Eli Lilly Canada Inc. v. Mylan Pharmaceuticals ULC

Eli Lilly Canada Inc. v. Mylan Pharmaceuticals ULC
Court (s) Database
Federal Court Decisions
Date
2015-02-23
Neutral citation
2015 FC 178
File numbers
T-299-13
Decision Content
Date: 20150223
Docket: T-299-13
Citation: 2015 FC 178
Ottawa, Ontario, February 23, 2015
PRESENT: The Honourable Mr. Justice de Montigny
BETWEEN:
ELI LILLY CANADA INC.
Applicant
and
MYLAN PHARMACEUTICALS ULC AND THE MINISTER OF HEALTH
Respondents
and
ICOS CORPORATION
Respondent Patentee
PUBLIC JUDGMENT AND REASONS
(Confidential Judgment and Reasons issued February 13, 2015)
[1] This is an application by Eli Lilly Canada Inc. (Lilly) for an order under section 55.2(4) of the Patent Act, RSC 1985, c P-4, and section 6 of the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133, to prohibit the issuance of a Notice of Compliance (NOC) to Mylan Pharmaceuticals ULC (Mylan) for a generic version of tadalafil, sold by Lilly under the brand name CIALIS, until after the expiration of the Canadian Patent 2,379,948 (the ‘948 Patent). The ‘948 Patent is directed to a pharmaceutical formulation of reduced particle size of tadalafil with particular excipients for the treatment of erectile dysfunction (ED).
[2] Mylan, on the other hand, alleges in its Notice of Allegation (NOA) that the ‘948 Patent will not be infringed because its product will not contain the particle size of tadalafil and the quantities of excipients claimed in the ‘948 Patent. Mylan further alleges that the ‘948 Patent is invalid because it is obvious. Other grounds of invalidity were also alleged in the NOA, but they were subsequently abandoned.
[3] For the reasons that follow, I have found that Mylan’s allegations as to the invalidity of the ‘948 Patent and as to non-infringement are justified.
I. Facts [4] In order for any drug to be given to patients for use in the treatment of a targeted disease or disorder, it is necessary for the compound to be developed into an acceptable formulation. The drug alone is generally not administered to a human, but is combined with other components, often called excipients, in order to be delivered to a human. To be considered acceptable, the formulation must comprise only components that are non-toxic to humans and must be stable for a sufficient amount of time to be shipped, stored, distributed, and administered to patients. Equally important is that the formulation must be able to readily release the active compound to the patient. The task of developing a formulation is obviously more challenging when the drug is poorly soluble in water, or is chemically unstable.
[5] Tadalafil was first discovered at Glaxo Laboratories; for a time, Glaxo collaborated with ICOS on the development of the compound. The challenge was that tadalafil is poorly soluble. Glaxo and ICOS therefore had to do some work to find a suitable formulation, and two of these studies were transferred to Dr. Kral at Lilly US when the collaboration between ICOS and Glaxo ended and Lilly decided to partner with ICOS. Dr. Kral is the co-inventor of the invention disclosed and claimed in the ‘948 Patent, and she joined Lilly in November 1998. I shall have more to say about these reports and Dr. Kral’s affidavit when addressing the obviousness argument. It appears, though, that toxicology studies on tadalafil were delayed because it was unclear whether a commercial formulation could be developed. Many different cosolvents and excipients were tried in liquid formulations and suspensions, as well as different solid state forms and different particle sizes of tadalafil. All of these early attempts failed to produce a formulation that could be brought to the market, until the development of the new formulation that is the subject of the ‘948 Patent.
II. The ‘948 Patent [6] The ‘948 Patent is entitled “Beta-Carboline Pharmaceutical Compositions” and was filed on April 26, 2000; its priority date is August 3, 1999. Under the heading “Field of the Invention”, the Patent states that it is related to formulations of beta-carboline compounds, with the goal of achieving uniform potency, and desirable stability and bioavailability characteristics. These are standard goals of pharmaceutical formulation, as a product will not be approved by a regulator if it does not have uniform potency and desirable stability.
