., tablets, powders), a method for
treating a microbial infection, and a therapeutic package containing the dosage
forms.
[52] An
oral dosage form that does not exhibit an adverse food effect, paraphrasing the
disclosure, would be one in which there is substantially no inhibition of the
rate at which the azithromycin is absorbed into the blood stream for
therapeutic purposes.
[53] The
inventors assert at page 5 of the patent that they found it surprising that a
dosage form of azithromycin did not exhibit an adverse food effect because,
they state, azithromycin is unstable at low acid levels such as are found in
stomach acid. Apotex argues that this is clearly erroneous as the literature
does not support that conclusion with respect to azithromycin as opposed to
other related azalide antibiotics. Pfizer did not dispute this.
[54] The
inventors further say in the detailed description at page 7 that "[it] is
believed that the dosage forms of the invention do not exhibit a food effect in
large part because they either provide azithromycin ready for dissolution in
the GI tract, essentially immediately following ingestion (suspensions), or
they disintegrate rapidly following ingestion (tablets) and thereby provide azithromycin
rapidly for dissolution."
[55] They
conclude, on page 7, that "[w]hile not wishing to be bound by theory, it
is believed that if an azithromycin dosage form provides azithromycin
immediately following ingestion for dissolution in the GI tract, or at
least...within a certain time period following ingestion, the azithromycin will
be absorbed into the bloodstream at a rate which results in substantially no
adverse food effect."
[56] The
disclosure discusses how the rate of absorption into the blood stream is
measured and how to determine whether there is no food effect. For an adequate
rate of absorption to occur, at least 90% of the azithromycin in the dosage
form should dissolve within 30 minutes of ingestion, preferably within 15
minutes. Rapid dissolution alone, however, is not enough to establish bio‑availability.
There are fast‑dissolving capsule formulations which continue to exhibit
an adverse food effect in testing of the blood samples of human subjects. The
object, according to the disclosure, is to strive for a high degree of
statistical confidence that the mean rate of absorption in the general
population would fall within specified values. The evidence of the expert
witnesses was generally in agreement with this proposition.
[57] An
adverse food effect is said not to exist if the ratio of the areas under the azithromycin
plasma concentration‑time curve in a subject ingesting the drug orally in
the fed state (AUCfed) compared to the fasted state (AUCfast),
AUCfed/AUCfast, is less than 0.8 and the lower 90%
confidence limit for this ratio is not less than 0.75. According to the '071'
patent disclosure, an adverse food effect will not occur as measured in in
vitro dissolution tests if at least 90% of the azithromycin in the dosage
form dissolves within about 30 minutes and, preferably, within about 15
minutes.
[58] The
parameters required for dissolution are set out in claims 1, 3, and 6 for the
different dosage forms as follows:
...the dosage form effecting at
least about 90% dissolution of azithromycin within about 30 minutes when an
amount of the dosage form equivalent to 200 mg of azithromycin is tested as set
forth in USP test <711> in a USP‑2 dissolution apparatus under
conditions at least as stringent as the following: 900 ml sodium phosphate
buffer, pH 6.0, 37oC, with paddles turning at 100 rpm, provided that
the dosage form contains less than a taste‑masking amount of an alkaline
earth metal oxide or hydroxide.
[59] The
inventors state, at page 7 line 9‑10 of the detailed description, that if
a non‑capsule dosage form of azithromycin satisfies the in
vitro dissolution requirements specified, they consider it to fall within
the scope of the claims. Thus you can determine whether a particular non‑capsule
dosage form exhibits an adverse food effect in two ways. Either through
absorption testing or through dissolution testing.
[60] This
conflicts with Dr. Rapp’s evidence, at paragraph 63 of his affidavit, in which
he says that dissolution alone cannot be used to predict food effect. The
patent disclosure is supported by Dr. Shefter’s affidavit in which he states at
paragraph 31 that
It was well established that prior
to 1995 that in vitro dissolution provides a correlation with in vivo
dissolution. In other words, the rate at which a dosage form dissolves in a
dissolution test is a reflection of how that dosage form will perform in the
gastrointestinal tract fluids. The ‘071 Patent was clearly aware that this type
of correlation existed for tablets...
[61] Having
carefully reviewed the whole of the specifications and the evidence of the
expert witnesses, I conclude that the purpose of the invention claimed in the
‘071 patent was to offer a solution to the problem of the adverse food effect
caused by azithromycin capsules. It was not a new use for azithromycin but a
new method of administering azithromycin. The essential elements are:
1. the use of
"enough" azithromycin
2. in
an oral pharmaceutical dosage form, excluding capsules;
3. to treat
microbial infections;
4. in
patients who have eaten;
5. which
does not result in an adverse food effect;
6. as measured within
the parameters of standard scientific tests for dissolution or absorption.
Validity
of the patent
Anticipation
[62] Apotex
alleges anticipation by prior publication and by prior use and sale. As
anticipatory prior art, the notice of allegation cites United States Patents
No. 4, 963,531 (the ‘531 or Remington patent), No.4,474, 768 (the Bright or ‘
768 patent), Canadian Patent No. 2,101,466 (the ‘466 or Catania patent),
European Patent EP‑A‑307128 (equivalent to the ‘531 patent),
excerpts from the Gazetta Ufficiale Della Repubblica Italiana, an
Italian data sheet on ZITHROMAX dated in 1992 and a Spanish invoice for a 250
mg azithromycin formulation dated December 1993.
[63] In
asserting that a patent claim has been anticipated, the argument is that the
invention has already been disclosed to the public and is therefore not novel.
The well‑established approach to anticipation is found in Justice Hugessen’s
decision in Beloit Canada Ltd.,v. Valmet Oy, (1986) 8 C.P.R. (3d)
289, [1986] F.C.J. No. 87 at page 297 [Beloit cited to C.P.R.]:
It will be recalled that anticipation,
or lack of novelty, asserts that the invention has been made known to
the public prior to the relevant time. The inquiry is directed to the very
invention in suit and not, as in the case of obviousness, to the state of the
art and to common general knowledge. Also...anticipation must be found in a
specific patent or other published document; it is not enough to pick bits
and pieces from a variety of prior publications and to meld them together so as
to come up with the claimed invention. One must, in effect, be
able to look at a prior, single publication and find in it all the information
which, for practical purposes, is needed to produce the claimed invention
without the exercise of any inventive skill. The prior publication
must contain so clear a direction that a skilled person reading and
following it would in every case and without possibility of error be led to the
claimed invention. Where, as here, the invention consists of a combination
of several known elements, any publication which does not teach the combination
of all the elements claimed cannot possibly be anticipatory.
[Emphasis added]
[64] This
approach was cited with approval by the Supreme Court of Canada in Free
World Trust, supra at paragraph 26. Justice Binnie, in that decision, also
cautioned against the use of ex post facto deduction in evaluating
whether an invention was anticipated by a particular publication, since
assembling a dossier of prior art with the benefit of hindsight is "all
too easy after an invention has been disclosed" (Free World Trust,
supra at para. 25).
[65] The
priority date for the assessment of anticipation as determined by subsection
28.2 of the Patent Act, is a year before the Canadian filing date, hence
April 27, 1994. Nothing turns on the two day difference between that date and
the date of the US filing, April 29, 1994.
Disclosure
by publication
[66] The
Remington or ‘531 patent, cited as prior art, was issued in 1990 and assigned
to Pfizer. The abstract describes it as a method of use of azithromycin or its
derivatives in the treatment of a microbial infection (toxoplasma gondii). Apotex
argues that two of the examples provided in Remington are of formulations that
fall within the scope of claim 23 of the ‘071 patent as they are identical in
all significant respects to two examples in the ‘071 patent and must therefore,
exhibit the same properties. Further, formulations made by Apotex’ experts
following the two Remington examples were shown to meet the in vitro
dissolution criteria specified in the ‘071 patent.
[67] Apotex
submits that the Remington patent anticipates the ‘071 patent as it teaches and
discloses powders for suspension and fast‑dissolving tablets made using azithromycin
that, upon administration to fed patients, would not exhibit adverse food
effects as defined in the ‘071 patent. This was supported by and addressed at
length by Dr. Langer in his affidavit at paragraphs 77‑81, by Dr. Shefter
at paragraphs 21‑24 to his affidavit, by Dr. Dordick at paragraphs 61 ‑
66 and by Dr. Mayersohn at paragraphs 13‑18.
[68] Shefter
and Langer both agreed on cross‑examination that there is no mention in
Remington that any of these oral dosage forms exhibit an adverse food effect.
Further, there is no discussion of dissolution rates.
[69] The
base azithromycin patent for antibacterial use is the ‘768 patent issued in
1984 to Gene Bright, a Pfizer research scientist. Related to the ‘768 patent,
for the purpose of Apotex’ prior art submission, is a 1989 international patent
application by Allen et al for a new form of azithromycin. The Allen
application, also assigned to Pfizer, incorporates Bright. There is no
restriction in either to the administration of the formulations disclosed with
or without food. However, neither discuss a food effect.
[70] In
his affidavit, Dr. Langer states at paragraph 71 that the inventors of the ‘768
patent (referred to as the ‘071 patent in error) teach the formulation of azithromycin
with pharmaceutically acceptable carriers by conventional methods for the
production of tablets, suspensions and solutions. A person skilled in the art
would understand that to mean, among other things, fast dissolving tablets made
via direct compression, dry or wet granulation containing azithromycin and a disintegrant.
