Novartis Pharmaceuticals Canada Inc. v. Rhoxalpharma Inc.

Novartis Pharmaceuticals Canada Inc. v. Rhoxalpharma Inc.
Court (s) Database
Federal Court Decisions
Date
2004-03-29
Neutral citation
2004 FC 474
File numbers
T-462-02
Notes
Digest
Decision Content
Date: 20040329
Docket: T-462-02
Citation: 2004 FC 474
BETWEEN:
NOVARTIS PHARMACEUTICALS CANADA INC.
and NOVARTIS AG
Applicants
- and -
RHOXALPHARMA INC. and
THE MINISTER OF HEALTH
Respondents
REASONS FOR ORDER
LEMIEUX J.:
INTRODUCTION
[1] Pursuant to the Patented Medicines (Notice of Compliance) Regulations (the "Regulations"), the applicants seek an order from this Court prohibiting the Minister of Health from issuing to RhoxalPharma ("Rhoxal") a Notice of Compliance ("NOC") under the Food and Drug Act in connection with its 25mg and 50mg capsules of the drug
cyclosporine for oral administration (the "Rhoxal capsule") until the expiry of a number of Canadian patents including patent 1,308,656 (the "656 Patent").
[2] At the hearing of the application, the parties agreed only the '656 Patent was in issue. Novartis AG is the owner of the '656 Patent and Novartis Pharmaceuticals Canada Inc. ("Novartis"), holds NOCs to market its cyclosporine drug products. Novartis covers both applicants in these reasons.
[3] The Novartis application was filed after Rhoxal had sent to Novartis, on January 31, 2002, a Notice of Allegation ("NOA") its Rhoxal capsule would not infringe the '656 Patent. Rhoxal stated the following:
This patent is directed to and claims pharmaceutical preparations containing a hydrosol, the particles of which comprise cyclosporine as the active agent, these particles having a diameter of from 1 to 10,000 nanometres, stabilized whereby the particle size distribution is maintained constant; or the freeze-dried form thereof. We have available cyclosporine soft gel capsules which will not contain a hydrosol and, more precisely, will not contain the hydrosol as described and claimed in this patent. Accordingly since at least one essential feature of each claim will not be found in our product, the patent will not be infringed. [emphasis mine]
[4] Claims 1 and 2 of the '656 Patent read:
1. A pharmaceutical preparation for intravenous administration the active agent of which comprises a cyclosporin, said preparation comprising either:
(a) a hydrosol, the particles of which comprises said active agent in solid form, have a diameter of from 1 to 10,000 nanometres, and which are stabilized whereby the particle size distribution of said particles is maintained constant; or
(b) the stabilized particulate phase of the above hydrosol in dry or isolated form
2. A pharmaceutical preparation the active agent of which comprises a cyclosporin said preparation comprising either:
(a) a hydrosol, the particles of which comprises said active agent in solid form, have a diameter of from 1 to 10,000 nanometres, and which are stabilized whereby the particle size distribution of said particles is maintained constant; or
(b) the stabilized particulate phase of the above hydrosol in dry or isolated form. [emphasis mine]
[5] Only the introductory lead to Claim 2 and its paragraph (a) are at issue. Claim 1 of the '656 Patent does not apply as it is limited textually to a pharmaceutical preparation for intravenous administration; the Rhoxal capsules are taken orally. Also, paragraph 2(b) is not in play because the Rhoxal capsule does not contain a dry or isolated form of the stabilized particulate phase of the hydrosol. It encapsulates a solution.
[6] The principal issue raised in this proceeding, relating to the scope of the claim, is whether claim 2(a) of the '656 Patent can be construed as covering a hydrosol, as described, is formed in situ, that is, in a human stomach since Novartis does not dispute the Rhoxal capsule, before ingestion, does not contain the described hydrosol. It only contains a solution (the "Rhoxal formulation"). What Novartis does say is the described hydrosol will necessarily be formed in the human stomach after ingestion of the Rhoxal capsule when it comes into contact with water or other liquids present in the human stomach. As a result, the patent would be infringed.
[7] Novartis also raises the issue whether the variant Rhoxal as substituted is in respect of a non-essential limitation and thus within the patent under the doctrine of equivalents.
[8] Rhoxal raised as a preliminary issue whether the doctrine of res judicata applied to the circumstances of this application because of a previous court proceeding involving the same parties, the same patent and the same Rhoxal cyclosporine capsules but with a different dosage form of 100mg.