[7] The chemical structure of tadalafil and its use in the treatment of ED were disclosed in prior Canadian Patent Nos. 2,181,377 (the ‘377 Patent) and 2,226,784 (the ‘784 Patent). The international equivalents of these patents are cited on page 2 of the‘948 Patent. These patents disclosed tadalafil tablets for oral administration. Prior formulations of tadalafil were also disclosed in PCT Application No. WO 96/38131 (the ‘131 Application or Butler Patent; see Potter affidavit, Exh “D”, Doc #4, AR Vol 5, p 860).
[8] The Patent then identifies the problem to be solved. It notes that many beta-carbolines exhibit poor solubility, which a formulator would know needed to be addressed for oral administration. The ‘948 Patent states that prior formulation efforts by Butler focused on overcoming poor solubility by co-precipitating tadalafil with a polymer such as hydroxypropyl methylcellulose phthalate (HPMCP), but notes problems of reproducibility and slow bioavailability ensued. Those are the studies that Dr. Kral discussed in her affidavit. Additionally, these clinical studies involving the administration of tablets containing such a co-precipitate revealed that maximum blood concentration on oral administration was not achieved until 3 to 4 hours after ingestion, which was considered to be undesirably slow when used for the treatment of ED.
[9] Under the heading “Summary of the Invention”, the Patent teaches the formulation of tadalafil (and not the broader class of beta-carbolines) and pharmaceutically acceptable salts and solvates thereof:
provided as a free drug, in admixture with a diluent, a lubricant, a hydrophilic binder selected from the group consisting of a cellulose derivative, povidone, and a mixture thereof, a disintegrant selected from the group consisting of crospovidone, croscarmellose sodium, and a mixture thereof, and, optionally, microcrystalline cellulose and/or a wetting agent. Optionally the formulation additionally comprises a second diluent.
(‘948 Patent, p 4, lines 4-12, AR Vol 1, p 13)
The Patent then goes on to describe a most preferred formulation, states that the invention relates to the use of such formulations for treatment of sexual dysfunction, and states that they can be administered orally as a tablet or in capsules.
[10] The Patent then defines a number of terms and abbreviations, the most relevant of which being “free drug”. That term refers to “solid particles consisting essentially of the compound of structural formula (I) [tadalafil], as opposed to the compound intimately embedded in a polymeric coprecipitate” (‘948 Patent p 5, lines 24-27). The Patent also describes “lubricant”, “water-soluble diluent” and “wetting agent”.
[11] The specific amounts of the different excipients that are required are then set out, and the reader is instructed that tadalafil itself can be made according to established procedures such as those disclosed in the Daugan Patent (the equivalent of the ‘377 Patent).
[12] The Patent also indicates that the particle size of tadalafil enhances “the bioavailability and handling” of the formulation (p 8, lines 10-12). The skilled formulator would therefore understand the patentee to be asserting that both the chosen excipients and the particle size distribution are responsible for the identified salient effects of the formulation. Since this paragraph is the subject of much dispute, I shall quote it in full:
The particle size of the active compound also has been found to enhance the bioavailability and handling of the present formulations. Thus, the particle size of the compound of structural formula (I) [tadalafil] prior to formulation is controlled by milling the raw compound (as a crystal, amorphous precipitate, or mixture thereof) such that at least 90% of the particles have a particle size of less than about 40 microns (d90=40), and preferably less than about 30 microns. More preferably, at least 90% of the particles have a particle size of less than about 25 microns, still more preferably, less than about 15 microns, and most preferably, less than about 10 microns.
(‘948 Patent, p 8, lines 10-20)
[13] The Patent next teaches in detail how the particle size distribution of tadalafil in the invention formulation is to be achieved and measured. With respect to measurement, the Patent states that “[m]ethods for determining the size of particles are well known in the art. The following nonlimiting method disclosed in U.S. Patent No. 4,605,517 can be employed” (p 8, lines 22-24). The ‘948 Patent also provides a highly detailed procedure describing how the particle size measurement was obtained for the examples of the Patent (p 8, line 24 - p 9, line 23). Since Mylan has not discussed that issue, there is no need to go into the details of the explanation given in the Patent as to how to measure particle size.
[14] Beginning at page 9 of the Patent, definitions of water-soluble diluent, hydrophilic binder, disintegrants, lubricants and wetting agents for the purposes of the Patent are provided, as well as examples from each category of excipient. It is stated that a hydrophilic binder is provided in an amount sufficient to act as an adhesive to hold tadalafil and excipients together in a tablet, but is also present in a powder formulation introduced into a hard gelatin shell. Some of the claims of this Patent deal with capsules and other types of formulations, but the only claims at issue in this case are the ones relating to tablet formulations.