As a result, Langer says, while the ‘768 tablet does not explicitly discuss the
absence of adverse food effects, it teaches the use of azithromycin for the
production of oral dosage forms that include solution, suspension and fast‑dissolving
tablet dosage forms that would not exhibit an adverse food effect when
administered to a fed patient. He reaches a similar conclusion with respect to
the Allen application.
[71] Further
cited as anticipatory prior art is the Canadian ‘466 or Catania patent. Catania has a priority date of July
30, 1992 and a publication date of January 31, 1994. Catania addresses the reduction of
the bitter taste of pharmaceutical compositions, including azithromycin,
through the addition of a taste masking component. Azithromycin, apparently,
has a particularly bitter
flavour.
Catania discusses the use of
chewable tablets or suspension oral dosage forms for azithromycin. It suggests
that the tablets may be ground up, mixed with, placed in or sprinkled on
cereals, ice cream or other food and drinks. Alternatively they may be
swallowed whole without chewing or mixing. The suspension may be mixed with
food and drinks. No concern about an adverse food effect is mentioned. What it
teaches, Apotex submits, is the use of azithromycin in a dosage form to be administered
to a patient who has eaten with no food effect to treat microbial infections.
Precisely one of the alternative constructions for claim 23 of the ‘ 071
patent.
[72] Again,
Apotex relies on the evidence of Drs. Langer, Shefter, Mayersohn and Dordick in
support of this interpretation of Catania. They all say that the formulations being virtually identical in
both Catania and the ‘071 patent, the
results should be identical. The only difference being the inclusion of taste‑masking
agents in the formulations disclosed in the Catania patent. Dr. Langer, at paragraph 99 of his affidavit, says that
in his experience he would not expect those agents to make any difference on
the dissolution behaviour of the dosage forms or the lack of a food effect.
[73] Dr.
Dordick notes first at paragraph 51 of his affidavit that the taste‑masking
agent in Catania would have no effect on
dissolution rates as its purpose is solely to mask the taste in the mouth. He
goes on to say, at paragraphs 57, that it is clear to anyone skilled in the art
of drug formulation, that Catania teaches that azithromycin can be used in
conjunction with food. He concludes at 59 that it is clear that rapidly
dissolvable azithromycin formulations existing as powders for oral suspension
or tablets were known and formed part of the state of the art prior to
the
priority date of the ‘071 patent. Further, because there were teachings
correlating in vitro dissolution to in vivo bio‑availability,
claims in the ‘071 patent directed towards bio‑availability are also
anticipated by the prior art. Finally, because azithromycin could be
administered with solid food, its use as a purported new medical indication was
anticipated by the prior art. Again, there is no specific reference to whether
the dosage forms referenced exhibit an adverse food effect. Dr. Mayersohn
stated on cross that he knew they would not because of the results of the tests
disclosed in the ‘071 patent.
[74] Incidentally,
all of the claims in the ‘071 patent, save for claim 23, exclude a taste‑masking
amount of an oxide. There is no exclusion in claim 23.
[75] Dr.
Rapp, at paragraph 53 of his affidavit, states that it had always been possible
to administer an azithromycin compound that does exhibit a food effect (such as
capsules) with food. He suggests that a person skilled in the art would know to
administer a higher dose because of the food effect. But that is not what Catania teaches. There is no
suggestion in the patent that excessive amounts of the drug be administered to
counter a food effect. On cross‑examination, Dr. Rapp conceded that there
was nothing in Catania to support his hypothesis
(p.1481 of the record) of higher doses.
[76] Apotex
acknowledges that the patents described as prior art for anticipation by
publication in its notice of allegation do not speak of solving the food effect
problem with tablets. But, Apotex argues, the tablets were a known, obvious
alternative to capsules and that the
skilled
person reading and following a cited patent would have gone directly to the
tablets using routine workshop activity and no inventive skill.
[77] Apotex
relies upon SmithKline Beecham Pharma Inc.et al.v. Apotex Inc.et al.,
(2001) 14 C.P.R. (4th) 76 (F.C.T.D.), aff’d (2002) 21 C.P.R.
(4th)129, 2002 FCA 216 in support of this position. In SmithKline, the
patent in suit addressed a problem which resulted from the formulation of paroxetine
tablets by a wet granulation process (they turned pink). Justice Gibson held
that the claimed invention was anticipated by the parent patent which provided
for alternative formulation methods that did not involve water. Thus a logical
first step for a person skilled in the art would be to turn to those
alternative formulations. All the information required to produce the claimed
invention could be found in the prior patent without the aid of inventive
genius but purely mechanical skill.
[78] In
a subsequent decision involving paroxetine, GlaxoSmithKline Inc. v.Apotex
Inc., (2003) 27 C.P.R. (4th) 114, 2003 FCT 687. . Justice Kelen
reached the conclusion, as had Justice Gibson, that the divisional patent at
issue was anticipated by its parent as it was merely an application of one of
the alternatives taught in the parent. It was further invalid for evergreening
or double patenting. That the use of a dry formulation was the solution to the
pink hue problem would be obvious to a skilled formulator.
[79] Pfizer
argues that the ultimate difficulty with any and each of the cited prior art
references, as Apotex witnesses Langer and Shefter conceded on cross‑examination,
is that none
of
them refer to the 90 per cent confidence limit for no food effect set out in
the ‘071 patent disclosure. There is no demonstration that any dosage form of azithromycin
administered to a patient that had eaten food in the three hour window would
not have an adverse food effect.
Disclosure
by sale or use
[80] For
the purpose of analysing anticipation in the context of disclosure by prior
sale or use under paragraph 28.2(1)(a) of the Patent Act, the Federal
Court of Appeal has observed that the Beloit principles may need to be "tailored to fit the particular
circumstances": Baker Petrolite Corp.v. Canwell Enviro‑Industries
Ltd.,(2002) 17 C.P.R. (4th) 478 at 494, 2002 FCA 158. . At paragraph 35 of
Baker, Justice Rothstein notes by way of example that anticipation by
publication involves the skilled person reading the prior art. With
anticipation by sale or use, reading may not be relevant.
[81] At
paragraph 42 of Baker, Justice Rothstein identifies a number of
principles or factors relevant to disclosure by prior sale or use. First is
that sale or use by the public alone is insufficient; there must be disclosure
of the invention. Use makes the invention part of the state of the art only so
far as the necessary information is disclosed. The second principle is that the
prior use or sale must amount to an enabling disclosure such as to allow the
public to make or obtain the invention.
[82] The
third principle identified by Justice Rothstein is that the prior sale or use
of a chemical product will constitute enabling disclosure if its composition or
internal structure can be discovered through analysis of the product. Apotex
contends that this means that if an analysis of the product sold revealed that
it did not have an adverse food effect, that would constitute disclosure by
prior sale or use. But that would be disclosure of the properties or effects of
the chemical, not its composition or internal structure.
[83] The
fourth principle addresses disclosure where reverse engineering is available of
products sold to the public, the sixth says that it is not necessary for any
member of the public to actually analyse the product, the seventh says that the
amount of time and work is not determinative and the eighth, that it is not necessary
that the product be capable of exact reproduction. It is the subject matter of
the patent claims that must be disclosed through analysis.
[84] Apotex
alleges that there was prior disclosure by the sale and use of tablets
containing azithromycin which were publically available before the priority
date. It asserts that the evidence establishes that these formulations, when analysed,
show that they would have no food effect.
[85] The
evidence relied upon by Apotex for this allegation relates primarily to the
sale of azithromycin tablets in Italy. The first evidence tendered in support are extracts from the Gazetta
or Official Journal of the Italian Republic dated May 5, 1992. Reproduced at pages 3199 to 3248 of the
record are translations of pages from the journal containing references to four
products RIBOTREX, ZITHROMAX, AZITROCIN and TREZID relating to 250 mg
capsules, pediatric use powder for oral suspension and 500 mg splittable
tablets of azithromycin dihydrate manufactured by Pfizer Italiana S.p.A. . The
therapeutic indications provided for these products are similar to those
described for the ZITHROMAX product sold in North America.
[86] Apotex
submits that the powder for oral suspension cited in the Gazetta is
essentially the same as referenced in Example 2 of the prior ‘531 patent and
referable to that in Example 6 of the ‘071 patent and tables XII and XIII. The
tablets are virtually identical to Examples 3‑5 of the ‘071 patent. At
page 26 of the ‘071 patent, Table VII, there is a listing of 500 mg tablets
that do not exhibit a food effect. Support for this interpretation of the
formulations described in the Gazetta is found in Dr. Langer’s evidence
at paragraph 42 where he states that such dosage forms, upon routine testing,
meet the dissolution constraints defined in the ‘071 patent. Further he states
at paragraphs 88‑91, that the Gazetta references are essentially
the same with minor non‑material differences. Similar evidence was
provided by Drs Shefter, Dordick and Mayersohn.
[87] Also
tendered in evidence was an extract from an Italian data sheet entitled "GioFil"
which bears the year 1992 and contains information on the composition and
properties of ZITROMAX 500 mg splittable tablets consistent with the Gazetta
references described above. I note that it also contains a warning not to
administer the drug after an "abundant meal" as that would reduce the
bioavailability of azithromycin by 50%.
[88] It
appears from a document, submitted by Apotex, purporting to be an invoice from
a Barcelona pharmacy and reproduced in
translation at page 1917 of the record, that a product described as 250 mg
packets of ZITROMAX was being sold in Spain in December 1993. There is no direct evidence of the nature of
the formulation employed in these packets.
