Janssen Inc. v. Teva Canada Limited

Janssen Inc. v. Teva Canada Limited
Court (s) Database
Federal Court Decisions
Date
2015-02-16
Neutral citation
2015 FC 184
File numbers
T-2195-12
Decision Content
Date: 20150216
Docket: T-2195-12
Citation: 2015 FC 184
Ottawa, Ontario, February 16, 2015
PRESENT: The Honourable Mr. Justice Barnes
BETWEEN:
JANSSEN INC.
Applicant
and
TEVA CANADA LIMITED AND
MINISTER OF HEALTH
Respondents
and
MILLENNIUM PHARMACEUTICALS, INC.
Respondent Licensee and Sub-Licensor
and
UNITED STATES OF AMERICA REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES
Respondent Patentee
JUDGMENT AND REASONS
[1] This is an application by Janssen Inc. [Janssen] under the Patented Medicines (Notice of Compliance) Regulations, SOR 93-133 as amended [NOC Regulation] for an Order prohibiting the Minister of Health [Minister] from issuing a Notice of Compliance [NOC] to Teva Canada Limited [Teva] for a generic version of the drug VELCADE® bortezomib mannitol boronic ester for injection (velcade bortezomib). Velcade bortezomib is a very effective medicinal adjunct in the treatment of the blood cancer multiple myeloma.
[2] The Patent in issue in this proceeding is Canadian Letters Patent 2,435,146 [the 146 Patent]. The only remaining issue in contention is whether Claim 30 of the 146 Patent was, as of January 25, 2001, invalid for obviousness.
I. Background [3] The active pharmaceutical agent [API] that underlies the 146 Patent is the compound bortezomib, known to be an active proteasome inhibitor. Prior to the formulation in the 146 Patent, bortezomib was sufficiently stable to enable clinical trials but it was not stable enough for commercial exploitation. The 146 Patent addresses the issue of formulation stability.
[4] Velcade bortezomib is, in practical terms, a stable formulation of bortezomib but it is also a different compound from bortezomib. Claim 30 of the 146 Patent is for the lyophilized (freeze-dried) mannitol ester of bortezomib which forms as a reaction product when the bulking agent, mannitol, is combined with bortezomib.
[5] The 146 Patent states that boronic acid and ester compounds were known to be useful as inhibitors of certain proteolytic enzymes that, in some forms, were capable of inhibiting the growth of cancer cells. These compounds were also known to be unstable, particularly in the presence of oxygen. This instability was said to limit the pharmaceutical utility of the compounds and, hence, the need for improved formulations that could be conveniently prepared, that exhibited enhanced stability and shelf life as compared to free boronic acid compounds and that would readily liberate the API when administered. The invention is described at paragraph 6 as follows:
[0006] The present invention provides stable, pharmaceutically acceptable compositions prepared from boronic acid compounds. The invention also provides methods for preparing such compositions. The invention provides the discovery that lyophilization of an aqueous mixture comprising boronic acid compound and a compound having at least two hydroxyl groups produces a stable composition that readily releases the boronic acid compound upon dissolution in aqueous media.
[6] The 146 Patent asserts claims over a genus of “novel” boronate ester compounds as well as non-ester boronic acid compounds [see para 35, 38 and 135]. The claimed compounds are not limited to those constituted through lyophilization although that is said to be a preferred embodiment [see para 101]. Similarly, the use of mannitol is not asserted to be an essential embodiment for all of the claims although it, too, is said to be particularly preferred and most preferably D-mannitol. In other preferred embodiments, the dihydroxy compound (eg mannitol) remains “free” or unresolved [see para 99].
[7] It is also of some note that the Patent specification does not maintain that the formation of a boronate ester from the reaction between mannitol and a chosen boronic acid compound is required for efficacy. Similarly, the Patent does not assert that the lyophilized ester was shown to have an enhanced stability profile over the other boronate esters formed by other means.
II. Burden of Proof [8] Teva has met its evidentiary burden and the ultimate burden therefore rest with Janssen on a balance of probabilities.