[15] The Patent then goes on at page 10 to talk about preferred hydrophilic binders, and it discusses povidone and some of the disintegrants that are used. It then discusses lubricants and identifies some preferred lubricants and some preferred amounts (p 11). It talks about microcrystalline cellulose, which can serve multiple functions in the formulation, e.g. a disintegrant and/or a second diluent; it appears in some of the dependent claims as one of the possible diluents. It then goes on to talk about wetting agents and other possible optional ingredients such as coloring or flavouring agents.
[16] On page 12 we have an example of a preferred formulation with different weight percentage amounts, and then a list of techniques that can be used to prepare the formulations of the present invention. On pages 13 and 14, we have the preferred dose and dosage form (including tablet and hard capsule) of the target compound.
[17] At pages 15 to 28, the Patent describes thirteen examples, which are “illustrative only” and are not intended to limit the scope of the invention. Example 1 first directs the use of 12 inch pancake style jet mill to produce an active compound (i.e. tadalafil) characterized by a d90 of 4 microns. (A “d90” is a measure of particle size distribution: for example, a d90 of 40 means that at least 90% of the particles have a particle size less than 40 microns.) It then directs the formulation of a tablet containing the reduced-size active compound and the preferred excipients discussed above, using a wet granulation process. This process involves dry blending the active ingredient with the diluent, binder, and disintegrant excipients to form a powder, followed by the formation of wet granules from that powder using an aqueous solution containing additional binder and the surfactant (wetting agent) in a high shear granulator. A mill is then used to “delump” the wet granulation, the wet granulation is dried, and then sized to eliminate large agglomerates. Additional diluent and disintegrant, as well as the lubricant, are then dry mixed with the dry granules and compressed into tablets.
[18] The remaining Examples 2 to 13 modify the formulation by changing the relative proportion of ingredients.
[19] Following the examples, the Patent lists 33 claims. Lilly has brought this application on the basis of claims 1 to 8, 10 to 15, 17 to 21, 23 to 31 and 33, all of which are reproduced in the Annex to these reasons.
[20] Claim 1 is the only independent claim. It claims the pharmaceutical formulation comprising tadalafil, provided as free drug comprising particles wherein at least 90% of the particles of tadalafil have a particle size of less than about 40 microns; a water-soluble diluent; a lubricant; a hydrophilic binder; and a disintegrant; all at various percentages by weight.
[21] Claims 2 to 8, 10 to 15 and 17-18 claim specific components of the formulation.
[22] Claims 19 to 21 claim a tablet comprising the formulation of claim 1.
[23] Claims 23 to 25 claim specific particle sizes of the formulation in claim 1.
[24] Claims 26 to 29 claim tablets comprising the formulation of claim 1 where the compound is present in an amount of about 10 mg, 1 to 5 mg, 2.5 mg and 20 mg per tablet, respectively.
[25] Claims 30, 31 and 33 claim the use of the formulation and the tablets to treat sexual dysfunction, and specifically ED.
III. The evidence [26] Lilly has presented the evidence of a fact witness (Dr. Kral), two expert witnesses (Dr. Bugay and Dr. Bodmeier) and a law clerk (Ms. Potter). This last affidavit introduces as exhibits the ‘948 Patent, Mylan’s NOA, all the attachments to Mylan’s NOA, a related patent, a scientific paper, and documents related to Mylan’s testing. Mylan, on the other hand, has presented the evidence of only one expert witness (Dr. Brittain). I shall now briefly review their evidence.
A. Lilly’s Witnesses Dr. Kral [27] Lilly’s fact witness is Dr. Martha Kral, one of the three inventors of the ‘948 Patent. She is a Research Advisor at Lilly, and has been employed at Lilly since 1998. Starting in 1998, Dr. Kral led the formulation work at Lilly that led to the ‘948 Patent. Her evidence consists of an affidavit with exhibits and a cross-examination with exhibits.