[89] Apotex
sought, over Pfizer’s objections, to rely upon evidence filed in European
opposition proceedings to the equivalent of the ‘071 patent to establish the
composition of the Spanish formulation. As I was not satisfied that the
evidence in those proceedings was properly before the Court, I have given it no
consideration.
[90] However,
Pfizer refused to answer written interrogatories concerning the manufacturing
and marketing of Pfizer branded products in Europe put to its corporate witness
Madeleine Pesant, except to the extent that they related to Canada, on the grounds that they
were not relevant to her affidavit. Apotex submits that the objections were
improper as the questions were within the scope of proper cross‑examination
and the witness could easily have obtained the information from Pfizer Canada
Inc.’ parent company. I am asked to draw the inference that the answers would
have been unfavourable to Pfizer and would have established that Pfizer
manufactured and sold azithromycin tablets and powders in Italy and Spain, in the formulations shown
in the Gazetta pages.
[91] Apotex
submits that support for this proposition can be found in a decision by Justice
Wetson, Pharmacia Inc.v. Canada (Minister of National Health and Welfare),(1995) , 60 C.P.R.
(3d) 328, 92 F.T.R. 253 [Pharmacia cited to C.P.R.] in which he refers
to a common law principle that where the subject matter of an allegation lies
particularly within the knowledge of one of the parties, that party must prove
it. In that case, only the respondent knew the precise composition of their
product. Apotex argues that the same is true here. Only Pfizer knows exactly
what it was manufacturing and selling in Europe prior to 1994. See also Hoffman‑LaRoche Ltd.v.Apotex
Inc., (1983) 41 O.R (2d) 84, 71 C.P.R. (2nd) 20 (Ont.H.C.)at 25, aff’d
(1984) 47 O.R. (2d) 287, 1 C.P.R. (3rd) 507 (Ont. C.A.) and Eli Lilly and Co.
v. Nu‑Pharm Inc, (1996), 69 C.P.R. (3d) 1 at 18, [1997] 1 F.C. 3.
Pfizer submits that the scope of cross‑examination in these PM(NOC)
proceedings is limited and they were not obliged to answer the question.
[92] I
am satisfied that Pfizer could and should have answered the interrogatories as
the information was properly the subject matter of cross‑examination upon
Ms. Pesant’s affidavit and the information could easily have been obtained from
within the Pfizer family of companies. I accept that an inference may be drawn
that is unfavourable to Pfizer respecting the manufacture and sale of azithromycin
products in Europe prior to 1994. However, that doesn’t add much to the case
that Apotex has made through other evidence that Pfizer was selling azithromycin
tablets of an essentially identical formulation to those in the ‘071 patent in
Europe prior to 1994.
[93] The
GioFil document indicates that the 500 splittable tablets were marketed, at
least in Italy, with a warning respecting
reduced bioavailability if taken with a substantial meal. Pfizer contends that
this shows that the invention claimed in the ‘071 patent was not disclosed
through prior use and sale in Europe. Apotex argues that the warnings in themselves don’t establish a
food
effect for tablets. That can only be determined by looking at the tablet
formulations and by testing. Dr. Shefter addressed that point in paragraph 79
of his affidavit in which he attests that whether or not the tablets were sold
with a warning, the tablets themselves do not inherently exhibit a food effect.
Dr. Rapp conceded this in cross‑examination (pages 1312 and 1483 of the
record).
[94] Apotex
has put forward an Italian doctor named Giovanni Donadio who attests that
before April 1994, he prescribed azithromycin by suspension and tablets to
patients without any restrictions or warnings as to whether it was to be taken
on a full or empty stomach. He attests that this was the standard practice
among Italian physicians and that pharmacists distributed azithromycin without
any instructions as that is the domain of physicians in Italy.
[95] Dr.
Donadio was cross‑examined on his affidavit and taken to references which
did not support his understanding. Charitably, the confusion he exhibits in the
cross examination may be attributable to the poor quality of the simultaneous
translation. In sum, his evidence, at best, establishes that medical practitioners
in Italy may not have been aware of
or may have disregarded Pfizer’s instructions that the drug should be taken in
the fasted state for the best effect.
Conclusion
on Anticipation
[96] As
stated in Beloit, supra the test for
anticipation is a very strict one. A patent will be found to be invalid on the
ground of anticipation where there exists a prior disclosure which contains
sufficient information to enable a person of ordinary skill and knowledge in
the art to understand, without access to the patent in issue, the nature of the
invention and to carry it into practical use without the use of inventive
genius but purely by mechanical skill. As stated in Baker, supra,
sale or usage is not enough to satisfy the test for anticipation, there must be
actual disclosure of the nature of the invention.
[97] The
Catania patent comes the closest, in
my view, to establishing anticipation through publication. But to conclude that
the tablets disclosed in that patent do not exhibit a food effect, one has to
have reference to the test results obtained for the dosage forms disclosed in
the ‘071 patent. This was conceded by Apotex’ witness Dr. Mayersohn in cross‑examination.
Thus Catania alone does not lead directly
to the claimed invention. Nor, in the absence of clear undisputed evidence to
satisfy the Baker analysis am I satisfied that anticipation through sale
or use has been established.
[98] Thus,
I am unable to conclude that the ‘071 patent was anticipated. However, the
prior art cited for anticipation is relevant to the question of obviousness and
on that question, I reach a different conclusion.
Obviousness
[99] Section
28.3 of the Patent Act requires that the subject-matter defined by a
claim in an application for a patent in Canada must not have been obvious on the claim date to a person skilled
in the art or science to which it pertains. As noted above, the priority date
for assessing obviousness with respect to the ‘071 Patent is April 29, 1994,
the date of the filing of the U.S.
application.
[100] As
a preliminary matter with respect to this issue, I would note that Pfizer
contended at paragraph 28 of its memorandum of argument that the prior art
relied upon by Apotex for obviousness was not readily accessible to persons of
ordinary skill in the art at the relevant time. This was not pressed by counsel
for Pfizer at the hearing and properly so as it was not raised as an issue by
Pfizer in its Notice of Application. As provided for in Rule 301(e) of the Federal
Court Rules, 1998 an application shall set out a complete statement of the
grounds intended to be argued. As noted by Wetson J., in Pharmacia, supra
at page 339, it also flows from the legal burden on the applicants under
section 6 of the regulations to inform the respondent as to what
"vexes" the patentee so that it may, if necessary, tender evidence in
response.
[101] With
obviousness, the invention need not be disclosed in one single patent or piece
of prior art, as is the case for anticipation. The Court is entitled to look at
all the patents and other publications that a skilled technician would discover
in a "reasonable and diligent search" to determine whether the
resulting "mosaic" leads directly to the invention: Illinois Tool
Works Inc. v. Cobra Fixations Cie. (2002), 221 F.T.R. 161, 2002 FCT 829 aff’
d on this point, varied only with respect to costs: (2003), 312 N.R. 184, 2003
FCA 358. There is no suggestion before me that the prior art cited by Apotex
could not have been found in such a search by such a technician.
[102] The
commonly accepted test for obviousness was also set out in Beloit, supra by Hugessen, J.A. as he then
was, at page 294:
The test for obviousness is not to
ask what competent inventors did or would have done to solve the problem.
Inventors are by definition inventive. The classical touchstone for obviousness
is the technician skilled in the art but having no scintilla of inventiveness
or imagination; a paragon of deduction and dexterity, wholly devoid of
intuition; a triumph of the left hemisphere over the right. The question to
be asked is whether this mythical creature (the man in the Clapham omnibus
of patent law) would, in the light of the state of the art and of common
general knowledge as at the claimed date of invention, have come directly and
without difficulty to the solution taught by the patent. It is a very
difficult test to satisfy.
[Emphasis added]
[103]
In determining whether a patent claim is obvious, the Court must avoid using
the benefit of hindsight. The question to ask is whether the solution taught
by the patent would be "plain as day" to the skilled technician who
was searching for something novel, without having to do experimentation or
research. Suggestions or signposts in the prior art are not sufficient to make
a patent invalid for obviousness: Apotex Inc. v. Wellcome Foundation Ltd. (1998),
79 C.P.R. (3d) 193, 145 F.T.R.161 (F.C.T.D.), varied but not on the issue of
obviousness, [2001] 1 F.C. 495 (C.A.), (2000) 10 C.P.R. (4th) 65 aff’d [2002] 4
S.C.R. 153, 2002 SCC 77, Bayer Aktiengesellschaft v. Apotex Inc.
(1995), 60 C.P.R. (3d) 58, [1995] O.J. No. 141 (Ont. Gen. Div.), varied on
other grounds (1998), 82 C.P.R. (3d) 526, 11 O.A.C. 1 (O.C.A.), leave to
appeal
to the Supreme Court of Canada denied [1998] S.C.C.A. No. 563 (QL) and Fabwerke
Hoechst v. Halocarbon (Ont) Ltd., [1979] 2 S.C.R. 929, 42 C.P.R. (2d) 145.
[104] In
order to address obviousness, one must have some sense of how the claimed
invention represents an advance over the prior art. The azithromycin compound
and function is not claimed in the ‘071 Patent. The structure, function and use
of azithromycin were well known in the art and the specific form of azithromycin
used, azithromycin dihydrate, was covered by a patent dating back to 1984. Also
known was the therapeutically effective amount required to treat humans as an
antimicrobial, that azithromycin had a long half‑life and that less
dosing was required, that azithromycin was acid stable, that it had an
increased absorption capability and decreased gastro‑intestinal
intolerance over erythromycin. The various dosage forms were all known. None of
this was disputed in these proceedings.