THE PREVIOUS PROCEEDINGS
[9] It is useful, I think, to set out the circumstances of the previous NOC proceeding decided by Justice Tremblay-Lamer in 2001 FTC 137. She held Novartis failed to show that Rhoxal's 100mg cyclosporine capsules for oral administration would infringe the '656 Patent.
[10] She first identified the proper principles applicable to patent claim construction as stated by the Supreme Court of Canada in two recent cases, namely, Free World Trust v. Électro Santé Inc., [2000] 2 S.C.R. 1024, and Whirlpool Corp. v. Camco Inc., [2000] 2 S.C.R. 1067. She then applied those principles to the facts before her.
[11] She rejected Novartis' argument the term "pharmaceutical preparation" used in claim 2(a) covered a hydrosol formed in situ.
[12] She came to this conclusion by examining the wording of the patent claim, its disclosure and specification stating at paragraph 31 of her reasons:
¶ 31 Nowhere in the patent could I find any reference to a hydrosol that could be formed after ingestion in the body. The patent teaches variations of a process, requiring human intervention, for making an intravenous solution consisting of a hydrosol:
A solution of the active agent in a solvent which is miscible with water is mixed with a comparatively large amount of water. Mixing preferably is effected rapidly to promote formation of the particles at the same time and in a narrow distribution. Rapid mixing also produces large numbers of colloidal particles. Permanent fixing of the particle size is possible if the influence of the organic solvent is in minimalised and for that reason the solvent is preferably removed. Removal may take place by evaporation, e.g. in a rotary [page172] evaporator. Evaporation can be continued so that the water of the hydrosol is also evaporated. Preferably this is effected by lyophilisation, so as to facilitate redispersibility. Upon complete evaporation of the water, a dry lyophilisate may be formed, especially with Cyclosporin A, gelatin, mannitol and acid additive. [emphasis mine]
[13] She continued her analysis in paragraphs 32, 33 and 34:
¶ 32 The portion of the disclosure identifying stable, solid cyclosporin particles in a "dry and re-suspendable" form as falling within the scope of the invention clearly indicates that the inventor intended such particles to be re-suspended for use in an intravenous application.
¶ 33 The patent provides 12 examples illustrating the invention. In each example, the hydrosol forms by a series of mechanical operations involving dissolving the active agent in an alcohol, adding water and stirring. The resulting preparation is suitable for intravenous injection. The hydrosol never spontaneously generates, and never generates in situ. The examples do not contemplate oral administration.
¶ 34 Neither the disclosure nor the patent claims refer to a hydrosol formed in situ. The lack of such a reference in what is otherwise a complete description of the hydrosol, its advantages, uses and the process by which it is made, leads to the conclusion that an ingested pharmaceutical preparation which forms a hydrosol in situ is not covered by the patent. [emphasis mine]
[14] In the end, she construed claim 2 as follows:
¶ 35 Although Claim 2 is silent with regards to the route of administration and therefore may not be limited only to pharmaceutical preparations for intravenous use, I am satisfied that a contextual examination of the patent can only lead to the conclusion that it covers pre-ingestion solutions. [emphasis mine]
[15] She then addressed the House of Lords decision in Beecham Group Ltd. v. Bristol Laboratories Ltd., [1978] R.P.C. 153 (H.L.) which had been cited by Novartis and found:
¶ 36 The applicants cite Beecham Group Limited as determinative of the issue. In Beecham, the patent covered the medicine ampicillin. The defendant's [page173] drug, hetacillin, converted to ampicillin on ingestion. The House of Lords held that the pith and marrow of the plaintiff's patent had been taken since hetacillin had no antibacterial activity of its own. Its only value as an antibacterial agent arose by virtue of converting into ampicillin.
¶ 37 The present case differs in material respects. As pointed out by the respondent, it is not the value of cyclosporin which must be considered but that of the hydrosol. The purpose of the applicants' invention is to provide a hydrosol with small, stable pharmacologically active agent particles for intravenous use. Obviously, that is not the purpose of the respondent's product which is administered orally. Simply, the respondent's capsules do not perform "substantially the same function in substantially the same way to obtain substantially the same result" as the applicants' invention.
¶ 39 For the above reasons, the applicants have failed to show that the respondent's capsules would infringe the patent. The notice of compliance proceedings are therefore dismissed. [emphasis mine]
[16] Novartis appealed Justice Tremblay-Lamer's decision to the Federal Court of Appeal but before the appeal could be heard, the Minister of Health (the "Minister") issued to Rhoxal a NOC for its 100mg capsules.