[28] In her affidavit, Dr. Kral reviews the formulation work for tadalafil both before and during her involvement. She reviews the early formulation work at Glaxo and ICOS, including the filing of the Butler Patent. She then describes her team’s formulation work at Lilly leading up to the ‘948 Patent. Finally, she appends the formulations and related clinical study reports for all the examples in the ‘948 Patent. The following summary of her affidavit is largely based on Lilly’s oral and written representations.
[29] Two of the initial studies conducted by Glaxo were transferred to Dr. Kral after she joined Lilly US. The first one, marked as Exhibit “B” to her affidavit, was a preliminary formulation study where the Glaxo researchers were trying to formulate tadalafil for intravenous (i.v.) administration in dogs. Their goal was to develop a [redacted] formulation with a concentration of [redacted] of tadalafil. If that failed, they were looking for a [redacted] that was capable of delivering at least [redacted]. Glaxo wanted to start toxicology studies in animals, and needed a formulation capable of reaching the high doses necessary for these studies.
[30] Initially, i.v. solutions were attempted, as it was thought this could maximize the dose of tadalafil for the toxicology studies. However, high concentrations of [redacted] and other excipients were required to increase the solubility of tadalafil. Many excipients were tried, but they all resulted in toxicity of the excipients rather than the improved solubility of tadalafil. At that point, the researchers concluded that an acceptable [redacted] formulation could not be found and shifted to searching for an [redacted] formulation. Once again, many of the [redacted] formulations could not achieve acceptable stability, and those that did showed unacceptable toxicity. At the end of that report, the Glaxo researchers concluded that none of the formulations tried in vivo gave a satisfactory toxicological profile for the vehicle alone. Thus, the early toxicology studies could not be started.
[31] The next study that was transferred to Dr. Kral is found at Exhibit “C” to her affidavit. Again, the poor solubility of tadalafil was confirmed. The report also states that tadalafil [redacted]. The Glaxo researchers investigated 27 formulations, without success. They tried i.v. formulations, to no avail. They then moved on to oral formulations. First, suspensions were tried in [redacted], a glyceride emulsifier. Studies were done with both [redacted] and [redacted] tadalafil. Glaxo found that tadalafil’s bioavailability was about 32% when it was mixed with [redacted]. When particle size was reduced to between [redacted] microns, bioavailability increased [redacted]. Bioavailability of [redacted] tadalafil in [redacted] was even higher, at [redacted]. Since Glaxo was looking for at least [redacted] bioavailability in a formulation, this result was considered to be good. However, formulation studies with [redacted] had to be discontinued due to reports of adverse effects during multiple dose dosing regimens in safety studies.
[32] Aqueous suspensions were then tried, using [redacted] and [redacted] tadalafil. All of these attempts ultimately failed. [redacted] tadalafil has acceptable bioavailability but has two major disadvantages. Firstly there is the potential problem of physical instability, and secondly, solvents are required for [redacted] the drug and as the solubility of tadalafil in [redacted]. There was some success when tadalafil was [redacted], an excipient that had shown some enhancement of bioavailability in the past; this attempt exhibited [redacted] bioavailability. However, there was also an increase in variability of bioavailability making these formulations unusable. As for [redacted] tadalafil, previous studies had shown that it did not produce adequate bioavailability in aqueous suspension. The use of particle size reduction to enhance bioavailability being a well known stratagem in the industry, [redacted] were prepared with tadalafil particle sizes of [redacted] microns. The bioavailability of these formulations in fasted dogs was [redacted] respectively, which was unacceptably low. The researchers then tried adding [redacted], but this did not enhance the bioavailability of the [redacted] material.
[33] Because of the good results that researchers had seen with the [redacted], they then investigated a number of solid dispersion techniques: 1) co-evaporates, where the drug and a carrier are dissolved in a solvent, which is then slowly evaporated; 2) co-melts, where the drug and a carrier are both melted and then resolidified together; 3) co-milling, where the drug and a carrier are milled together; and 4) co-precipitation, where the drug and the carrier are dissolved together in a solvent, and then precipitated from that solvent using an anti-solvent. Most did not work, but the researchers discovered that when tadalafil was mixed with [redacted] in a [redacted], it exhibited [redacted] bioavailability.