[105] What
is disputed is the scope of the knowledge about adverse food effects. Apotex
submits that taking all that was known about the drug, what was known about
avoiding adverse food effects, what was known about azithromycin dosage forms
already made and used and the knowledge that other closely related macrolides
such as clarithromycin were being administered in tablet form with no food
effect, the result claimed in the patent was obvious.
[106] Pfizer’s
expert Dr. Rapp deposed that as a person skilled in the arts of medicine and
pharmacology his understanding of the state of the art prior to publication of
the invention claimed in the ‘071 patent was that azithromycin exhibited a food
effect. Accordingly, Pfizer contends that the discovery that azithromycin could
be administered in tablets, powders or sachets, without an adverse food effect
was an advance over the prior art as it was inconsistent with the experts’
understanding of the interaction between food and the drug based on the
available scientific literature.
[107] Dr.
Rapp attested that this view about the azithromycin food effect persisted even
after the publication of the 1996 report by the Pfizer scientists which
disclosed their findings regarding the absence of a food effect for tablets and
suspension dosage forms. Rapp cited that report in a 1998 paper in which he
repeated the food effect caution. Indeed it continued to appear in his
university ’s drug interaction guidelines, for which he was co‑author, as
late as June 2003. Rapp says that he only became aware that the labelling
instructions for ZITHROMAX had changed at the outset of this litigation.
[108] As
indicated above, I have some difficulty accepting Dr. Rapp’s evidence about
what a person of ordinary skill in the art would have known before the priority
date when it appears that he was not reasonably diligent in keeping up with the
literature in the field in which he professes expertise.
[109] The
section of the ‘071 patent disclosure headed "Background" refers to a
1980 review paper by authors Toothaker and Welling of the School of Pharmacy at
the University of Wisconsin entitled "The Effect of Food on Drug Bioavailability".
Pfizer cites this paper as illustrating the common understanding of persons
skilled in the art at that time, that the formulation in which a drug is
administered can have a profound effect on the extent of drug‑food
interaction. At page 176 of the article, 267 of the record, the authors note
that "[w]ith capsule and tablet dosage forms, not only is
dissolution likely to be affected by the presence of food but also the delay in
gastric emptying due to food is likely to have a greater effect when the drug
is contained in a single dose." (emphasis added). The study goes on to
note, however, that the food effect can vary widely depending on the dosage
form and other factors such as disintegration and dissolution rates.
[110] Apotex
submits that the Toothaker & Welling paper teaches that you can’t assume
that because you have one formulation that has a food effect, a different
formulation of the same medicine will perform in the same way. That, in
essence, is what Pfizer scientists demonstrated when they tested the bio‑availability
of non‑capsule oral dosage forms.
[111]
The ‘071 patent disclosure states further, at page 2, that at least one
unpublished study had shown that the absorption of azithromycin can be
adversely affected if the patient is in a fed state. From the evidence, it
seems that this study was conducted by Pfizer’s employee, Scott Hopkins, who
published a report on the study in a supplement to the American Journal of
Medicine in 1991. The report is cited in Dr. Rapp’s affidavit and was produced
in evidence. In the Hopkins study, adult patients were treated with azithromycin contained in
capsules but those under 15 were given the drug in suspension form. Dr. Hopkins
reported that the capsules produced an adverse food effect. His report says
nothing with respect to whether a food effect was experienced by the children
and youth treated with the suspension dosage form.
[112] It
appears from the evidence that Hopkins’ findings that an adverse food effect was associated with the
capsules formed the basis for Pfizer’s product labelling caution that ZITHROMAX
should not be taken with food. Other scientists, such as Drew and Gallis in
their 1992 evaluation of azithromycin, relied upon that information and
repeated the food effect warning. But the source of that information related
solely to the use of capsule dosage forms and not to the use of azithromycin in
tablets or any other dosage forms.
[113] None
of the references in the literature cited by Dr. Rapp as supporting his
understanding of the conventional wisdom among persons skilled in the art, were
based on new testing. Rapp conceded on cross‑examination that all of them
rely directly or indirectly on Hopkins and Pfizer’s information leaflet. He further conceded that prior
to April 1994, the only data that existed on azithromycin in terms of food
effect was referable to azithromycin capsules.
[114] Apotex’
expert, Dr. Langer, attested that as of a year prior to the priority date of
the ‘071 patent, a person skilled in the art would have been aware of the fact
that the occurrence of adverse food effects for oral dosage formulations was
often associated with a particular dosage form, with fast‑dissolving,
suspension or solution dosage forms often exhibiting a lack of food effect as
compared to dosage forms such as capsules. Support for this view is also found
in Dr. Shefter’s affidavit.
[115] Dr.
Rapp says that this general information was superceded by the specific
references in the literature addressing azithromycin. As I have noted above,
these references were based solely on Pfizer’s testing of the capsules. Dr.
Langer’s view, conveyed at paragraph 118 of his affidavit, is that Rapp appears
to either ignore or to not fully appreciate or understand the teachings about
the relationship between the nature and type of oral dosage forms and the
occurrence or lack of an adverse food effect that were available to those
skilled in the art in the early 1990's.
[116] Dr.
Shefter, citing a 1980 pharmaceutical text on tablet dosage forms referenced in
Apotex’ notice, attested that the type of testing described in the ‘071 patent
is commonly known and routine in formulation development and that the lack of
an adverse food effect of the described fast‑dissolving formulations
would have been easily demonstrated as an inevitable consequence of routine
testing carried out by a person skilled in the art. (Shefter affidavit
paragraph 47).
[117] Dr.
Langer points out that other macrolide antibiotics in oral dosage forms such as
tablets and suspensions that could be administered without regard to meals were
commercially available prior to the filing date of the ‘ 071 patent. He cites
erythromycin ethylsuccinate suspensions and tablets and clarithromycin tablets
(BIAXIN). Both were known not to have an adverse food effect. Langer
concludes that these examples of drugs related to azithromycin would have led a
person skilled in the art to consider performing routine testing on similar
tablet formulations containing azithromycin. (Paragraphs 55‑59). Langer’s
evidence in this regard was supported by Dr. Dordick (at paragraph 46) and by
excerpts from the 1990 and 1993 Physicians’ Desk Reference texts.
[118] In
essence, Apotex’ argument on obviousness is that as of the priority date Pfizer
had all of the information it required from the state of the art to conclude
that if the capsules exhibited an adverse food effect, simply testing the
tablets or suspension forms, which they had already produced, would demonstrate
whether they too exhibited the same effect, a routine and non‑inventive
step. As Dr. Rapp conceded on cross‑examination, the means or techniques
to do this in vivo or in vitro were known as of April 1994.
[119] Pfizer
says, on the other hand, that prior to the claimed invention, there existed a
prejudice in the art with respect to the association of an adverse food effect
with oral azithromycin dosage forms and teachings in the literature that would
have dissuaded a person skilled in the art from testing non‑capsule
dosage forms of azithromycin for a lack of an adverse food effect.
[120] Pfizer,
in effect, is asking the court to conclude that because it proceeded on the
assumption, based on Dr. Hopkin’s 1991 study of the effects of its capsules,
that all oral dosage forms of azithromycin would exhibit the same adverse food
effect, that this reflects the state of the art prior to the testing it later
conducted that demonstrated otherwise. In my view, that is not supported by the
evidence.
Commercial
Success
[121]
As stated by the Federal Court of Appeal in Diversified Products Corp v. Tye‑sil
Corp.(1991), 35 C.P.R. (3d) 350 at 367‑368, 125 N.R.218,
evidence of commercial success in the introduction of a patented product is not
to be disregarded but is not determinative of obviousness.
[122] Pfizer
offered the evidence of Ms. Pesant who attested that ZITHROMAX 250 mg tablets
are successful in the marketplace. Shortly after their introduction, Pfizer
discontinued marketing the capsule version. Sales of the tablets have grown
steadily. Ms. Pesant attaches a graph indicating the prescription sales of the
capsules and tablets respectively between 1993 and 2003. Ms. Pesant
acknowledges that part of the sales since the introduction of the tablets
simply reflects substitution for the capsules but asserts that the tablet form
has added to the market beyond the substitution effect. This assertion is based
entirely upon Pfizer’s sales projections for the capsules and their conclusion
that they have sold considerably more tablets than they had expected to do with
the capsules.
[123] In
response, Apotex has tendered the affidavit of Aslam H. Anis, Associate
Professor of Health Economics in the Department of Health Care and Epidemiology
at the University of British Columbia. Professor Anis claims expertise in all
areas of the pharmaceutical industry, especially in the interface between
government regulation and corporate behaviour. He disagrees with Ms. Pesant’s
assertion that the ZITHROMAX tablets were a commercial success. Rather, he
finds that there has been no more growth in the sale of tablets than would have
been expected of capsule sales (had they not been phased out) based on data
related to the previous sales for capsules.
[124] Pfizer
argues that Apotex has not laid a proper foundation for the reception of
Professor Anis’ opinion evidence in that the reliability of the data he used to
form that opinion, including drug store and hospital sales figures and the
prices paid by government drug plans for azithromycin capsules and tablets, as
hearsay, was not proven through admissible evidence in these proceedings. On
cross‑examination, Professor Anis indicated that this was the data he
usually relied upon in his work and that he did logical checks to verify its
consistency. However, he received the data employed for this analysis from Apotex
counsel.