[17] Rhoxal then brought a motion to the Federal Court of Appeal to have the Novartis appeal dismissed on the basis it was now moot having regard to the issuance of the NOC.
[18] Novartis disputed that motion. One of the arguments it raised was the appeal was not moot because further NOCs for different dosage strengths could be applied for by Rhoxal who would rely on Justice Tremblay-Lamer's decision in support of possible future NOC proceedings.
[19] Rhoxal's written memorandum before the Court of Appeal addressed Novartis' contention about future NOCs in different dosage forms than the 100mg capsules and the evidentiary bases upon which the issue of whether Rhoxal's NOA could be justified should new NOC proceedings be launched. Rhoxal wrote:
7. . . . Each of these issues would obligatorily be submitted to judicial scrutiny of a court of law to which new evidence relevant to the issue would be presented. Thus, it is not appropriate in this forum to anticipate these cases.
. . .
15. In any event, if further NOC proceedings are filed, they will be decided on the evidence before the Court at the time they are filed. An appeal in this case, whether or nor Novartis is successful, would not bar RhoxalPharma from sending further NOA's or bar Novartis from responding to these NOA's with NOC proceedings. [emphasis mine]
[20] On November 28, 2001, the Federal Court of Appeal dismissed the Novartis appeal on the grounds it was moot.
[21] I mention two other proceedings between Novartis and Rhoxal involving Rhoxal's capsule.
[22] First, Rhoxal sought to dismiss this application on the grounds of res judicata, issue estoppel and abuse of process. Rhoxal, at the hearing, only argued the ground of abuse of process. I heard that motion and dismissed it in Novartis Pharmaceuticals Canada Inc. et al. v. RhoxalPharma Inc. et al. 2002 FCT 742, essentially for the following reasons:
¶ 35 I am of the view Novartis' application filed on March 18, 2002, is not an abuse of process and, as a result, should not be dismissed under subsection 6(5) of the Regulations.
¶ 36 The circumstances surrounding the application which Novartis filed are unique and arise when Rhoxal was successful in having the Novartis appeal from Justice Tremblay-Lamer's judgment dismissed for mootness.
¶ 37 As noted, in that proceeding before the Federal Court of Appeal, Rhoxal said if it filed new NOAs for different dosage strengths of its cyclosporine capsules, Novartis could respond with new evidence in NOC proceedings.
¶ 38 Novartis' application which Rhoxal seeks to strike, is in response to Rhoxal's new NOAs for its cyclosporine capsules in dosage strengths of 25 mg and 50 mg. In the circumstances, Novartis' application cannot vex Rhoxal, cannot be unfair to it and cannot bring the administration of justice into disrepute.
[23] That decision was not appealed by RhoxalPharma.
[24] Second, in another context, Novartis brought an action against RhoxalPharma for patent infringement claiming RhoxalPharma infringed its '656 Patent in marketing the 100mg Rhoxal capsules. Rhoxal moved for summary judgment on the basis of Justice Tremblay-Lamer's decision.
[25] That motion was dismissed by Justice Martineau, in part, on the ground whether the variant that Rhoxal had made was a non-essential limitation and thus within the patent on the doctrine of equivalents, raised a genuine issue for trial. (See, docket T-1158-01, September 19, 2002, FCTD.)
FACTUAL BACKGROUND
[26] There are certain facts not in substantial dispute.
[27] Cyclosporine is a drug that has utility as an immunosuppressant agent useful in treating patients who have undergone transplant surgery; the drug assists in preventing a rejection of the transplant.
[28] Cyclosporine has low solubility in water and thus is unstable and difficult to formulate in a manner that it can be optimally absorbed by the human body.
[29] The '656 Patent is a formulation patent; it claims a pharmaceutical preparation of cyclosporine in the form of a hydrosol. Its invention is in providing for the creation of a method of delivering the active ingredient, cyclosporine. That method of delivery is a hydrosol with specific characteristics: the suspension of a dispersion in an aqueous medium of fine, stabilized (from 1 to 10,000 nanometres) of solid particles of the active ingredient cyclosporine (hydro meaning water; sol meaning a solid).
[30] The fine sizes of the solid particles of cyclosporine improves its absorption into the human body providing for an overall increase in the efficacy of the drug.
[31] The predecessor to Novartis Canada, Sandoz Canada, brought to the marketplace, in 1984, its first oral dosage form of cyclosporine; it was in the form of an oral solution.