III. Obviousness – Legal Principles [9] Section 28.3 of the Patent Act, RSC, 1985, c P-4, requires that the subject matter of a patent claim not be obvious on the claim date to a person skilled in the art or science to which it pertains. The parties agree that the relevant date for determining whether Claim 30 is obvious is January 25, 2001.
[10] In Apotex v Sanofi, 2008 SCC 61, [2008] 3 SCR 265 , the Supreme Court of Canada set out a four-part test for assessing obviousness:
a. Identify the notional ‘person skilled in the art’ and the relevant common general knowledge of that person;
b. Identify the inventive concept of the claim in question or if that cannot readily be done, construe it;
c. Identify what, if any, differences exist between the matter cited as forming part of the ‘state of the art’ and the inventive concept of the claim or the claim as construed; and
d. Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to a person skilled in the art or do they require any.degree of invention.
[11] The fourth step of an obviousness inquiry may require an “obvious to try” analysis which the Court in Sanofi described in the following way:
a. Is it more or less self-evident that what is being tried ought to work? Are there a finite number of identified predictable solutions known to persons skilled in the art?
b. What is the extent, nature and amount of effort required to achieve the invention? Are routine trials carried out or is the experimentation prolonged and arduous, such that the trials would not be considered routine?
c. Is there a motive provided in the prior art to find the solution the patent addresses?
[12] An obviousness challenge will not succeed if the prior art only establishes that something might work. On the other hand it does not require that there be a guarantee of success. The test is whether there would be a fair expectation of success: see Apotex v Pfizer, 2009 FCA 8 at para 8, [2009] 4 FCR 223.
[13] As with Justice Roger Hughes in Novartis Pharmaceuticals Canada Inc. v Teva Canada Limited., 2013 FC 283 at para 161, 2013 FCJ No 303 (QL), I endorse the view of obviousness and obvious to try expressed in the following passage from by Kitchin L. J. in MedImmune Ltd. v Novartis Pharmaceuticals UK, [2012] EWCA Civ 1234:
90. One of the matters which it may be appropriate to take into account is whether it was obvious to try a particular route to an improved product or process. There may be no certainty of success but the skilled person might nevertheless assess the prospects of success as being sufficient to warrant a trial. In some circumstances this may be sufficient to render an invention obvious. On the other hand, there are areas of technology such as pharmaceuticals and biotechnology which are heavily dependent on research, and where workers are faced with many possible avenues to explore but have little idea if any one of them will prove fruitful. Nevertheless they do pursue them in the hope that they will find new and useful products. They plainly would not carry out this work if the prospects of success were so low as not to make them worthwhile. But denial of patent protection in all such cases would act as a significant deterrent to research.
91. For these reasons, the judgments of the courts in England and Wales and of the Boards of Appeal of the EPO often reveal an enquiry by the tribunal into whether it was obvious to pursue a particular approach with a reasonable or fair expectation of success as opposed to a hope to succeed. Whether a route has a reasonable or fair prospect of success will depend upon all the circumstances including an ability rationally to predict a successful outcome, how long the project may take, the extent to which the field is unexplored, the complexity or otherwise of any necessary experiments, whether such experiments can be performed by routine means and whether the skilled person will have to make a series of correct decisions along the way. Lord Hoffmann summarised the position in this way in Conor at [42]:
"In the Court of Appeal, Jacob LJ dealt comprehensively with the question of when an invention could be considered obvious on the ground that it was obvious to try. He correctly summarised the authorities, starting with the judgment of Diplock LJ in Johns-Manville Corporation's Patent [1967] RPC 479, by saying that the notion of something being obvious to try was useful only in a case where there was a fair expectation of success. How much of an expectation would be needed depended on the particular facts of the case."
92. Moreover, whether a route is obvious to try is only one of many considerations which it may be appropriate for the court to take into account. In Generics (UK) Ltd v H Lundbeck, [2008] EWCA Civ 311, [2008] RPC 19, at [24] and in Conor [2008] UKHL 49, [2008] RPC 28 at [42], Lord Hoffmann approved this statement of principle which I made at first instance in Lundbeck:
"The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success."
