Federal Court Decisions

     T-1721-95

     IN THE MATTER of an Application for an

     Order of Prohibition pursuant to s. 55.2(4) of

     the Patent Act and s. 6 of the Patented

     Medicines (Notice of Compliance) Regulations

BETWEEN:

     ABBOTT LABORATORIES, LIMITED

     and ABBOTT LABORATORIES

     Applicants

     - and -

     NU-PHARM INC.

     and THE MINISTER OF HEALTH CANADA

     Respondents

     REASONS FOR ORDER

LUTFY J.:

     The Applicants ("Abbott") seek an order prohibiting the Minister of National Health and Welfare ("the Minister") from issuing a Notice of Compliance ("NOC") to the Respondent Nu-Pharm Inc. ("Nu-Pharm") with respect to 1 mg, 2 mg, 5 mg and 10 mg tablets "of the drug known as terazosin hydrochloride" until after the expiration of Canadian letters patent 1,081,229 ("the Abbott Patent"). The order is sought pursuant to section 6 of the Patented Medicines (Notice of Compliance) Regulations¹ ("the Regulations"). Another Abbott patent mentioned in the application is expired and no longer in issue.

     The Abbott Patent is entitled "1-(4-Amino-6, 7-Dimethoxy-2-Quinazolinyl)-4-(2-Tetrahydrofuroyl)Piperazine Hydrochloride Dihydrate" also known as terazosin hydrochloride dihydrate. The drug is an anti-hypertensive agent used to control high blood pressure. The Abbott Patent will expire on July 8, 1997 when this summary proceeding will become moot.

     The Abbott Patent is for terazosin hydrochloride dihydrate. The drug is described in Nu-Pharm's Notice of Allegation, in Abbott's patent list and in the originating notice of motion as terazosin hydrochloride. The patent list includes a reference to the appropriate number of the Abbott Patent. The parties knew precisely which drug was in issue. In my view, both parties referred to terazosin hydrochloride when in fact they intended terazosin hydrochloride dihydrate. Nu-Pharm's submission that Abbott's application must fail for the sole reason that the name of the drug on the patent list is incomplete is rejected. Form should not prevail over substance, particularly in the absence of uncertainty or ambiguity.

     Nu-Pharm's Notice of Allegation of June 23, 1995 stated:

RE: Terazosin Hydrochloride

This is a Notice of Allegation pursuant to Section 5(3)(b) of the Patented Medicines (Notice of Compliance) Regulations.

With respect to patent 1081229, we allege that no claim for the medicine itself and no claim for the use of the medicine would be infringed by our making, constructing, using or selling tablets containing Terazosin Hydrochloride.

The legal and factual basis for the aforesaid allegation is as follows.

In patent 1081229, the claims are limited to Terazosin Hydrochloride made in accordance with certain processes.

If Nu-Pharm Inc. receives a Notice of Compliance for Terazosin Hydrochloride tablets before the expiration of patent 1081229, Nu-Pharm Inc. will use only Terazosin Hydrochloride made by a process that does not infringe the claims of patent 1081229. We are prepared to disclose details of the non-infringing process under a confidentiality agreement or order.

     The Abbott Patent sets out its relevant claims and Nu-Pharm has disclosed its process for preparing terazosin hydrochloride dihydrate:

The Abbott Patent (Claims)

1.      A process for preparing [terazosin] hydrochloride dihydrate, comprising slurrying [terazosin] in a lower alcohol, heating the slurry to a temperature of about 35 to about 40C, adding concentrated aqueous hydrochloric acid, heating the mixture to a temperature of about 70 to about 75C, and thereafter recovering the [terazosin] hydrochloride dihydrate.

2.      A process according to Claim 1, wherein the lower alcohol is ethanol or a denatured alcohol.

3.      A process according to Claim 2, wherein the first heating step is carried out to a temperature of about 35C and the second heating step is carried out to a temperature of about 70C.

...

6.      [Terazosin] hydrochloride dihydrate, whenever prepared according to the process of Claim 1, 2 or 3, or by an obvious chemical equivalent.

The Nu-Pharm Process

Terazosin free base (10 g, 25.8 mmol) is suspended in water (20 mL). 10 N.HCl (3.52 g, 25.8 mmol HCl) is added to the suspension which results in the formation of a solution. This solution is stirred at room temperature for 15-24 hours during which the product crystallizes out. The mixture is filtered and the cake is washed with cold water to yield the desired terazosin hydrochloride dihydrate salt (yield, ca. 90%).

[Emphasis added.]