[34] At the end of all of these studies, the Glaxo researchers determined that the [redacted] and the [redacted] formulations were the only ones with acceptable bioavailability. The [redacted] material had a more consistent bioavailability, but manufacturing would be much more difficult. Furthermore, there was concern that the [redacted] drug would convert to [redacted] drug over time. Thus, the [redacted] was chosen to move forward, even if the researchers did not know the exact mechanism whereby improved bioavailability was obtained for either of these formulations.
[35] The early Phase I studies used [redacted] of the [redacted] tadalafil. However, a tablet formulation was needed for Phase II clinical trials and for the market. The Glaxo report indicates that the co-precipitate was selected for the tablet formulation. However, Glaxo seemed to be concerned about the pharmacokinetic profile of the co-precipitate. Thus, they also developed the [redacted] material as a tablet. When both of the tablets were developed and tested, the Glaxo researchers recommended proceeding with the co-precipitated tadalafil material.
[36] The conclusion of this report is worth quoting:
A variety of techniques have been explored in an attempt to optimise the bioavailability of [tadalafil]. This culminated in the development of the HPMCP co-precipitate which allowed the drug to be well absorbed and used well established and inexpensive techniques in its preparation. The co-precipitate has been formulated as tablets which had similar bioavailability to an [redacted]. The tablets are prepared using well established techniques which are amenable to large scale manufacture.
Obtaining acceptable bioavailability for insoluble drugs such as [tadalafil] can be a formidable challenge. Some of the techniques described in this report are being used successfully with [redacted] in suitable organic solvents. Although [tadalafil] is not being progressed within GlaxoWellcome the [redacted] should be considered amongst a range of other techniques for delivering other poorly soluble drugs.
(Kral affidavit, Exh “C”, AR Vol 10, p 1848)
[37] ICOS then chose Lilly to partner with them to bring a tablet formulation to the market. With a view to achieving the advantage of early onset, Lilly started investigating new possible formulations. Dr. Kral and her group conducted further studies to determine how to formulate the tadalafil and what excipients could be used. In particular, Lilly evaluated the potential for [redacted] to improve the [redacted] of tadalafil. [redacted] excipients were tested in [redacted] solutions in combination with tadalafil. This test was designed to examine how different excipients affected the [redacted] of tadalafil in solution, which in turn can affect dissolution rate. Leading candidates were selected and studied in a formal compatibility study. Lilly also conducted stress studies on potential excipients. Furthermore, some of the excipients were substituted in an alternate excipients study.
[38] At the same time as the excipient studies were ongoing, Dr. Kral and her team had an idea that a [redacted] may work with a smaller [redacted] if a [redacted] was part of the [redacted]. This formulation was tested in [redacted] and compared to the results from [redacted] version of the new formulation. The [redacted] results were quite variable. However, the new wet granulation formulation showed acceptable absorption. Thus it was moved forward.
[39] The new wet granulation formulation, the [redacted], and one of the [redacted] formulations were all tested in humans. This study determined the formulation that would provide the foundation for the final commercial formulation. The new wet granulation had a Tmax (time to reach peak blood levels) that averaged [redacted] shorter than the [redacted], indicating that it would allow for a faster onset.
[40] A second clinical study was conducted at the same time, also involving the [redacted] and the new wet granulation formulation. This second study measured time to patient response. By [redacted], there was a statistically significant response to the new wet granulation formulation, as compared to both placebo and the [redacted]. Furthermore, the trend to significance was seen at [redacted], and some patients responded as early as [redacted]. Successful results of this study determined that the new wet granulation was the formulation of choice.
[41] Mylan argued that the Court should give no weight to the evidence of Dr. Kral because she was never employed by Glaxo and had no personal involvement with the initial research conducted by Glaxo and ICOS. On cross-examination, Dr. Kral confirmed that she only became involved with tadalafil when she joined Lilly in November 1998. Her knowledge of the earlier Glaxo and ICOS work comes only through the reports of Glaxo and ICOS.