93. Ultimately the court has to evaluate all the relevant circumstances in order to answer a single and relatively simple question of fact: was it obvious to the skilled but unimaginative addressee to make a product or carry out a process falling within the claim…
Also see: Eli Lilly and Company v Janssen Alzheimer Immotherapy, [2013] EWHC 1737 at para 232.
[14] The strength of the ability to predict success is important to an obvious to try analysis and not necessarily whether the means or methods employed to arrive at the result were well-known. Nevertheless, the employment of known or routine testing to arrive at a solution is a relevant consideration. This point was recognized by Pelletier J. A. in the following passage from Apotex Inc. v Sanofi-Aventis, 2013 FCA 186, [2013] FCJ No 856 (QL):
81 Given that the Trial Judge applied the test for obviousness set out in Plavix, and given that he applied it to the same material facts as the Supreme Court, he ought to have come to the same conclusion. His error lay in failing to recognize that the unknown nature of the properties of the enantiomers of PCR 4099, or of any of the other compounds of the '875 Patent, was fatal to the "obvious to try" analysis. Put another way, the distance between the common general knowledge and the inventive concept of the '777 Patent could not be bridged by routine experimentation since the results to be obtained were unknown. On the facts, this was confirmed by the fact that the inventors, who had more knowledge that the person of ordinary skill in the art, attempted to resolve a number of other compounds before finally trying PCR 4099: see Reasons, at paragraphs 752-759. [Emphasis added]
IV. The Expert Witnesses [15] Janssen led evidence from one expert witness, Dr. Roland Bodmeier. Dr. Bodmeier’s evidence is mainly in the area of formulation science, that being his field of specialization.
[16] Teva led evidence from two expert witnesses. Dr. William Bachovchin is a bio-chemist and he gave evidence primarily from that perspective. Dr. Raj Suryanarayanan is a formulation scientist with a particular focus on the use of lyophilization. His evidence was provided from the perspective of a skilled formulator.
[17] Both parties challenged the qualifications of the opposing expert witnesses with respect to some or all of the evidence they provided.
[18] Teva argued that Dr. Bodmeier essentially disqualified himself on the topic of lyophilization when he testified that he did not “consider myself a freeze-drying expert because this is not my major research area, but I would say I’m expert enough and have a lot of experience with lyophilization to give a sound opinion or scientifically sound opinion about the 146 Patent”. I do not consider this to be an acknowledgement of a lack of expertise on the part of Dr. Bodmeier. An issue of science need not be a focal aspect of a witnesses’ expert knowledge or experience before it can be addressed in an opinion. That is particularly true of a formulation technique as basic as lyophilization. This is not a topic at the cutting edge of formulation science where general knowledge may not be sufficient; and even there the issue would generally go to the weight of the evidence and not to its admissibility.
[19] Janssen criticized Dr. Bachovchin, saying that he lacked formulation experience. That reservation was borne out somewhat by Dr. Bachovchin when he acknowledged his limitations in that area. Dr. Bachovchin was, however, put forward by Teva for his experience as a medicinal chemist. He did express some views on the practices of formulation scientists based on his experience working with them. Much of this evidence was elicited under cross-examination. In the end Dr. Bachovchin gave evidence about what the person of skill would understand from a medicinal chemistry point of view and that evidence was left unchallenged. There is no basis to reject Dr. Bachovchin’s evidence in whole or in part.
[20] Janssen also asserted that Dr. Bachovchin’s evidence ought to be excluded because he had been involved in the development of a compound that might ultimately be useful to treat multiple myeloma, thereby creating a commercial conflict of interest with the Janssen product. The mere possibility that this other compound might ultimately be shown to be useful and obtain regulatory approval to treat multiple myeloma is so remote that no reasonable person would conclude that a conflict existed. Furthermore, this argument cannot be isolated from Janssen’s approach to Dr. Bachovchin’s evidence which was, essentially, to leave it unchallenged. In the absence of conflicting evidence there is no reason to be suspicious of Dr. Bachovchin’s evidence about what a person of skill with medicinal chemistry expertise would understand from the relevant prior art.