[125] It
is well established in the jurisprudence that experts can rely upon hearsay
information as background knowledge in forming their opinions. The fact that
the opinion is based on information that is not before the court does not
render the opinion inadmissible. The weight to be given to the opinion will
however depend on the extent to which the facts upon which the opinion is based
are proven. In the absence of proof of any of the underlying factual basis for
the opinion, it is appropriate for a trier of fact to give no weight to the
opinion: R. v. Abbey, [1982] 2 S.C.R. 24.
[126]
Accordingly, I am unable to give any weight to Professor Anis’ opinion
notwithstanding that it appears to have been formed in an appropriately scientific
manner.
[127] However,
it is not clear to me that the commercial success described by Ms. Pesant
should be accorded much weight in the determination of the question of
obviousness. That success is based solely on Pfizer’s own sales projections for
the capsules and does not allow for other variables. The growing recognition of
the value of azithromycin by clinicians and other factors may have accounted
for the increased sales. I am not satisfied that Pfizer’s sales projections on
their own serve as an adequate basis for concluding that the discovery claimed
in the ‘071 patent was the cause. Accordingly, while I have considered it, I
give little weight to Ms. Pesant’s evidence in this respect.
Conclusion
on obviousness
[128] Pfizer
does not dispute that azithromycin was a known drug, that there were known
suspension and tablet dosage forms for it before 1994 and disintegrants that
could be used in the tablet formulations. Despite all of that, its argument
goes, there was a long‑held sense of "resignation" that the
drug, otherwise exceptionally useful, came with a known and accepted downside,
namely the adverse food effect. No one solved the problem until the inventors
added and advanced the state of the art with the ‘071 patent. There is no
discussion in the literature that suggested that the tablets and other non‑capsule
dosage forms used with azithromycin earlier might not have a food effect.
[129] But
was it open to others to experiment with and address the problem while the base
patents, all of them held by Pfizer, were still active? While the Patent Act
subsection 55(2) permits experimental use there has to be some incentive for
conducting the research. The capsules came out in 1992, the ‘071 patent
application was filed in 1994. There was not was not much time to conduct
research on the food effect problem. In those circumstances, I find it
difficult to accept the argument that if it wasn’t novel, why didn’t someone
else do it?
[130] It
is clear from the evidence that some persons treating patients with azithromycin,
including Dr. Rapp, acted inconsistently with the development of the art and
continued to believe that there was a food effect with the tablets and the
suspensions even after that had been shown to be wrong by Pfizer’s scientists.
Pfizer counsel describes this as a "prejudice" in the art in favour
of the food effect. On the evidence as to how the literature was influenced by
Pfizer’s own information leaflets, that should be taken as no more than an
indication that some persons skilled in the art did not question that
information. It does not mean that an ordinary skilled technician, familiar
with the art, would not be led directly to the invention.
[131] In
my view, the test for obviousness does not exclude routine testing to determine
the characteristics of known compounds. I conclude that testing the tablet and
other non‑capsule dosage forms to verify that they did not exhibit an
adverse food effect was an entirely obvious and routine step for the
unimaginative skilled drug formulator to take and did not constitute undue
experimentation. The evidence of the applicant’s subsequent commercial success
with its 250 mg tablets does not convince me that the claimed invention was
truly novel. Accordingly, I
am
satisfied that the respondent has established on a balance of probabilities
that the subject matter of the ‘071 patent was obvious and the patent is
invalid for that reason.
Ambiguity
[132]
Subsection
27(4) of the Patent Act provides that patent specifications must end
with a claim or claims defining distinctly and in explicit terms the
subject-matter of the invention for which an exclusive privilege or property is
claimed.
[133] Apotex
alleges that the phrase in claim 23 "which does not exhibit an adverse
food effect for administration in the treatment of an antimicrobial infection,
to a patient that has eaten" is ambiguous because it can be read as
meaning (a) that it is infringed only when a dosage form of azithromycin is
administered without a food effect in a patient that has eaten or (b) that it
is infringed by any dosage form of azithromycin. Apotex argues that the claim
is thus ambiguous under the first interpretation as not being sufficiently
explicit to inform the reader as to what is within and what is not within the
claim, and in the second instance to claiming more than the alleged new use the
inventor discovered for the known dosage form. Apotex relies on Hoffman‑LaRoche
Ltd.v. Apotex Inc., (1989), 24 C.P.R. (3d) 289, 23 C.I.P.R. 1 (F.C.A.)in
support of its ambiguity submissions.
[134] Pfizer
contends that a claim is not ambiguous simply because one part of it is capable
of more than one construction. But, in any event, the impugned phrase is not
ambiguous as claim 23 would be infringed only when a dosage form of azithromycin,
which does not exhibit a food effect, is administered to treat a microbial
infection in a fed patient. A dosage form has no food effect if, when tested,
it meets the minimum confidence levels discussed above. Hoffman, Pfizer
says, doesn’t assist Apotex as it dealt with a claim for a therapeutic
composition. Here, claim 23 is for a new use of azithromycin.
[135] In
Hoffman, supra, the questioned phrase was "effective in the
treatment of smx‑resistant bacterial infections". I think it is
irrelevant that it was in a combination claim. The Court of Appeal found that
the phrase could be read in at least two ways. One could read the words as
limiting the scope of the claim to the combination when and only when it was
effective in treating such infections. If read in that manner, it would be
impossible to know whether use of the combination would infringe the claim
until its effectiveness had been demonstrated. Alternatively, the phrase says
that such a combination is effective for treating infections but does not
restrict the claim to the combination when made or sold for that purpose. Thus
it was held to be ambiguous and invalid for not being sufficiently explicit to
inform the reader of what was within or not within the claim.
[136] In
this case, claim 23 is limited to dosage forms that do not produce a food
effect when azithromycin is administered to a fed patient for the treatment of
an infection. But whether there is or is not a food effect can be determined
through standard in vivo or in vitro testing of the dosage form.
As the Apotex witnesses have stated, that would be standard preformulation
work. I don’t, therefore, find that claim 23 is ambiguous or invalid for
insufficiency.
Overbreadth
[137] A
claim will be considered overbroad and, therefore, invalid if it asserts an
exclusive property or privilege in something the inventor did not actually
invent, or, something the inventor claimed exceeding that which was disclosed
in the patent: Farbwerke Hoechst AG.v Canada (Commissioner of Patents), (1965,
50 C.P.R. 220 at 222, [1966] Ex. C.R. 91, aff’d (1966), 50 C.P.R. 220, [1966]
S.C.R. 604.
[138] Apotex
contends that claim 23 is broader than the invention disclosed which is limited
by the restrictions set out in the patent disclosure. These include the use of disintegrants,
the use of less than a taste‑masking amount of an alkaline oxide, the
exclusion of capsules and for suspensions, thickening agents and that it is
limited to oral dosage forms. The claim itself does not include any of these
restrictions. While the disclosure purports to invent a new use for azithromycin
formulations that do not exhibit a food effect, the claim itself covers any
formulation that does not have that effect. As conceded by Dr. Rapp on cross‑examination
(AR, pp. 1280, 1286), claim 23 would cover any and every formulation of an azithromycin
tablet that does not exhibit a food effect. Further the claim is silent as to
the ingredients that would be necessary for the dosage form and the processing
details for making the dosage forms.
[139] Pfizer
concedes that there are no restrictions in claim 23 on the type of oral dosage
forms, excepting capsules, that could be used to treat a fed patient for a
microbial infection with azithromycin. The applicant argues that to have any
practical value, the patent has to cover every embodiment that can yield the
desirable result, otherwise anyone could use the invention in the
"unfenced" area and it would be as worthless as if invalid: Burton Parsons Chemicals, Inc.v.
Hewlett‑Packard (Canada) Ltd., [1976] 1 S.C.R. 555, (1974) 17 C.P.R. (2d) 97.
[140] The
patent states, at page 8, that in addition to azithromycin, a necessary
ingredient of the tablets for the invention would be a disintegrant. This is to
facilitate dissolution in the GI tract. Apotex argues that claim 23 covers any
tablet form of azithromycin, including those which can be made without a disintegrant.
The claim is also silent as to whether the dosage form has to be oral or
whether you can use a capsule.
[141] As
I read the claim with the aid of the disclosure, it is clear that the dosage
forms have to be oral and that capsules are excluded. Dr. Mayersohn was cross‑examined
on the statements in his affidavit that the nature of the dosage forms in claim
23 could not be determined or limited. He conceded that a food effect would be
inconsistent with methods of administration other than oral dosage forms. As I
have construed the patent, the purpose was to deal with the problem caused by
capsules. It is conceivable that a capsule or tablet without a disintegrant
could be developed that would have no food effect. Dr. Rapp suggested as much
in his cross‑examination.
[142] I
acknowledge the force of the argument that claim 23 by purporting to assert a
claim for all azithromycin dosage forms that do not exhibit a food effect is
overreaching. But this is not such a case, in my view, to warrant invoking
Justice Binnie’s felicitous phrase from Camco,
supra about claiming anything that
grows hair. I would not find the claim invalid solely by reason of overbreadth.