[42] Mylan raised that objection for the first time in its Memorandum of Fact and Law, and did not put much emphasis on it during oral argument. The fact that Dr. Kral was not personally involved with the early studies done by Glaxo does not prevent her from introducing these studies into evidence. As an inventor, she used those studies to take the formulation process to its final stage, and the portion of her testimony devoted to the early formulation work on tadalafil at Glaxo is really confined to a description of that work on the basis of these studies. I fail to see anything improper in her doing so; she refrained from offering her own views of these studies, as she was not called as an expert witness, and she did not give evidence on Glaxo’s work on tadalafil beyond the four corners of the studies that were transferred to her. In any event, as Mylan itself pointed out, the culmination of Glaxo’s work – the co-precipitate formulation of tadalafil – was disclosed in the Butler Patent, and to that extent Dr. Kral’s testimony about formulation work at Glaxo is redundant.
Dr. Bodmeier [43] Dr. Bodmeier is a professor of pharmaceutical technology. He teaches and researches pharmaceutical sciences, including formulation and use of excipients. He testified both as to infringement issues relating to the formulation of Mylan’s tadalafil product and as to the validity of the ‘948 Patent.
[44] In his affidavit, Dr. Bodmeier gives his background and mandate, and recites his legal instructions. He then gives a scientific background on drug formulation, before describing the ‘948 Patent and giving his opinion on claims construction. He opines on several validity issues initially raised by Mylan, including obviousness, and then offers his opinion on infringement with respect to the hydrophilic binder.
[45] With respect to obviousness, Dr. Bodmeier first assesses the common general knowledge of the person skilled in the art and reviews the various references found in Mylan’s NOA. He then states that the inventive concept of the ‘948 Patent is “a particular pharmaceutical formulation of tadalafil, a poorly soluble compound, that provides an early onset of therapeutic effect as well as sufficient concentration of tadalafil at the intracellular site of action, which permits relatively prolonged duration of action” (Bodmeier affidavit, para 133, AR Vol 2, p 221). He then opines that a person skilled in the art would not find it self-evident that an early onset of therapeutic effect would be obtainable in light of the poor solubility of tadalafil in water, and that it would be known that it will likely be difficult to find a way to provide an early onset of therapeutic effect for that drug.
[46] In its NOA, Mylan laid out the excipients of the claims of the ‘948 Patent compared with specific ranges suggested for these excipients in the 1994 edition of Wade et al, Handbook of Pharmaceutical Excipients, 2d ed (London: American Pharmaceutical Association, 1998; see Potter affidavit, Exh “D”, Doc #9, AR Vol 6, p 1061 [Wade]), and claimed that the differences are minor. Dr. Bodmeier disagrees for a number of reasons. First, the ranges in the ‘948 Patent are in some cases outside the ranges in the reference book, and Mylan’s chart does not refer to a wetting agent; these, in his view, are not minor differences. Moreover, Mylan admits that tadalafil with particle sizes having a d90 of less than or equal to 40 microns were not known in the art. In his opinion, these are significant and inventive differences between the prior art and the ‘948 Patent. There are almost infinite possibilities for every formulation of a drug, between selecting each individual excipient to use, and the range of possible quantities for each excipient; moreover, selecting an appropriate particle size for a drug is not as simple as Mylan is implying, as each drug has different properties that are affected by particle size.
[47] In his opinion, therefore, the claims asserted by Lilly are not obvious:
Until each formulation and particle size is made and tested, the PSA would not know for certain that such a formulation or particle size would work, let alone provide the rapid onset of the invention of the ‘948 Patent.
Furthermore, these differences would not be obvious to try and likely to succeed. As discussed above, the number of possible solutions to a formulation problem is infinite, and a PSA would not be able to predict the outcome of each possibility without testing. This testing would require numerous experiments and take a great deal of time. This is further evidenced by the experiments found in the Kral affidavit. Glaxo and Lilly conducted many different experiments over several years, in their search for a formulation for tadalafil. These would not be considered routine trials.
(Bodmeier affidavit, paras 143-144, AR Vol 2, pp 223-224)
[48] Dr. Bodmeier agrees with Mylan that a person skilled in the art would know the different techniques that may be used to increase the dissolution rate of a drug. One could increase the solubility of the drug such as by using a more soluble salt, by using a more soluble polymorphic form of the drug, or by forming solid dispersion systems. One could also increase the surface area by reducing the size of the drug particles or by using surfactants, although this would not necessarily lead to increased absorption and there are disadvantages that would have to be taken into account in deciding whether to try particle size reduction. Processing is always a challenge with smaller particle sizes, and electrostatic charging and agglomeration can occur; it can also be difficult to get good homogeneity with smaller dosages. A person skilled in the art may also consider chemical modification of the drug molecule in order to change the solubility. If these strategies are unsuccessful, there is the field of solid solutions and solid dispersions. Dr. Bodmeier is of the view that it would not be self-evident that use of any, or all, of these techniques would be successful in achieving a formulation of tadalafil that provided an early onset of therapeutic effect. As he stated:
There is no guarantee that any of the options would work to result in a usable formulation. In other words, it is not self-evident that it would be possible to obtain a workable formulation that provided an early onset of action.