[21] Janssen’s criticism of Dr. Suryanarayanan was limited to the idea that he had a bias favouring the use of lyophilization as a stabilizing method. There is no plausible evidentiary support for this allegation and I reject it.
[22] In my view, each of these witnesses was appropriately qualified to put forward the opinions they gave. They each had relative advantages and disadvantages in terms of their experience but there is nothing in the record that could properly disqualify any of them as an expert witness. My conclusions about their respective evidence turn, therefore, on weight and primarily on issues of clarity, consistency, logic and the presence of contradictions.
V. Dr. Bodmeier’s Evidence [23] Dr. Bodmeier is a Professor of Pharmaceutical Technology in the College of Pharmacy at the Frere University in Berlin, Germany. His teaching focuses on pharmaceutical technology, biopharmaceutics, doseage forms (including the formulation and characterization of doseage forms), use of excipients, parenteral drug delivery and lyophilization. He holds several editorial positions for international pharmaceutical publications and he sits on a number of scientific advisory boards.
[24] Dr. Bodmeier’s research includes the publication of 170 scientific articles and several book chapters. Some of his published work involves the process of lyophilization. He is clearly a skilled formulation scientist.
[25] Dr. Bodmeier was asked by Janssen to review the 146 Patent to address some of the allegations of invalidity asserted by Teva and, in particular, obviousness.
[26] Dr. Bodmeier’s description of the person of skill was that of a drug formulator with a university degree and at least two years of experience working in a laboratory. That person would be familiar with drug formulation and with generally accepted textbooks in the field.
[27] In his affidavit, Dr. Bodmeier discusses the usual approach to the development of a pharmaceutical formulation. Before beginning this work the formulator is typically given general information about the desired formulation including the pharmacokinetic profile of the compound and its stability parameters.
[28] The usual first choice route of administration for a drug is oral. If that approach is unworkable, other methods will be considered including transdermal, injectable and nasal.
[29] The formulator must consider the physiochemical properties of the subject compound including its solubility in a variety of solvents such as water. Stability of a formulation is almost always a requirement and a two-year shelf-life is the usual minimum goal. Instability can be caused by oxidation (reaction with oxygen or the removal of hydrogen), hydrolysis (reaction with water) and photochemical exposure (reaction to light).
[30] According to Dr. Bodmeier, when the formulator’s choice is an injectable formulation, ready-to-use is generally preferred over reconstituted solid state doseage forms. Solid state doseages require additional steps before administration to a patient thereby inviting human error. Problems can also be encountered in efficiently reconstituting a powder into a liquid injectable form. Nevertheless, when a compound is too unstable to be formulated in a liquid form it is sometimes necessary to consider other options such as a lyophilized or a dry powder formulation.
[31] Dr. Bodmeier described the method of lyophilization and noted that it requires the formulator to make certain processing choices.
[32] A bulking agent may also be necessary to increase the amount of solid material in a doseage. Dr. Bodmeier pointed out that the formulator has various options for bulking agents and for solvents (ideally water). The primary concern is that those choices not be harmful to humans.
[33] Paragraph 54 of Dr. Bodmeier’s affidavit states that lyophilization is sometimes unsuccessful for a particular compound because of unresolved stability issues or problems with reconstitution. He concludes that paragraph with the assertion that “there is no guarantee of success with a lyophilized formulation”. [Emphasis added]
[34] Paragraphs 54 and 55 of Dr. Bodmeier’s affidavit discuss a variety of other options that may be useful to formulate poorly soluble compounds. Paragraph 57 then states:
57. Most formulators have personal preferences for certain techniques. As a result, there are often a number of paths that could be taken by different formulators to arrive at a solution to a given formulation problem. In any event, the process of formulation is an iterative process that typically involves trying any number of formulations using any number of different options as discussed above. The job of the formulator is to narrow the options and ultimately come up with a workable formulation. Sometimes this can be extremely challenging and sometimes the formulator is met with failure and no workable formulation is developed.
[35] In considering the 146 Patent, Dr. Bodmeier acknowledged that the first aspect deals with compounds and the second aspect relates to the composition of claimed compounds in lyophilized powder form.