[32] Then, in 1987, SANDIMMUNE capsules were introduced.
[33] It is acknowledged by one of Novartis' deponents in this proceeding, Andreas Orfanos, that in spite of its great value in preventing transplant rejections, SANDIMMUNE's oral solution and capsules had serious drawbacks in terms of the low bioavailability of the cyclosporine delivered. In addition, patient variability of cyclosporine in a patient's bloodstream as well the variability within the same patient, was quite large.
[34] Mr. Orfanos informed in his affidavit, to address these problems, Novartis developed an improved formulation of cyclosporine consisting of a new formulation which formed a microemulsion when administered, i.e. when added to water or the contents of the stomach. This product was introduced in Canada in 1995 and sold under the name NEORAL. According to Mr. Orfanos, NEORAL was a significant improvement over SANDIMMUNE.
[35] The parties do not disagree how, at least theoretically, the hydrosol is formed.
[36] There are two basic steps to the preparation of the formulation which, when added to water, may create a hydrosol.
[37] The first step is the preparation of the solution. The solution consists of cyclosporine which is first dissolved in a solvent such as ethanol to which is added a surfactant, a stabilizer and a compound to help dissolve the capsule if that dosage form is used.
[38] The next step is the mixing of the solution with water and the result is a fine opalescent system, i.e. particles are formed and stay suspended in the liquid. The particles are stabilized in that they do not grow or change in distribution relative to one another. When the dosage form is a solution, the patient mixes the solution in a glass of water according to the drug manufacturer's instructions and drinks the microemulsion. In capsule form, water contact occurs in the stomach where the hydrosol is formed.
[39] The active ingredient is then released at a slow rate and absorbed into the bloodstream where the beneficial effect of the medicine is experienced.
THE EVIDENCE
[40] Both parties filed expert evidence serving fundamentally two different purposes. The first set of affidavits describes laboratory experiments conducted for the purpose of determining whether, after mixing with water, the Rhoxal formulation created a hydrosol with the precise characteristics identified in the '656 Patent. The second set of affidavits went to the issue of proper patent construction and to the doctrine of equivalents.
(a) Does the Rhoxal capsule create a hydrosol when ingested?
[41] As noted, the answer to this question was sought to be answered by both sides conducting laboratory experiments in vitro but not in vivo.
[42] Novartis led affidavit evidence from Michael Ambühl who holds a doctorate from the Federal Institute of Technology at Zurich, Switzerland. From April 1995 to February 1997, he was engaged as a post-doctoral student at Sandoz (now Novartis) in the drug delivery systems department. Since 1997, he has been a full-time employee with Novartis and is their laboratory head of the drug delivery systems department.
[43] The purpose of his affidavit, dated April 16, 2002, was to confirm a previous affidavit dated September 17, 1999, which he had sworn and had been filed in the proceeding before Justice Tremblay-Lamer. That affidavit described the tests he conducted. The second purpose of his affidavit was to answer certain criticisms levelled at his experiment by Dr. Louis Cartilier, who, on behalf of Rhoxal, also had filed expert evidence in the proceeding before Justice Tremblay-Lamer.
[44] To perform his experiment conducted in 1998, Dr. Ambühl had been provided with the exact specifications of the ingredients for the formulation of Rhoxal's solution which would be packaged into the Rhoxal capsule shell. Those specifications came from then Rhoxal's U.S. supplier EON. He formulated the solution, mixed it with water and observed the formation of the opalescent system which he determined, through examination by a laser light scattering instrument, to be particles in the aqueous medium.
[45] Because the emulsion had not settled, Dr. Ambühl placed some of it in a test tube centrifuge, obtained a settlement, dried it and subjected it to electron microscopy of a specific type. He stated he observed solid, spherical particles which were further tested and, after subsequent analysis, confirmed as solid particles of cyclosporine A. As a result of this experiment, he concluded the mixing of the Rhoxal formulation with results in the formation of a fine suspension of spherical cyclosporine A particles having an average diameter of about 200nm with the suspension being stable not readily sedimenting. He concluded the particles were hydrosol particles and was of the opinion that a hydrosol would form when the RhoxalPharma capsules were ingested.