Improper
Subject Matter
Method to Treat
[143] In
Canada, as in other Commonwealth countries, methods of medical treatment have
been held not to fall within the definition of "invention" in s. 2 of
the Patent Act. The authority most frequently cited for that proposition
is Tennessee Eastman Co. et al v. Commissioner of Patents [1974] S.C.R.
111, (1972), 8 C.P.R. (2nd) 202.
[144] Apotex
submits that claim 23 simply amounts to a method for instructing doctors and
pharmacists in how to treat patients with azithromycin and, is therefore, not
patentable under the Tennessee Eastman principle. The rest of the
components of the claim are old, namely the use of azithromycin in the
treatment of microbial infections and the formation of azithromycin in various
dosage forms.
[145] Pfizer
counsel submits that the conclusion reached in Tennessee Eastman stemmed
from a repealed provision of the Patent Act. Subsection 41(1) of the Act
as it read in 1972 provided that a substance intended for food or medicine
could not be claimed except as part of a product by process claim. With the
repeal of that provision, it should be an open question as to whether the
method of treatment exception should remain. In any event, Pfizer submits, the
recent jurisprudence is clear that a new use for an old drug is patentable: Apotex
Inc.v. Wellcome Foundation Ltd.,[2001] 1F.C. 495, (2000) 10 C.P.R. (4th)
65 (F.C.A.) aff’d [2002] 4 S.C.R. 153, [2002] SCC 77.
[146] Apotex
points to decisions in the United Kingdom and Australia which dealt with changes to the dosing regimes of known drugs. In
a case dealing with the drug taxol, the U.K. Court of Appeal held unpatentable
the discovery that a three hour infusion produced the same treatment results
with less neutropenia as a 24 hour infusion: Bristol‑Myers Squibb Co.v.
Baker Norton Pharmaceuticals Inc., [1999] R.P.C. 253 at paragraphs 43‑44
[Bristol‑Myers].
[147] With
respect to the drug alendronate, used to treat osteoporosis, 10 mg was
prescribed on a daily basis under strict dosing instructions that were
difficult to comply with, particularly for the elderly. The daily regime caused
significant gastro‑intestinal side effects in some patients. It was
discovered that these effects could be significantly reduced and the therapeutic
value maintained by a once weekly administration of 70 mg. The Court of Appeal,
substituting the word alendronate for that of taxol in its analysis, reached
the same conclusion that it had in Bristol‑Myers, as did also the
Australian Federal Court of Appeal: Instituto Gentili SpA.v. Teva
Pharmaceutical Industries Ltd., [2003] All E.R. 62 at para.59 (F.C.A.); Arrow
Pharmaceuticals Ltd., v. Merck & Co.,Inc . [2004] F.C.A. 1282 at
paras.80‑97 (Austl.).
[148] In
Merck & Co. Inc.v. Apotex Inc., (2005) 41 C.P.R. (4th) 35, 2005 FC
755, I declined to find that the Canadian patent for a weekly dose of alendronate
was invalid as a method of treatment on the ground that patents are taken out
of the reach of Tennessee Eastman as long as the claims are
distinguishable from the work of a physician which requires the exercise of
specialized skill.
[149] As
I read claim 23, it merely instructs physicians and pharmacists that the azithromycin
tablets can be administered to treat microbial infections without concern as to
the patient’s fed or fasted state. It doesn’t instruct them on how to treat the
patient. Accordingly, I see no reason to find that it is invalid on the Tennessee
Eastman principle.
Mere
Discovery
[150] Apotex
submits that the purported inventors of the ‘071 patent merely disclosed the
inherent characteristics of fully disclosed prior art tablets and suspension
formulations, a non‑ inventive discovery. The respondent argues that if
the discovery was inevitable by following the instructions in the prior art
then it does not matter whether it would have been realized by the skilled
reader of the prior art.
[151] Pfizer
argues that this is simply an attempt to argue obviousness twice. This case is
not simply about a tablet claim. It is a new use for azithromycin. It can now
be used to treat patients that formerly would have been told they could not
take it unless they fasted. Finding a new use
for a
known compound is inventive and patentable as a "new and useful art":
Apotex Inc.v. Wellcome Foundation Ltd., [2001] 1 F.C. 495 at paras. 64‑65,
(2000) 10 C.P.R. (4th ) 65 (F.C.A.); Shell Oil Co. v. (Canada)Commissioner of Patents, [1982] 2 S.C.R. 536 at 548‑9
[Shell Oil].
[152] Apotex
cites Sharpe & Dohme Inc.v. Boots Pure Drug Co.Ltd, (1928), 45
R.P.C. 153 at 191‑192 (C.A.) in which it was held by the English Court
of Appeal that the ascertainment of the valuable properties of certain alkyd
chemicals, while important as a useful development in itself, was not a
patentable invention but at most verification. Pfizer relies on Shell Oil.,
supra where it was concluded that a new use for an old compound is
patentable subject matter.
[153] In
Riello Canada Inc. v. Lambert (1986), 9 C.P.R. (3d) 324, 8 C.I.P.R. 286
(F.C.T.D.) at 335, Justice Strayer quoted a statement of Lord Buckley in Reynolds
v.Herbert Smith & Co.,Ltd.(1902), 20 R.P.C. 123 (Ch.D) as the classic
distinction between a "discovery" and an "invention":
Discovery adds to human knowledge,
but does so only by lifting the veil and disclosing something which before had
been unseen or dimly seen. Invention also adds to human knowledge but not
merely by disclosing something. Invention necessarily involves the suggestion
of an act to be done, and it must be an act which results in a new product or a
new result or a new process or a new combination for producing an old product
or an old result.
[154] Here
the use is the same. The only difference lies in the condition of the patient
who receives the treatment. The evidence does not indicate that food effect was
a major problem. At best, there was some inconvenience in avoiding taking the
capsules one hour before or two hours after eating. This is not a problem that
had waited solution for many years.
[155] In
Bristol‑Myers, supra at paragraph 59, the U.K. Court of Appeal,
dealing with the discovery that the three hour taxol infusion would be just as
effective as the 24 with less ill effects, stated "this is not a case of
second medical use at all.The use is the same. All you have new in the patent
is more information about that use."
[156] In
my view, the ‘071 patent is not a case of a new medical use for azithromycin.
The use, treatment of a microbial infection remains the same. The dosage forms
were known. The therapeutically effective amount of the drug required is the
same. The bio‑availability of the drug is maintained. All that is new is
that it was found that the drug can be taken after eating in tablet or
suspension form without adverse effect. That is not a new result, a new product
or a new process but a mere discovery of the existing properties of the drug in
a different dosage form.
Infringement
[157] As
I have found that the ‘071 patent is invalid as obvious and a mere discovery,
it follows that the Apotex product, 250 mg tablets of azithromycin isopropanolate
monohydrate, will not infringe.
[158] In
the event that I am found to have erred in those conclusions, I will comment
briefly on the infringement issues.
Gillette
Defence
[159] A
Gillette defence as recognized by the House of Lords in Gillette Safety
Razor, supra, is available when the product alleged to infringe the
patent in question is made in accordance with the prior art. If the product
infringes the patent as written, then the patent must have been anticipated by
the prior art, and is consequently invalid. Apotex’ assertion of the defence is
based on the claim that it’s formulation is the tablet preparation described in
Example 4 of the ‘531 patent.
[160] Pfizer
does not question that the Apotex tablet will be formulated as disclosed in the
prior art. However, it argues that the Gillette defence is irrelevant as
the invention in claim 23 is the new use of azithromycin to treat a
patient who has eaten, not to a tablet formulation in the abstract. As
indicated above, I do not accept that construction of claim 23.
[161] Both
Pfizer experts, Drs Rapp and Andriole, described claim 23 of the ‘071 patent as
a claim for the use of azithromycin in the preparation of a pharmaceutical
formulation that does not exhibit a food effect (Andriole affidavit para. 47,
AR p.968; Rapp Affidavit, para.61, AR.pp.51‑52). That accords with how I
have construed the claim. Accordingly, I would find that as the Apotex
formulation falls within the prior art ‑ the ‘531 patent ‑ that
formulation would not infringe claim 23 of the ‘071 patent or the latter is
invalid for claiming the prior art.
No
direct or indirect infringement
[162] Apotex
says that its product, Apo‑azithromycin, will not directly or indirectly
infringe the claims of the ‘071 patent. With respect to direct infringement, if
claim 23 is as Pfizer contends, a use to treat claim, as a corporation that
neither prescribes nor dispenses, Apotex can never directly infringe the
patent. Moreover, the tablets will not be specifically identified as intended
for administration to a patient who has eaten. The product monograph issued
with its NOC will not stipulate that the tablets will be ingested after the
patient has eaten, subject to the patent found to be valid. In any event, Apotex
says, there is no evidence that its tablets if given to fed patients will not
exhibit a food effect. The only testing of its product in the record is the
bioequivalence testing which was done in the fasted state. Thus there is no
evidence before the court that approval of its version of azithromycin will
result in direct infringement of the ‘071 patent.
[163] Pfizer
has not directly addressed the direct infringement question but contends that
indirect infringement is inevitable. As the Apotex product will be
bioequivalent to ZITHROMAX, the undertaking or product monograph will not
prevent physicians from prescribing and pharmacists from dispensing Apotex’ azithromycin
product for use in patients who have eaten.
[164] In
support of the infringement claim, Pfizer offered the evidence of Mr. Spiridon Goussios
a licensed pharmacist and Dr. Frank Martino, a family physician, obstetrician,
and emergency practitioner, both currently practising in Ontario.