     The three steps in each process are set out in Abbott's memorandum:

Step One

Claim 1 of the Patent Slurrying the terazosin free base in a lower alcohol and heating the slurry to a temperature of 35C to 40C

Nu-Pharm's Process      Suspending the terazosin free base in water

Step Two

Claim 1 of the Patent      Adding concentrated aqueous hydrochloric acid which result in a mixture which is then heated to a temperature of about 70 to 75 C

Nu-Pharm's Process      Adding 10N HCl to the suspension which results in the formation of a solution

Step Three

Claim 1 of the Patent      Recovering the terazosin hydrochloride dihydrate

Nu-Pharm's Process      Stirring of the solution at room temperature for 15-24 hours during which the product crystallizes out. Filtering of the mixture and washing the cake with cold water to yield the desired terazosin hydrochloride dihydrate

     There are two readily apparent differences. The solvent claimed in the Abbott Patent is a lower alcohol while water is used in the Nu-Pharm process. The second difference relates to temperature. External heat is applied to the mixture of the terazosin free base and the lower alcohol both before and after the addition of concentrated aqueous hydrochloric acid. The Nu-Pharm process is carried out at room temperature throughout.

     Nu-Pharm suggests that there exists a third difference. Its process "suspends" the terazosin free base in water while the Abbott Patent specifies the "slurrying" of the terazosin free base in a lower alcohol. The evidence does not disclose any material difference between "slurrying" and "suspending" the free base in the solvent. The experts, including Nu-Pharm's, use the words interchangeably. I attach little, if any, significance to this suggested difference.

     In my view, this case turns on the relevance of the first two differences. Is the Nu-Pharm process, which uses water instead of lower alcohol and stirs the solution at room temperature without external heat, an obvious chemical equivalent within the meaning of claim 6 of the Abbott Patent?

     Nu-Pharm, of course, answers this question in the negative. Its position is substantially set out in the following extracts of its affiants:

(a)      The affidavit of October 6, 1995 of Dr. K.S. Keshava Murthy, the Director of Scientific Affairs at ACIC (Canada) Inc. and one of the inventors of the Nu-Pharm process:

36.      In my opinion, the use of the lower alcohol in which the Terazosin free base is slurried, the heating of the slurry to a temperature of about 35 to 40C, the adding of the concentrated aqueous hydrochloric acid and the subsequent heating of the mixture to a further elevated temperature (70 to 75C) are essential elements of the process of manufacture taught by the [Abbott Patent].

37.      Without the inclusion of all these steps in the process of manufacture of the Terazosin hydrochloride dihydrate, there would be no process taught for the manufacture of the Terazosin hydrochloride dihydrate in the [Abbott Patent]. The dependent claims, 2 to 5, reinforce my conclusions in regards to this patent.

     ...

65.      [Nu-Pharm's] process makes use of water, HC1 (Hydrochloric acid) and Terazosin free base, the building blocks of Terazosin hydrochloride dihydrate. The process is carried out at ambient temperature (20-25C.).

66.      Thus, the [Nu-Pharm] process is different from the claimed process in the [Abbott Patent]. Other than adding the common building blockes (sic) (Terazosin free base, water and HCl), the processes are different.

...

72.      The [Nu-Pharm] process and the differences between the [Nu-Pharm] process and the process taught and claimed in the [Abbott Patent] were not obvious at the date of the [Abbott Patent]. In fact, no specific discussion is provided in the[Abbott Patent] with respect to other processes which can be used to produce Terazosin hydrochloride dihydrate. No reasons are given in the [Abbott Patent] for the restriction to the specific process. No reasons are given in the [Abbott Patent] for the restriction to the use of the alcohol and heat in the claimed process.

73.      In my opinion, persons skilled in the art reading the [Abbott Patent] would conclude the use of the alcohol and heat are essential to the successful use of the process to manufacture Terazosin hydrochloride dihydrate by the process taught and claimed.

74.      In my opinion, persons skilled in the art reading the [Abbott Patent] would also conclude the Patentee did not foresee any other process being successfully employed to produce Terazosin hydrochloride dihydrate.

(b)      The affidavit of October 10, 1995 of Dr. Robert A. McClelland, a professor in the Department of Chemistry of the University of Toronto:

25.      An organic chemist experienced in crystallization processes knows that the success or failure of the crystallization of a particular compound depends on the use of precise conditions of solvent and temperature. Thus an organic chemist reading the claims and disclosure of the [Abbott Patent] would recognize from the relatively narrow temperature ranges provided that such temperaures (sic) were essential if terazosin hydrochloride dihydrate is to be obtained.

26.      The [Nu-Pharm] process and the process claimed in the [Abbott Patent] does (sic) not work in a similar way.

(a)      The [Abbott Patent] requires elevated temperatures whereas the [Nu-Pharm] process functions at room temperature;

(b)      The solvent in the [Abbott Patent] is a lower alcohol whereas in the [Nu-Pharm] process it is water. Lower alcohols tend to be good solvents for most organic compounds whereas they are poor solvents for salts. In contrast water is an excellent solvent for salt but not a good one for most organic compounds.

27.      Both the [Nu-Pharm] process and the [Abbott] process are crystallizations. It is my considerable experience after 30 years in organic chemistry that it is very difficult to predict the correct solvents and the conditions for crystallizing an organic compound, or salts of organic compounds. In particular, having been provided with one set of conditions, as in the [Abbott Patent], it is not obvious that a change involving both different solvents and temperatures would work.

(c)      The affidavit of October 10, 1995 of Dr. James B. Hendrickson, a professor in the Department of Chemistry of Brandeis University:

22.      The [Abbott Patent] is very specific about:

         (a)      the use of a lower alcohol as a solvent; and

         (b)      the temperature at which the process is heated.