[46] Rhoxal, to counter Dr. Ambühl, filed the affidavit of Dr. Harry Brittain, dated August 1, 2002. Dr. Brittain earned, in 1975, a Ph.D. in physical chemistry from the City University of New York. He is presently the Director of the Centre for Pharmaceutical Physics working in the area of pharmaceutical physics and physical pharmacy, especially pre-formulation, formulation design and product characterizations. From 1979 to 1985, he was then Associate Professor at Seton Hall University. From 1985 to 1994, he was employed at Bristol-Myers Squibb Pharmaceutical Research Institute and after that, until 1999, was Vice-President of Pharmaceutical and Chemical Development at Discovery Laboratories Inc. and was responsible for certain aspects of drug development and management of all analytical, pharmaceutical, and chemical development efforts.
[47] In separate experiments, Dr. Brittain dispersed the contents of a 100mg capsule of the Rhoxal formulation in either distilled water or other aqueous media such as 0.1 N HCL ("HCL") or simulated gastric fluid ("SGF"). Dr. Ambühl also had tested the Rhoxal formulation in HCL and SGF media.
[48] After mixing the Rhoxal formulation in either the water, HCL or SGF, a cloudy dispersion formed. He extracted a small quantity of that cloudy dispersement and examined it under a scanning optical microscope ("SEM"). He reached the following conclusions:
1. The cloudy substance did not disclose any solid particles. Rather, what he observed were not particles but liquid globules;
2. The cumulative particulate size distribution in his exhibit 11 [applicants' record, page 464] revealed the cloudy dispersion contained significant contribution from globules whose size exceeded 10 microns therefore exceeded the upper limit of the particle size specified in the '656 patent; and
3. The liquid globules were not stable; they grew in size over a period of observation of three hours.
[49] Dr. Brittain was cross-examined after he filed a rebuttal affidavit. The results of that cross-examination and rebuttal affidavit will be discussed later in these reasons.
[50] Rhoxal, in chief, also filed the reply affidavit of Dr. Louis Cartilier, who holds a Ph.D. degree in Pharmaceutical Science from the Institut de Pharmacie de l'Université Libre de Bruxelles. He teaches the science of pharmacy at the Faculty of Pharmacy of the University of Montreal. While the thrust of Dr. Cartilier's affidavit speaks to the issue of whether a hydrosol formed in situ is a pharmaceutical preparation within the meaning of the '656 Patent, he made a number of points on the issue of whether the Rhoxal formulation could lead to the creation of a hydrosol after the Rhoxal capsule was ingested.
[51] He criticized the Ambühl experiment because he said Dr. Ambühl did not follow the exact steps when manufacturing the Rhoxal formulation. Instead of dissolving the cyclosporine in the ethanol solvent prior to being mixed with the other ingredients, all ingredients were mixed together.
[52] He stated the results of an in vitro experiment were no proof of in vivo results.
[53] He expressed the opinion the Rhoxal formulation is an oil-based formulation similar to the formulation in the Novartis product sold under the trademark SANDIMMUNE. He then referred to research papers by researchers at Sandoz and other papers and concluded no in situ spontaneous generation of a hydrosol upon ingesting an oil-based formulation of cyclosporine was possible. He stated the experiments presented in the Ambühl affidavit indicate the existence of lipid droplets containing cyclosporine, i.e. a dispersed system oil-in-water or an emulsion and lacked a demonstration of the existence of a hydrosol or a suspension of solid particles in aqueous media. Dr. Cartilier was also cross-examined which I will address later.
[54] Novartis was permitted to file reply evidence. One of its two deponents in reply was Dr. David E. Bugay who holds a Ph.D. degree in Physical Chemistry from the University of Vermont in 1987. Prior to his current employment as Vice-President of Analytical Chemistry at SSCI Inc. which he joined in March of 1998, he had been employed at the Bristol-Myers Squibb Pharmaceutical Research Institute.
[55] Dr. Bugay's reply affidavit served two purposes: he commented on the Brittain and Ambühl affidavits. He also described experiments he conducted. Dr. Bugay was not cross-examined.
[56] On the first aspect of his reply affidavit and limiting himself to a review of the Ambühl and Brittain affidavits, Dr. Bugay concluded the results of the experiments they conducted were not contradictory simply because they were not examining the same set of particles which had formed after the Rhoxal formulation was mixed in water.
[57] Dr. Bugay stated that, although Dr. Brittain's experiments showed or disclosed, in his exhibit 11, the existence of particles in sizes between 100 to 500nm, he did not examine them.
[58] Dr. Bugay stated Dr. Brittain did not look for the particles Dr. Ambühl said were present in the opalescent system. Dr. Brittain did not find them because he did not look for them. Dr. Bugay was of the opinion Dr. Brittain's finding that no solid particles were formed was not supportable.