Furthermore, I would expect that an inventor setting out to make such a formulation would not just be carrying out a routine trial. A great deal of skill and thought goes into the work of a PSA in coming up with a new formulation, and often a large number of experiments are necessary in order to determine the precise formulation. There are countless variables that affect every decision. Finding a formulation for a drug is not simply a matter of plugging that drug into a well known formulation. The selection of each element involves a new set of decisions and is typically a long iterative process.
(Bodmeier affidavit, paras 161-162; AR Vol 2, pp 226-227)
[49] With respect to infringement, Dr. Bodmeier’s analysis is relatively short and does not address Mylan’s argument that it will not infringe any of claims 1 to 33 because its product will not contain the required particle size.
[50] Claims 1 to 33 of the ‘948 Patent require the presence of several excipients in addition to tadalafil, including a hydrophilic binder, which are essential elements of claims 1 to 33. Mylan claims that its product will not contain about 1% to 5% by weight of a hydrophilic binder, and thus will not infringe any of claims 1 to 33. Mylan bases its claim on the fact that [redacted] which is primarily known as a hydrophilic binder, is present in an amount equal to [redacted] in its tablets.
[51] Dr. Bodmeier disputes that assertion, and comments that this [redacted] proportion is more binder than would be typically added as an excipient in a tablet formulation. This is explainable, in his view, by the fact that [redacted] may also function as a solubilizer, which is particularly the case when it is used as an excipient for a lipophilic drug such as tadalafil.
[52] It appears from Dr. Bodmeier’s review of Mylan’s manufacturing process that [redacted]. Then, [redacted] to make granules.
[53] Dr. Bodmeier’s key finding as to the exact function of [redacted] is found at paragraph 188 of his affidavit:
Typically, with a lipophilic drug such as tadalafil, one would expect solubilizers to be present in an amount ranging from about 10% to about 12%, by weight of the tablet. [redacted]. Thus, one would expect that the [redacted] is acting as a solubilizer in the amount of [redacted] of the tablet. That would leave [redacted] of the [redacted] to act as a binder.
(Bodmeier affidavit, para 188, AR Vol 3, p 328)
Dr. Bugay [54] Dr. Bugay is an analytical chemist, specialized in analysis of pharmaceuticals. He provided evidence on the particle size infringement issue. More particularly, the subject of his analysis was to determine the particle size of tadalafil incorporated into Mylan’s tadalafil drug product. He was also asked to comment on the particle size testing in Mylan’s Abbreviated New Drug Submission (ANDS) documents and Mylan’s report from Micron Technologies Inc. (Micron).
[55] After construing the claims of the ‘948 Patent with respect to particle size and explaining some principles of particle size analysis, he comments on Mylan’s own tests of its particle size. Having critically reviewed the report from Micron Technologies, he came to the conclusion that the results are inaccurate and not reliable for a variety of reasons (at para 44 of his affidavit): 1) a particle refractive index value was not used and was set instead at zero, which could be a contributing factor ultimately leading to inaccurate results; 2) the residual value is higher than 0.5% for the majority of the experimental determinations, which indicates that the model is not able to fully fit the data; 3) the report notes that the test method has not been formally qualified or validated by Micron, which is critical to the reliability and accuracy of any reported results; 4) the reported relative standard deviation value for each batch of tadalafil is greater than the accepted criteria of the ISO guidance, which means that the determined values for the Mylan-Tadalafil should not be accepted; and 5) each graphical particle size distribution displays a multimodal distribution of particles. The presence of a high second mode indicates that agglomerates are present, which means that the samples have not been properly prepared for analysis. As a result, the particle size distribution is also inaccurate for this reason.