[36] Dr. Bodmeier noted the poor solubility and instability of bortezomib which makes the development of an acceptable formulation “more difficult”. The problem of improved solubility is said to be overcome by lyophilization with mannitol.
[37] According to Dr. Bodmeier, the instability of bortezomib in solution and in solid state is confirmed in the 146 Patent disclosure inasmuch as neither was stable for longer than six months. In contrast, the lyophilized product presented no evidence of degradation. The lyophilized product was also shown to be readily reconstituted within 10 seconds and stable for at least 43 hours. The bortezomib component of the composition also became available after reconstitution. On the basis of this evidence, Dr. Bodmeier concluded [see para 74] that “the 146 Patent addresses the key objectives of a formulator, namely the necessary stability of a minimum two year shelf life, while also making the bortezomib component of the drug product readily available at the time of use, in respect of a compound that was clearly highly unstable and poorly soluble”. Dr. Bodmeier then went on to consider the obviousness of the claimed invention as of the claim date of January 25, 2001.
[38] Dr. Bodmeier dismissed many of the prior art references relied upon by Teva on the basis that they would not be considered to be part of the common general knowledge of a formulator and were directed towards an organic or medicinal chemist. Furthermore, references dealing with other compounds “that are not related” to the subject compound are “not particularly useful either”. That is said to be so because “every compound presents with different properties and different problems” [para 96].
[39] Dr. Bodmeier acknowledged that the person of skill would search for literature concerned with bortezomib. Depending on those results, the search could be broadened to look at other boronate references. The person of skill would consider the Wu reference (Wu et al., “Degradation Pathways of a Peptide Boronic Acid Derivative”) which is said to be the only prior art that discusses stability issues relating to bortezomib. Dr. Bodmeier took Wu to be teaching the following:
101. The authors noted that bortezomib exhibits “erratic stability behaviour” and is “quite unstable” in a range of different solvents that are used commonly in development. The authors were attempting to understand the mechanism of degradation of bortezomib and therefore studied the stability and degradation products.
102. The article discloses that oxidation is a serious issue to be addressed. A PSA would read this as indicating that measures should be taken during preparation to avoid oxidation, such as filling the dosage form under a nitrogen atmosphere.
103. The article sets out that bortezomib is unstable in solution. The degradation occurred fairly rapidly and most likely too rapidly for a liquid formulation to be possible. Further, a PSA would have been directed away from an aqueous solution formulation because of the magnitude of degradation. A PSA would have understood from this Reference that the aqueous formulations are less stable than solid bortezomib, and would have been dissuaded from developing them.
104. The steps taken by the authors to address the instability, such as adding ascorbate and a metal chelator, namely EDTA, were reasonable. If oxidation is suspected or known to occur, a formulator would generally consider these two compounds. However, these measures actually increased the degradation.
105. In light of the information disclosed in this Reference, a PSA may consider using differing co-solvents or changing the pH. There is no information in the article proposing next steps the authors planned to take.
[40] Dr. Bodmeier’s affidavit states that “solid bortezomib would be the best starting point” but the person of skill would not have considered dissolving bortezomib in an aqueous medium, adding mannitol and then lyophilizing the solution because of bortezomib’s susceptibility to hydrolytic degradation [para 106]. According to this view, the person of skill would expect a lower degree of storage stability from a lyophilized form of bortezomib because of the higher water content present in such a formulation. Furthermore, Wu did not teach that the stability of bortezomib could be improved through a reaction with a diol. That information only came from the disclosure of the 146 Patent.
[41] Dr. Bodmeier also discussed the prior art in relation to the use of mannitol. That prior art indicated that mannitol would be expected to be generally safe but offered little else of value to a formulator. The references dealing with lyophilization would be unhelpful because the person of skill already understood that technique to be one option among others.
[42] Dr. Bodmeier expressed the opinion that the person of skill would not consider references concerning boron compounds different than bortezomib. He also stated that the person of skill would review only the titles of the references cited in Wu and, in so doing, would see nothing of interest. In the result, the skilled formulator would just start working with the compound to develop different formulations.