[59] Dr. Bugay expressed the opinion it would still be within the scope of claim 2 of the '656 Patent if some of the opalescent system was in the form of solid particles as described in the '656 Patent while others were not. In his view, all that Dr. Brittain had done was merely to say some of the opalescent system had not formed solid particles and therefore there was no hydrosol within the patent. He disagreed with that interpretation.
[60] The second aspect of Dr. Bugay's affidavit was to describe his two environmental scanning electron microscopy ("ESEM") experiments to determine whether the opalescent system contained solid particles. He stated he chose ESEM as it permitted one to obtain a picture of the small particles in the 200 to 500nm range if they existed.
[61] In his first experiment, Dr. Bugay placed the contents of a 100mg RhoxalPharma cyclosporine capsule into 200ml of HCL. The solution was agitated for approximately 10 minutes in water. A small aliquot was then placed into the scanning electron microscopy mount and images were obtained.
[62] For the second experiment conducted by Dr. Bugay, he placed the entire 100mg capsule, with its shell, in 200 ml of HCL and then performed the other steps described in respect of his first experiment.
[63] He concluded as follows at paragraphs 31 and 32 of his affidavit:
31. Scanning electron microscopy of both solutions revealed that the 0.1 N HCL solution contained small particles between 100 nm and 500 nm. Marked as Exhibit B and C are representative scanning electron microscopy pictures of the small particles obtained when the RhoxalPharma 100 mg cyclosporine capsule contents or capsule is added to 0.1 N HCL, respectively. These pictures establish that a solid particle is present in the particle size range investigated by Dr. Ambühl.
32. Based on all of the above, it is my opinion that when the Rhoxal Pharma capsules are added into 0.1 N HCL solution, solid particles of the hydrosols in the size range of between 100 to 500 nm that is of the type described in the '656 patent are formed.
[64] Again, as noted, he was not cross-examined on any of his affidavits.
[65] The other Novartis deponent to file a reply affidavit was Dr. McGinity whose qualifications I have yet to describe because the main thrust of his affidavit evidence was to speak to patent construction which will be discussed later. However, he touched upon certain aspects of hydrosol formation.
[66] Briefly put, Dr. McGinity disagreed with Dr. Cartilier that the use of SGF or HCL is not a fair representation of what would happen in vivo in the stomach. He stated it was standard in the pharmaceutical industry to use HCL or SGF to simulate in vitro what occurs to a pharmaceutical formulation in the human stomach in vivo. He stated the use of these fluids is recognized and accepted by regulatory authorities such as the USFDA and the United States Pharmacopoeia lists several monographs which contain HCL and SGF as dissolution and disintegration media for various drug producers.
[67] He disapproved of the suggestion made by Dr. Cartilier a real test should have been conducted in vivo on a human by extracting a sample of his/her stomach contents after ingestion of the Rhoxal capsule. According to him, such a procedure was unnecessary and would require a detailed test protocol which would not receive the approval of an ethics review board of a qualified institution.
[68] He tackled Dr. Cartilier's suggestion Rhoxal's formulation is an oil-based one. He stated none of Rhoxal's components is an oil. More importantly, however, he stated what appears to be occurring when the Rhoxal formulation is added to water is precisely what was taught at page 10 of the '656 Patent which reads:
The novel hydrosol forms may particularly be prepared as follows: a solution of the active agent in a solvent which is miscible in water, e.g. in alcohol, e.g. ethanol or isopropanol, or in acetone, is mixed with a comparatively large amount of water, under such conditions that a hydrosol is produced.
[69] From this teaching of the '656 Patent, he stated one way to make a hydrosol is to dissolve cyclosporine in an organic solvent or solvents and to add the solubilized cyclosporine to a large volume of water. He stated each of the Rhoxal formula ingredients, including the surfactant were soluble. In his reply affidavit, Dr. McGinity touched upon certain statements Dr. Brittain had made on the stability of particle size distribution in the opalescent system which I need not describe given what occurred on Dr. Brittain's cross-examination.
[70] RhoxalPharma obtained leave to file rebuttal affidavits from Drs. Brittain and Cartilier to the reply affidavits of Drs. Bugay and McGinity.