[165] Dr.
Martino attested that he frequently prescribes ZITHROMAX, but states that he would
readily prescribe a generic equivalent. If the product monograph did not
provide directions with respect to food, he would believe that the drug could
be taken with food. He could not, of course, speak for all doctors, had not
read Apotex’ product monograph, was unfamiliar with the regulatory regime for
new drug submissions and conceded on cross‑examination that differences
in the tablet formulations could have significant effects on how the tablets
would function in the presence of food. Ultimately, he agreed with the
suggestion put to him on cross that if he was unsure about a generic’s
properties, he would not write a prescription for the generic or allow
substitution by the pharmacist.
[166] Mr.
Goussios attests that Apotex ’s assurance that it will not market its azithromycin
specifically for patients who have eaten is a hollow one in light of the
practice of pharmacists. The absence of instructions would lead a pharmacist to
either assume that there is no food‑drug interaction, or turn to the Compendium
of Pharmaceuticals and Specialties entry for ZITHROMAX. Dr. Goussios was
cross‑examined on his affidavit in the course of which he acknowledged
that if Apotex’s product was approved only for certain uses, he would likely be
made aware of that and would not dispense it for unapproved uses.
[167]
To successfully prosecute a prohibition application under the Regulations in
relation to a "use" patent where indirect infringement is alleged,
the patentee would have to prove that third parties would, in fact, use the
second person’s product for a claimed use in the first person’s patent, and
that the second person had actively induced or encouraged such use: AB
Hassle Inc.v.Canada (Minister of National Health and Welfare) (2002), 22
C.P.R. (4th) 1 at paras. 47‑59, 2002 FCA 421. To induce or procure
another to infringe a patent, something active must be done. Mere passivity is
not sufficient: Beloit, supra at 46‑47.
[168] There
is no evidence on the record that Apotex has or will actively encourage third parties
to infringe Pfizer’s patent, if it were held to be valid, and assuming Apotex
were to be granted a notice of compliance to market its product with the
stipulated monograph. One cannot assume that responsible physicians and
pharmacists will prescribe or dispense a drug for administration to patients in
a fed state if it is not indicated for that use. Therefore, despite my
suspicion that there is an air of unreality to Apotex’ position, I cannot find
that Pfizer has satisfied its burden to establish on a balance of probability
that the respondent’s intention to sell Apo‑azithromycin will infringe
the applicant’s patent, and must conclude that the allegation of non‑infringement
is justified.
Eligibility
for Listing on the Patent Register
[169] Apotex
contends that the ‘071 patent is improperly listed against 250 mg azithromycin
tablets on the Patent Register because the listing was made outside the time
requirements of the Regulations and was not relevant to the submissions with
which it was listed. Pfizer suggests that, if there is a legitimate concern
about the listing, the proper time for bringing it before the court would have
been my way of a preliminary motion under subsection 6(5) of the Regulations.
[170] Section
3 of the Regulations requires the Minister to maintain a register of
patents for drugs containing medicine in respect of which a NOC has been
issued. Subsection 4(3) and (4)
govern
the timing of listing patents on the registry:
PATENT LIST
4. (1) A person who files or has
filed a submission for, or has been issued, a notice of compliance in respect
of a drug that contains a medicine may submit to the Minister a patent list
certified in accordance with subsection (7) in respect of the drug....
|
|
LISTE DE
BREVETS
4. (1) La
personne qui dépose ou a déposé une demande d'avis de conformité pour une
drogue contenant un médicament ou qui a obtenu un tel avis peut soumettre au
ministre une liste de brevets à l'égard de la drogue, accompagnée de
l'attestation visée au paragraphe (7)....
|
(3) Subject to subsection (4), a person who submits a patent
list must do so at the time the person files a submission for a notice of
compliance.
|
|
(3) Sous réserve du paragraphe (4), la personne qui soumet une
liste de brevets doit le faire au moment du dé pôt de la demande d'avis de
conformité.
|
(4) A first person may, after the date of filing of a submission
for a notice of compliance and within 30 days after the issuance of a patent
that was issued on the basis of an application that has a filing date that
precedes the date of filing of the submission, submit a patent list, or an
amendment to an existing patent list...
|
|
(4) La première personne peut, après la date
de dépôt de la demande d'avis de conformité et dans les 30 jours suivant la
délivrance d'un brevet qui est fondée sur une demande de brevet don’t la date
de dépôt est ant érieure à celle de la demande d'avis de conformité,
soumettre une liste de brevets, ou toute modification apportée à une liste de
brevets,.....
|
[171] This
issue arises because the original new drug submission for Pfizer’s 250 mg
tablets was filed on or about September 15, 1994 (the notice of compliance was
issued on February 21, 1996) but the ‘071 patent did not issue until October
17, 2000. The 1994 submission was for a five day dosing regime in which 500 mg
were taken the first day, comprised of two 250 mg tablets, followed by 250 mg
on the second, third, fourth and fifth days. Pfizer subsequently filed a
submission for a supplemental NOC in respect of a 500 mg tablet and an accelerated
dosage regimen for azithromycin in adults which provides for daily dosing of
500 mg per day for 3 days. The supplemental NOC was granted on August 5, 2003.
On August 13, 2003, the ‘071 patent was listed on the patent register in
connection with both the 250 and 500 mg tablets.
[172] Thus,
Apotex argues, the ‘071 patent was improperly listed on the register in
connection with the 250 mg tablets, because by August 13, 2003, it was out of
time. Pfizer should have taken steps to list the patent within 30 days of its
issuance in October, 2000. Since the supplemental NOC was not for the 250 mg
tablets, but for the 500 mg tablet and the accelerated dosing regime, the ‘071
patent could not be properly listed as part of that submission. This case, Apotex
submits, is on all fours with the decision of Justice Huguessen in Novopharm
Ltd.,v.Canada (1998), 78 C.P.R.(3d) 54 (F.C.T.D.)
[173] Clearly,
the 500 mg tablet could be used for either the original dosing regime, as one
tablet on the first day instead of two, or for each day of the new three day
regime. How does that justify listing the ‘071 patent with respect to the 250
mg tablets so long out of time? It is not clear to me that there was any
justification for what appears to have been done. In response to written
interrogatories, Ms. Pesant, Pfizer’s employee responded that the 250 mg
tablets were listed with respect to the new three day treatment. But those
tablets had been approved long before and were not part of the new drug
submission. In response to a further question, Pfizer refused to provide the
product monograph that existed prior to the August 30, 2001 submission which
might have helped to resolve the question.
[174] Should
Apotex be allowed to raise this issue at this stage of the PM(NOC) proceedings?
[175] Subsection
6(5) of the Regulations provides that the NOC process may include a motion for
dismissal of a Notice of Application under section 6(1) if the patents in
question were not eligible for inclusion on the patent register. This allows the
respondent to a Notice of Application under 6(1) to apply for a procedural
remedy similar to striking out pleadings in appropriate circumstances: Proctor
& Gamble Pharmaceuticals v. Minister of Health (2003) 26 C.P.R.
(4th)180 at para14.
[176] The
primary purpose of striking out pleadings under rule 221 of the Federal
Court Rules, 1998 (and similar remedies, such as summary judgment under
rule 213) is to prevent the waste of time and resources by the litigants and
the courts. Where the process can be streamlined, it should be and these steps
should be taken as early as possible. I note that under rule 213 a motion for
summary judgment is not available after a trial date has been fixed and that a
motion to strike will not be considered if a party unduly delays in bringing
its motion: Radil Bros. Fishing Co. v. Canada (Minister of Fisheries and
Oceans) (2003), 230 F.T.R. 228, 2003 FCT 79..
[177] At
any time prior to the hearing of this application, Apotex could have brought a
motion under 6(5)(a). Apotex argues, however, that it would have been
imprudent to do so and would have likely wasted time and resources because of
the high standard required to strike out an application; that the listing was
so plainly improper to be bereft of any chance of success : David Bull
Laboratories (Canada) Inc. v. Pharmacia Inc. et al., [1995] 1 F.C. 588, 58
C.P.R. (3d) 209 (C.A.). If they can bring it at this stage, they also enjoy
the tactical advantage that the burden to disprove the allegations rests with
the applicants whereas Apotex would have carried the burden on a preliminary
motion to dismiss.
[178] I
accept that Apotex can make its allegation as part of these proceedings and is
not required to bring a motion under subsection 6(5) in advance of the hearing
of the 6(1) application. I am also satisfied that Pfizer has failed to
establish on a balance of probabilities that the ‘071 patent was properly
listed on the patent register as it was out of time when the NOC for the
accelerated dosing regime for the 500 mg tablets was issued.
Conclusion
[179]
For the foregoing reasons, I am satisfied that the ‘071 patent is invalid for
obviousness and for claiming a mere discovery. I am also satisfied that the Apotex
apo‑azithromycin product will not infringe. Accordingly, Pfizer has not
discharged its burden to establish that the allegations of invalidity and
infringement are not justified and this application will be dismissed.
COSTS
[180] The
parties agree that there is no reason to deviate from the normal scale of costs
in Column III. They ask and I agree that allowance should be made for second
counsel at the hearing. The Minister of Health made no representations in these
proceedings. Accordingly, there is no order in respect of costs made in the
Minister’s favour.
ORDER
THIS COURT ORDERS that the application is
dismissed with costs to the respondent in the normal scale with allowance for
second counsel at the hearing.