[43] Dr. Bodmeier’s description of the inventive concept of Claim 30 and why it was unexpected is set out in the following passages from his affidavit:
153. In my opinion, a PSA would consider the inventive concept of the ‘146 Patent to be a pharmaceutically stable formulation that also readily achieves a pharmaceutically active form upon dissolution. More specifically, as claimed in claim 30, it is a lyophilized mannitol ester of bortezomib that is easily reconstituted, and wherein a pharmaceutically active form is achieved upon dissolution.
154. This inventive concept was unexpectedly found to occur by reaction of the boronic acid with mannitol.
155. This is unexpected because the main reason for using mannitol as the bulking agent is because it is generally inert. For example, it is well known in the art that excipients should not react with the active ingredient. Excipients, and particularly bulking agents, are pharmacologically inactive substances. Indeed, what is disclosed to have happened in the ‘146 Patent is something that a formulator would want to avoid, namely the interaction between the active agent and the bulking agent. In this regard, it is clear that a PSA would not expect the mannitol to react with and form an ester with bortezomib. Even an expert formulator like myself would not expect this.
[44] Dr. Bodmeier’s conclusions about obviousness are discussed at paragraphs 160 to 168 of his affidavit. They include the following:
a. Notwithstanding the teaching of Wu, the person of skill “may continue to try to develop a liquid formulation”;
b. The person of skill would consider a variety of alternative approaches including lyophilization. This could include a dry powder doseage form; and
c. The person of skill using lyophilization will face a number of choices for solvents, bulking agents, other necessary excipients, pH and the drying cycle.
[45] In the presence of the available choices Dr. Bodmeier repeated the point that “there is no guarantee that any of these options would work to result in a useable formulation. In other words it would not be self-evident that it would be possible to obtain a workable formulation” [Emphasis added] [para 165]. It would similarly not be self-evident to the person of skill that the mannitol ester of bortezomib would be formed completely during lyophilization, that this would result in greater stability of bortezomib or that bortezomib would be easily reconstituted in an active form upon dissolution.
VI. Dr. Suryanarayanan’s Evidence [46] Dr. Suryanarayanan is a Professor in the Department of Pharmaceutics at the University of Minnesota where he has taught since 1985. His principal area of research focuses on pharmaceutical formulations, including the characterization of drugs and excipients, phase transitions that take place during pharmaceutical processing with particular emphasis on lyophilization of pharmaceuticals. He has published extensively on the subject of lyophilization including the behaviour of mannitol in such preparations. For a period of time, he was the supervisor of the Injection Manufacturing Department at Hoffman-La Roche Limited (India).
[47] Dr. Suryanarayanan was retained by Teva to provide an expert opinion concerning whether the subject matter of Claim 30 of the 146 Patent would have been obvious to the person of skill. His conclusion at paragraph 17 of this affidavit was that Claim 30 describes the invention of a lyophilized composition containing mannitol and bortezomib. At paragraph 26 of his affidavit he states that Claim 30 describes a lyophilized boronate ester of mannitol and bortezomib. According to Dr. Suryanarayanan it would have been obvious to a person skilled in the art to formulate bortezomib in this way.
[48] Dr. Suryanarayanan described the inventive concept of Claim 30 at paragraph 64 as follows:
Freeze-drying bortezomib and mannitol yields a pharmaceutically stable formulation.
[49] The underlying factual basis for Dr. Suryanarayanan’s obviousness opinion includes the following:
a. Bortezomib is a peptide drug. Peptide drugs present formulation challenges and parenteral administration is frequently indicated;
b. From reading Wu, the person of skill would know that bortezomib had been formulated as an injectable aqueous solution but, in that form, it was unstable. The very first thing the person of skill would think of doing to obtain better stability would be to remove the water by freeze-drying;
c. Lyophilization is routinely used to solve the problem of aqueous instability. It results in a powder that can be reconstituted immediately before use;
d. If the required amount of the active ingredient of a pharmaceutical preparation is small (a few mg), it is common to add a bulking agent;
e. Mannitol was and is often the bulking agent of choice for lyophilized injectable formulations. In this case, mannitol would have been one of the first excipients a person of skill would try; and
f. The person of skill would have had “every expectation that lyophilizing bortezomib with mannitol would yield a stable formation” [para 67]. This would be the case whether or not the person skill would expect the combination to form an ester.