[71] Dr. Brittain commented on Dr. Bugay's affidavit. He made two concessions. First, he readily admitted that the smallest particle he could visualize with the microscopy he used would be around 1 micron in diameter but added "[H]owever, I saw large numbers of much larger liquid globules, and never saw anything that could be characterized as a solid particle". The second concession was his admission Dr. Bugay was correct in finding he had not addressed the question of whether the particle size present in his Exhibit 11 was solid or not. "However, my experiments would not be able to yield this information" and he added, "[O]f note, however, is that the Applicant did not perform any definitive experiments that answered this question either".
[72] Throughout his affidavit, Dr. Brittain disagrees with Dr. Bugay when Dr. Bugay stated Dr. Ambühl found solid particles. In his view, Dr. Ambühl never proved the existence of any solid suspended colloidal particles.
[73] The final major point Dr. Brittain made was to criticize SEM which he found inappropriate because SEM requires extensive sample preparation which prevents discovery of what really existed in the original dispersions of the Rhoxal formulation.
[74] Dr. Cartilier challenged Dr. McGinity's reply affidavit. He did not criticise Dr. Bugay's rebuttal affidavit. His major point was Dr. McGinity's reluctance to accept his characterization of the Rhoxal formulation as an oil-based formulation. He stated what makes that formulation an "oil-based formulation" is the presence of an ingredient, the surfactant, which is derived from vegetable oil, a solubilizer and emulsifier which comprises hydrophobic and hydrophilic components and is commonly used to stabilize micellar systems of poorly water soluble drugs such as cyclosporine. He refers to learned articles. He disagreed that the ingredient was an organic solvent and he disagreed 0.1 N HCL or SGF is used to simulate any change in physical structure (e.g. formation of a hydrosol) which might occur in the stomach.
(b) Evidence relating to patent construction
[75] Novartis led extensive evidence, through Drs. Ambühl and McGinity, how claim 2(a) of the '656 Patent should be construed, evidence which the applicants said was not put before Justice Tremblay-Lamer because of the way the proceeding before her unfolded where, on this point, she apparently only had the evidence of Dr. Cartilier. I summarize Dr. Ambühl's evidence.
(i) Dr. Ambühl's affidavit evidence
[76] As noted, the purpose of Dr. Ambühl's affidavit was also to answer some of Dr. Cartilier's criticism about the way he conducted his experiment in 1998.
[77] First, Dr. Ambühl stated Dr. Cartilier, in the affidavit put before Justice Tremblay-Lamer, indicated, because a hydrosol could form in plain water, it was in no way proof of actual in vivo results. Dr. Ambühl answered based on his experience and his laboratory work with cyclosporine "that it is fair to say that demonstration that a hydrosol forms in plain water would mimic what occurs to the capsule in the stomach". (applicant's application record, volume 1, page 164). He added he also conducted similar experiments not only in water but in UPS simulated gastric fluid and in another acidic environment, i.e. HCL and the results were substantially the same.
[78] Dr. Cartilier criticised the manner in which Dr. Ambühl carried out his experiment and, in particular, he did not follow EON's detailed instructions for dissolving the cyclosporine in ethanol before mixing with the other agents to form the Rhoxal formulation. Dr. Ambühl stated the formulation was prepared by mixing the ingredients and stirring thoroughly. With respect to two agents, he said they were warmed to liquefy them prior to mixing them with the other components of the Rhoxal formulation. He concluded there was nothing inconsistent with RhoxalPharma's instructions.
[79] Dr. Ambühl stated Dr. Cartilier indicated, in the affidavit he filed before Justice Tremblay-Lamer, claim 2 of the '656 Patent purported to claim only pharmaceutical preparations which are completed at the time of manufacturing and, once ingested by the patient, what occurs is delivery of the active agent, as opposed to ongoing preparation. For these reasons, Dr. Cartilier disagreed with the very concept the '656 Patent could be infringed by what happens to a capsule once ingested by the patient (applicant's application record, volume 1, page 164, para. 7).
[80] Dr. Ambühl disagreed with those comments stating as follows (applicant's application record, volume 1, page 165):
8. . . . A pharmaceutical preparation means a number of things to a person skilled in the art. One aspect of a pharmaceutical preparation refers to what is completed at the time of manufacturing and shipped out the door. However, there are a number of other pharmaceutical preparations which exist. For example, one pharmaceutical preparation may be transformed into a second pharmaceutical preparation, and perhaps even a third, by virtue of further actions taken by persons other than the manufacturer.