" Richard G. Mosley
"
Judge
ANNEX "A"
The Claims
1. An oral dosage of azithromycin in the form of a tablet
made by wet granulation and administrable to a mammal that has eaten, which
comprises azithromycin and a disintegrant and which exhibits substantially no
adverse food effect, the dosage form effecting at least about 90% dissolution
of azithromycin within about 30 minutes when an amount of the dosage form
equivalent to 200 mg of azithromycin is tested as set forth in USP test
<711> in a USP‑2 dissolution apparatus under conditions at least as
stringent as the following: 900 ml sodium phosphate buffer, pH 6.0, 37oC,
with paddles turning at 100 rpm, provided that the dosage form contains less
than a taste‑masking amount of an alkaline earth metal oxide or
hydroxide.
2. A
dosage form as defined in claim 1, wherein the mammal is a human.
3. An
oral dosage form of azithromycin in the form of a powder for oral suspension
and administrable to a mammal that has eaten, which comprises azithromycin, one
or more thickening agents and an anhydrous buffer and which exhibits
substantially no adverse food effect, the dosage form effecting at least about
90% dissolution of azithromycin within about 30 minutes when an amount of the
dosage form equivalent to 200 mg of azithromycin is tested as set forth in USP
test <711> in a USP‑2 dissolution apparatus under conditions at
least as stringent as the following: 900 ml sodium phosphate buffer, pH 6.0, 37oC,
with paddles turning at 100 rpm, provided that the dosage form contains less
than a taste‑masking amount of an alkaline earth metal oxide or
hydroxide.
4. A
dosage form as defined in claim 3, wherein the mammal is a human.
5. A
dosage form as defined in claim 4, in the form of a suspension made from the
powder.
6. An
oral dosage form of azithromycin in the form of a unit dose packet and
administrable to a mammal that has eaten, which comprises azithromycin and a
dispersing agent and which exhibits substantially no adverse food effect, the
dosage form effecting at least about 90% dissolution of azithromycin within
about 30 minutes when an amount of the dosage form equivalent to 200 mg of azithromycin
is tested as set forth in USP test <711> in a USP‑2 dissolution
apparatus under conditions at least as stringent as the following: 900 ml
sodium phosphate buffer, pH 6.0, 37oC, with paddles turning a 100
rpm, provided that the dosage form contains less than a taste‑masking
amount of an alkaline earth metal oxide or hydroxide.
7. A
dosage form as defined in claim 6, wherein the mammal is a human.
8. A
dosage form as defined in claim 7, in the form of a suspension made from the
unit dose packet.
9. An
oral dosage form of azithromycin in the form of a tablet made by wet
granulation and administrable to a mammal that has eaten, which comprises azithromycin
and a disintegrant and which exhibits substantially no adverse food effect, the
dosage form exhibiting a value of (AUCfed)/AUCfst) of at
least 0.80 with a lower 90% confidence limit of at least 0.75, provided that
the dosage form contains less than a taste‑masking amount of an alkaline
earth metal oxide or hydroxide.
10. A
dosage form as defined in claim 9, wherein the mammal is a human.
11. An
oral dosage form of azithromycin in the form of a powder for oral suspension
and administrable to a mammal that has eaten, which comprises azithromycin, one
or more thickening agents and an anhydrous buffer and which exhibits
substantially no adverse food effect, the dosage form exhibiting a value of
(AUCfed)/AUCfst) of at least 0.80 with a lower 90%
confidence limit of at least 0.75, provided that the dosage form contains less
than a taste‑masking amount of an alkaline earth metal oxide or
hydroxide.
12. A dosage form as defined in claim 11, wherein the mammal
is a human.
13. A dosage form as defined in claim 12, in the form of a
suspension made from the powder.
14. An oral dosage form of azithromycin in the form of a
unit dose packet and administrable to a mammal that has eaten, which comprises azithromycin
and a dispersing agent and which exhibits substantially no adverse food effect,
the dosage form exhibiting a value of (AUCfed)/AUCfst) of
at least 0.80 with a lower 90% confidence limit of at least 0.75, provided
that the dosage form contains less than a taste‑masking
amount of an alkaline earth metal oxide or hydroxide.
15. A dosage form as defined in claim 14, wherein the mammal
is a human.
16. A dosage form as defined in claim 15, in the form of a
suspension made from the unit dose packet.
17. A therapeutic package, comprising a container, an oral
dosage form of azithromycin which is defined in any one of claims 1 to 16
contained therein, and, associated with the package, written matter non‑limited
as to whether the dosage form can be taken with or without food.
18. A therapeutic package as defined in claim 17, wherein
the dosage form is in the form of a tablet.
19. A therapeutic package as defined in claim 17, wherein
the dosage form is in the form of a powder for oral suspension.
20. A therapeutic package as defined in claim 19, wherein
the dosage form is in the form of a suspension made from the powder.
21. A therapeutic package as defined in claim 17, wherein
the dosage form is in the form of a unit dose packet.
22. A therapeutic package as defined in claim 21, wherein
the dosage form is in the form of a suspension made from the unit dose packet.
23. Use of a therapeutically effective amount of azithromycin
for the preparation of a pharmaceutical dosage form which does not exhibit an
adverse food effect for administration, in the treatment of an antimicrobial
infection, to a patient that has eaten.
24. A tablet of azithromycin for administration to a human
patient that has or has not eaten food, which comprises:
azithromycin in an amount of from 25 mg to 3 g,
a disintegrant in an amount of from 1 to 25% by weight
based on the total tablet, and
at least one pharmaceutically acceptable excipient,
provided that the tablet contains
no or less than a taste‑masking amount of an alkaline earth
metal oxide or hydroxide,
wherein the tablet exhibits substantially no adverse
food effect and exhibits a value of (AUCfed )/AUCfst) of
0.80 to 1.25 with a lower 90% confidence limit of 0.75 to 1.40 and is made by
wet granulation.
25. A tablet as defined in claim 24, which contains at least
one member selected from the group consisting of sodium croscarmellose, sodium
starch glycolate, microcrystalline cellulose and cross‑linked polyvinylpyrrolidone
in an amount of 3 to 15% by weight based on the total weight of the tablet as
the disintegrant.
26. A tablet as defined in claim 25, which contains sodium croscarmellose
and pregelatinized starch as the disintegrants.
27. A tablet as defined in any one of claims 22 to 26, which
is coated with a film of hydroxypropylmethylcellulose, hydroxypropylcellulose
or acrylate‑methacrylate copolymer.
28. A therapeutic package for commercial sale, comprising a
container, the tablet as defined in any one of claims 24 to 27, contained
therein, and, associated with the package, a written message that the tablet
can be taken with or without food.
29. A non‑caking free‑flowing powder of azithromycin
adapted to be made up by a pharmacist into an oral suspension which is to be
administered to a human patient that has or has not eaten food, wherein the
powder comprises an antimicrobial effective amount of azithromycin, at least
one thickening agent in an amount of 0.1 to 2% and in anhydrous buffer or pH‑alterning
agent for providing a pH of approximately 10 in the suspension in an amount of
0.1 to 2.5%, all by weight based on the total weight of the powder, and wherein
the powder contains no or less than a taste‑masking amount of an alkaline
earth metal oxide or hydroxide and exhibits substantially no adverse food
effect and exhibits a value of (AUCfed)/AUCfst) of 0.80
to 1.25 with a lower 90% confidence limit of 0.75 to 1.40.
30. A powder as defined in claim 29, wherein the thickening
agent is at least one member selected from the group consisting of xanthan gum,
guar gum, locust bean gum, gum tragacanth, sodium carboxymethylcellulose, polyvinylpyrrolidone
and hydroxypropylcellulose.
31. A powder as defined in claim 30, which contains
colloidal silicon dioxide as a dispersing agent in an amount of 0.2 to 2.0% by
weight based on the total weight of the powder.
32. A unit dosage packet or sachet containing therein the
powder as defined in claim 29, 30 or 31 and being designed to be emptied into
water or a natural or artificial fruit beverage to constitute the oral
suspension.
33. A therapeutic package for commercial sale, comprising a
container, the packet or sachet as defined in claim 32 contained therein and,
associated with the package, a written message that the suspension can be taken
with or without food.
FEDERAL COURT
SOLICITORS OF RECORD
DOCKET: T‑1937‑03
STYLE OF CAUSE: PFIZER CANADA INC., and PFIZER INC.
and
THE MINISTER OF
HEALTH and APOTEX INC.
PLACE OF HEARING: Toronto, Ontario
DATE OF HEARING: July 25 to 27, 2005
REASONS FOR ORDER
AND ORDER BY
: The Honourable Mr. Justice Mosley
DATED: October
17, 2005
APPEARANCES:
Sheila Block FOR
THE APPLICANTS
Andrew Shaughnessy
Andrew Bernstein
Harry Radomski FOR
THE RESPONDENTS
Andrew Brodkin
Sorelle Simmons
SOLICITORS OF RECORD:
SHEILA BLOCK FOR
THE APPLICANTS
ANDREW SHAUGHNESSY
ANDREW BERSTEIN
Torrys LLP
Toronto, Ontario
HARRY RADOMSKI FOR
THE RESPONDENTS
ANDREW BRODKIN
SORELLE SIMMONS
Goodmans LLP
Toronto, Ontario
JOHN H. SIMS,
Q.C. FOR THE
RESPONDENTS
Deputy Attorney General of Canada
Toronto, Ontario