[50] Dr. Suryanarayanan was also asked to describe the notional person of skill to whom the 146 Patent is addressed. In carrying out that task, he noted that the 146 Patent asserts claims to a large number of stable compounds and formulations of boronic acids and boronic esters, although Claim 30 is limited to a single boronate ester. Several of the Patent claims are for compounds without a particular drying technique being stipulated. Other claims cover the same compounds that are freeze-dried. Dr. Suryanarayanan concluded from reading the patent as a whole that the person of skill would be a formulation development team that would include a formulator and a medicinal chemist. This view is supported by paragraph 40 of his affidavit:
40. Lyophilization, including the selection of excipients and the method of carrying it out are clearly within the expertise of a formulation scientist or “formulator”. Paragraph 4 of the 146 Patent discloses that alkylboronic acid compounds readily form boroxines under dehydrating conditions and are often air sensitive, thereby limiting their pharmaceutical utility. The 146 Patent also discloses the ability of boronic acids to form esters with dihydroxy compounds such as sugars. These aspects of the 146 Patent which involve the chemistry of boronic acid compounds fall squarely within the expertise of a medicinal chemist.
[51] According to Dr. Suryanarayanan the skilled formulator would be familiar with the common stability issues encountered with peptide drugs. However, boronic acid chemistry is a relatively specialized field. Because the formulator would not be aware of the chemical properties of such compounds (including their capacity to form reaction products), he would not proceed with formulation work without input from a medicinal chemist.
[52] The common general knowledge of a skilled formulator would include the following:
a. Lyophilization was a known and standard technique for preparing stable drug products;
b. Freeze-drying can accelerate the dissolution rate of an active compound;
c. Although there is a general preference for ready-to-use injectable solutions, stability challenges may indicate that freeze-drying is the best option. Freeze-dried powders can usually be safely stored until they are reconstituted in solution for administration to a patient;
d. Freeze-drying was a known dry state stabilization technique for peptides and proteins. Prior to 2001, most such compounds were prepared as freeze-dried powders. One prior art reference in support of this approach was Wang (1994) which said the following:
Lyophilization of pharmaceuticals can yield high-quality products with an increased shelf life. Proteins or small drug molecules with stability problems are good candidates for lyophilization. Lyophilization is a process in which water is removed from formulations by sublimation at low temperatures under vacuum. The biological activity of proteins dried at low temperature is fairly well preserved and their shelf life prolonged in the dry state.
e. Mannitol is one of the most commonly used excipients in freeze-dried formulations (of only a few) and would be considered for use as a matter of course. It was known to be well tolerated for injectable use. The known advantages for mannitol were described in Kim (1998) in the following terms;
Mannitol is one of the most commonly used excipients in freeze-dried pharmaceutical products. One of the reasons for the widespread use of mannitol is its tendency to crystallize from frozen aqueous solutions and the high melting temperature of the mannitol/ice eutectic mixture (about - 1.5°C). This property promotes efficient freeze-drying and a physically stable, pharmaceutically elegant freeze-died solid.
[53] In comparing the state of the art as described above to the inventive concept of Claim 30 to ascertain the differences, Dr. Suryanarayanan found nothing inventive. He justified this view on the following basis:
71. Wu 2000 disclosed that bortezomib had been formulated for parenteral administration but that the compound was found to be unstable in various aqueous solutions. In particular, Wu 2000 disclosed that bortezomib had been studied in various mixed aqueous solutions (PEG 300/ethanol/water; ethanol/saline; propylene glycol/ethanol/water), and that significant degradation was observed when bortezomib was stored in these solutions, for periods ranging from one day to eight months. Wu 2000 also disclosed at page 762 that bortezomib was unstable when stored in saline (containing 2% ethanol) for short periods of time: 96% drug remaining after 5 days, 94.1% drug remaining after 14 days (see Table 1).