[56] Dr. Bugay also comments on Mylan’s additional testing (the ANDS testing). He is also critical of this testing because there is no ability to determine if the results are reliable. There is no description of how the materials were collected, and no verification that the instrument is working properly, nor any sample preparation or data acquisition parameter for the determinations.
[57] Dr. Bugay then comments on the impact of Mylan’s formulation process on the particle size. He states that not only is the reported particle size of tadalafil inaccurate, but Mylan’s formulation process further reduces the particle size of tadalafil that is eventually incorporated into their tadalafil drug product. He opines that the use of the [redacted] in Mylan’s manufacturing process of tadalafil drug product reduces the size of the granules after they are wet granulated. From this manufacturing process, he draws two conclusions:
a) since the tablet manufacturing process incorporates a particle size reduction step of the granules in which tadalafil API [active pharmaceutical ingredient] is incorporated within, Mylan’s particle size determination of the API is irrelevant to the actual particles size of tadalafil within Mylan’s drug product;
b) the only accurate determination of the particle size of tadalafil within Mylan’s drug product is via extraction of the tadalafil API from the drug product with subsequent particle size determination.
(Bugay affidavit, para 52, AR Vol 3, p 346)
[58] Dr. Bugay then explains that he developed an extraction procedure in which the tadalafil active pharmaceutical ingredient (API) is removed from the Mylan drug product and introduced into a particle sizing instrument for measurement. Since particle size analysis will measure any particles introduced in the instrument, one must first extract tadalafil from the drug product since it is the particle size of tadalafil which is the subject of the current litigation. While the separation of materials from a mixture can be accomplished by a number of different approaches, Dr. Bugay’s experience has shown him that an API can be extracted from a formulated drug product like a tablet utilizing a simple float/sink methodology that uses the different densities of each component as the basis of the separation. Dr. Bugay therefore developed an extraction procedure in which the various steps separated specific components leading to isolated tadalafil, and he describes that procedure at paragraphs 59 to 75 of his affidavit and in a flow diagram at Exhibit “O” of his affidavit.
[59] As discussed and taught in the ‘948 Patent, particle size analysis typically suspends the solid of interest in a medium for subsequent introduction in the measurement zone of the particle size instrument. Dr. Bugay therefore prepared a particle size dispersion medium to disperse the extracted tadalafil particles for subsequent particle size analysis. The particle size instrument was also subjected to a system suitability procedure which assessed the performance of the instrument on the day of sample analysis. The average results for the particle size analysis and reporting of the d90 value for tadalafil contained within the two lots of Mylan’s 20 mg drug product were [redacted] microns.
[60] In order to validate that the extraction procedure only extracted tadalafil from the Mylan drug product samples, a well-established and highly sensitive analytical technique (Raman spectroscopic analysis) was performed on the extracted solids from the two different lots of Mylan tablets. The results validate that the extraction procedure for the removal of tadalafil from the Mylan tablets is selective for tadalafil and tadalafil only. This is based on the fact that the Mylan tablet extracted materials display maxima only at the same wavelengths as that of a similar preparation of the corresponding United States Pharmacopeia (USP) reference standard, and that the Raman spectra do not indicate that there are any extra peaks that cannot be assigned to tadalafil.
[61] In the final paragraph of his affidavit, Dr. Bugay concludes:
My particle size analysis has shown that the tadalafil contained within the two submitted lots of Mylan 20-mg drug product tablets have a d90 of less than 40 microns and falls within the scope of this element of Claim 1 of the ‘948 Patent. Additionally, my particle size analysis has shown that these same two batches of Mylan 20-mg drug product display a d90 value for tadalafil of less than 10, 30, 25, and 15 microns in accordance with the additional elements present n Claims 15, 23, 24, and 25 of the ‘948 Patent, respectively.
(Bugay affidavit, para 91, AR Vol 3, pp 358-359)
B. Mylan’s Witness Dr. Brittain [62] Dr. Brittain is an expert in drug formulation and analysis. He gave an opinion both on infringement (particle size and hydrophilic binder) and obviousness. He also responded to the opinions of Drs. Bodmeier and Bugay. His evidence consists of an affidavit and cross-examination, both with exhibits. I note that Dr. Brittain has had extensive compendial experience as a member of the USP, an independent non-profit organization that publishes a compilation of methods, methodologies and specification ex