[81] Dr. Ambühl gave the example of a pharmaceutical preparation such as amoxicillin sold by a manufacturer as a powder. He noted this product was not yet in the form which may be taken by the patient which typically occurs when the pharmacist makes up a further pharmaceutical preparation by adding an appropriate amount of water to the powder and shaking up the product so that the product forms a suspension. According to Dr. Ambühl, this is the product which is sold to the patient by the pharmacist and it constitutes a different form of the pharmaceutical preparation than that which was shipped by the manufacturer. He added, when the patient goes to take the product, the product may have settled and therefore is no longer in the form of a suspension but in the form of a solution with some of the particles aggregated at the bottom of the bottle. The patient, he says, creates a further pharmaceutical preparation by shaking, thereby recreating the suspension.
[82] As another example, Dr. Ambühl cited Neo-Citran, a Novartis product, which is shipped in powder form in a foil package. The product is not intended to be taken in powder form which is considered a pharmaceutical preparation. A further pharmaceutical preparation is prepared by the consumer by adding a relatively large amount of boiling water.
[83] He also mentioned Novartis' NEORAL product which comes in the form of an oral liquid as well as capsule and stated:
13. . . . In respect of the oral liquid, the product which is sold by Novartis is not intended to be taken in that form. Thus, while as sold by Novartis, the product is a pharmaceutical preparation, the product is not yet in the form to be administered and absorbed by the patient. In particular, the directions which accompany NEORAL® oral solution indicate that it should be taken with orange juice or water or other such beverage. The cyclosporine formulation, upon addition of orange juice or water, takes a different form from that which it was as packaged. In particular, as packaged, the cyclosporine formulation is in the form of a microemulsion pre-concentrate and, like the RhoxalPharma product, is a solution in a capsule. Upon addition of the orange juice, the product spontaneously forms a microemulsion entirely analogously to the transformation of the RhoxalPharma product to a hydrosol. It is in the form of the microemulsion preparation which is then swallowed by the patient which permits the absorption of the active ingredient cyclosporine into the blood stream.
[84] At paragraphs 14 and 15 of his affidavit, he stated NEORAL cyclosporine oral capsules work in a similar manner but with some slight modification. He continued: (applicants' record, page 166)
14. . . . In particular, while the oral capsules themselves are a pharmaceutical preparation however, this preparation is not in the final form which will permit the absorption of the cyclosporine. It is only after ingestion of the oral liquid capsules, wherein the liquid inside the capsules has contact with the relatively large amount of fluids of the stomach and forms the microemulsion in the stomach, that it is in the form of a preparation which may allow the absorption of the cyclosporine into the blood stream.
15. This is entirely analogous to administration of the RhoxalPharma formulation.
[85] He concluded (applicants' record, volume 1, page 167):
17. Therefore, in my opinion, the RhoxalPharma product is within claim 2 of the '656 patent by virtue of the action of the product to form hydrosols in the stomach. Further, as I understand them, the words "pharmaceutical preparation" in claim 2 are not limited to the pharmaceutical preparation which is sold by the manufacturer, but include steps taken by a pharmacist or consumer to put the product into the final form of the pharmaceutical preparation for administration. I see no reason why a product in the oral liquid capsule form should not be covered by the claim when the oral liquid solution form would be covered.
(2) The affidavit evidence of Dr. James McGinity
[86] As mentioned, Dr. McGinity provided affidavit evidence on the construction of claim 2 of the '656 Patent which also included his observations on Dr. Cartilier's affidavit before Justice Tremblay-Lamer. Dr. McGinity was not cross-examined. He is a tenured professor of pharmacy at the College of Pharmacy, the University of Texas, at Austin, and, since 1985, has held the Johnson & Johnson Centennial Chair of Pharmacy. He holds his Ph.D. degree in Physical Pharmacy from the University of Iowa in 1972. He has been a university professor since 1973. He is also the Division Head of Pharmaceutics and the Director of the Drug Dynamics Institute. His areas of research include oral drug dosage forms, material science, pharmaceutical processing and topical and emulsion technologies. He is currently President of PharmaForm L.L.C. in Austin, Texas, which is a research and development company that works with both innovative and generic pharmaceutical companies.
[87] He makes the following points in his affidavit:
(1) He noted the '656 Patent is entitled "Hydrosols of Pharmacologically Active Agents and their Pharmaceutical Compositions Comprising Them". This patent concerns formulations of cyclosporine related to hydrosols of cyclosporine suspended or resuspendable in an aqueous medium. He quotes from page 2 of the patent specification which states "after administration as a suspension, the pharmacologically active ag