72. Knowing that bortezomib was a peptide drug formulated for parenteral administration and that it was unstable in solution, it would have been self-evident to the skilled formulator that freeze-drying would almost certainly improve the stability of bortezomib. As discussed above in relation to the common general knowledge, the skilled formulator would know that lyophilization is routinely used to resolve aqueous stability problems of parenteral formulations and that most peptide and protein drugs were prepared as freeze-dried powders to address stability issues, it would be obvious to the skilled formulator to follow this route and to prepare bortezomib in a lyophilized formulation.
73. Also, as discussed above in relation to the common general knowledge, the skilled formulator would also know that a lyophilized formulation of bortezomib would require a bulking agent, and that mannitol would be the first choice, given its widely accepted use for this purpose.
74. At paragraph 103 of his affidavit, Dr. Bodmeier states, with reference to Wu 2000, that degradation occurred fairly rapidly “and most likely too rapidly for a liquid formulation to be possible.” At paragraph 106, he states that a skilled formulator “…would not have considered dissolving solid bortezomib in an aqueous medium, adding mannitol and then lyophilizing this solution based on the information provided in this Reference about the degradation, and particularly hydrolysis, of bortezomib in an aqueous medium”. I disagree.
75. The key issue is the degradation kinetics, Table 1 of Wu 2000 (page 762) disclosed that 96% of intact bortezomib remained in normal saline solution (with 2% ethanol; pH 2.8) after 5 days at 25°C. This degradation rate would not deter a skilled team from using an aqueous medium for lyophilizing bortezomib. This rate of degradation is intolerable for long-term storage, but would be unlikely to pose any problem for the much shorter periods involved in the freeze-drying process and reconstitution. There would be no need to store bortezomib in an aqueous solution for extended periods at 25°C, either prior to lyophilizing it into a dried powder, or after it is reconstituted for use.
76. In paragraph 107, Dr. Bodmeier argues that, based on Wu 2000, a skilled person would expect that lyophilized bortezomib would have lower storage stability than non-lyophilized solid bortezomib because of the higher water content in the lyophilized formulation. The problem disclosed in Wu 2000 is a lack of stability when formulated as an aqueous solution. Removal of the water by lyophilization is the obvious answer to this problem, and as discussed above in relation to the common general knowledge, is particularly suitable for drugs that may be susceptible to thermal degradation when dried under elevated temperatures.
77. The issues relating to residual water content in mannitol containing formulations are well understood by the pharmaceutical community. The residual water content will be high only if a substantial fraction of the mannitol in the final lyophile is amorphous. Crystallization of mannitol can be brought about by annealing and differential scanning calorimetry (DSC) can be used to develop an appropriate annealing protocol. Thus the formulator can take fairly simple and straightforward steps to completely crystallize the mannitol and minimize the water content in the final lyophilized cake. Therefore, there is simply no support for Dr. Bodmeier’s suggestion that the amount of residual water in a lyophilized solid would dissuade a skilled formulator from pursuing a lyophilized formulation.
[54] Dr. Suryanarayanan then looked at the inventor’s actual course of conduct in obtaining the results supporting Claim 30. A lyophilized mannitol formulation was quickly achieved and Dr. Suryanarayanan could identify no material difficulties in obtaining the desired stable formulation.
[55] Dr. Suryanarayanan also considered the suggestion by Dr. Valentino Stella that the formation of an ester was unexpected. He noted that the 146 Patent claims were not limited to esters of boronic acid compounds but, in any event, the skilled formulator would find it self-evident that the stability and shelf-life of bortezomib could be enhanced by freeze-drying. That would be the case whether or not an ester was formed.
[56] Dr. Suryanarayanan considered the prior art concerned with the potential for the formation of esters as reaction products from the combination of boronic acid compounds and polyols like mannitol. He drew from that material that the person of skill, whether it be a properly informed formulator or a medicinal chemist, would expect the reaction exemplified by Claim 30. He concluded this part of his analysis in the following way:
95. As at 2001, bortezomib was a relatively new compound. The skilled formulator would not expect that the scientific, literature would include many references describing the compound, let alone pharmaceutical formulations containing the compound. Knowing this, the skilled formulator would in fact focus the search for useful information on references that describe the properties and formulation