23.      In the [Nu-Pharm] process the solvent is water and no heat is required.

24.      In my opinion, a person skilled in the art would understand that the Patentee intended the process to occur with those specific conditions.

     Abbott's position that the Nu-Pharm process is an obvious chemical equivalent of the one disclosed in Claim 1 of the Abbott Patent is supported by the following affiants:

(a)      The affidavit of Mr. Wayne R. Heitmann, a senior research investigator in the Chemical Development Department of Abbott Laboratories:

15.      The [Nu-Pharm] process simply imitates the Abbott Patent process by replicating the process in a different solvent. For anyone skilled in the art, this is a trivial modification because the solubility characteristics of Terazosin free base, Terazosin hydrochloride and Terazosin hydrochloride dihydrate follow the same pattern whether in lower alcohol or water, as shown below:

Terazosin free base      Terazosin hydrochloride      Terazosin hydrochloride dihydrate

lower alcohol      nearly insoluble      high solubility      low solubility

water      nearly insoluble      high solubility      low solubility

    

     16.      The solubility characteristics in lower alcohol are of course provided in the Abbott Patent. The solubility characteristics in water are readily available from the Merck Index, (Eleventh Edition, 1989, Merck & Co., Inc.), under the heading "Terazosin", which I attach as Exhibit B to this my Affidavit. Of course, the Merck Index is a common basic reference monograph for persons skilled in the art. The Merck Index states that Terazosin hydrochloride is about 31 times more soluble in water than Terazosin hydrochloride dihydrate (761.2 mg/ml versus 24.2 mg/ml).

     ...

     20.      Replacing one solvent (lower alcohol) with an equivalent solvent (water) does not affect the way the process works. The very substance of the invention revealed and claimed in the Abbott Patent is found in the [Nu-Pharm] process.

     ...

     22.      The contentions of Robert McClelland [at paragraph 26 of his affidavit] are clearly that:

a)      There is a dissimilarity in the way that the two processes work;

b)      The two processes differ in terms of their temperatures;

c)      The choice of water is a better solvent in which to dissolve salts than organic compounds;

     23.      Concerning contention a): on process dissimilarity:

Both processes react Terazosin free base with Hydrochloric acid which is the essential process to consider; both processes dissolve the resulting salt: the Abbott Patent suggesting ethanol as a solvent (see Example 2, page 6, Formula 3A 190 proof alcohol which includes, by definition 5% water) while the [Nu-Pharm] process dissolves the Hydrochloride salt in water alone. Therefore, the chemical process is clearly identical for both processes (formation of the hydrochloride salt and hydration with two molecules of water);

     24.      Concerning contention b): on temperature differences:

The use of ethanol suggested in the Abbott Patent requires higher temperatures to insure that all of the Terazosin hydrochloride molecules properly dissolve in the alcohol. It is simply a factor of solubility. Like in most cases, the higher the temperature, the higher the solubility. When water is used as a solvent, the temperature does not need to be raised since the Terazosin hydrochloride is readily soluble at ambient temperature. Thus, the difference in temperature is only momentary and relates only to solubility characteristics and not to the essential chemical reactions taking place.

     25.      Concerning contention c): on water as a solvent of choice;

Robert McClelland confirms my point that it was obvious, based on solubility characteristics alone, to think of using water. The Abbott Patent nevertheless suggests the use of lower alcohol because of preferable physical characteristics of the product, i.e., particle size or crystalline structure as opposed to the chemical nature of the Terazosin hydrochloride dihydrate product.

     ...

     27.      Dr. McClelland's comment about the unpredictability of crystallization success based on changes of solvents and temperatures [at paragraph 27 of his affidavit] is generally true. However, in this case, the usefulness of water as a solvent was highly predictable if not directly calculable from the data in the literature. I say this because of the wealth of information available on the solubility of terazosin hydrochlorides in water. For instance, solubility information is found in the Abbott Patent and the additional information is available from sources such as the Merck Index.

     28.      Furthermore, I believe obvious chemical equivalence is established by an identity in the core chemical reactions taking place, not the solvent in which they are conducted. In this case, the core chemical reactions are identical. Both processes operate exactly in the same way.

     (b)      The affidavit of December 12, 1995 of Dr. George Just, a professor of organic chemistry at McGill University:

     18.      For many good reasons (abundance, safety, ease of manipulation, etc.), in most industrial chemical syntheses, water is the preferred solvent. It is therefore immediately obvious to think of water as a possible replacement for lower alcohol. In this case, it is particularly obvious because of the contents of the Patent on which I will elaborate right now.

     19.      In the Patent, at page 3, line 3, it is stated that Terazosin hydrochloride is highly soluble in water. Still at page 3 of the Patent, at lines 24-25, it is further stated that the dihydrate form of Terazosin hydrochloride is less soluble in water than Terazosin hydrochloride. Furthermore this same information is available to all chemists in the well known Merck Index (source: Merck Index, 11th and Centennial Edition, under the heading "Terazosin" attached to this my Affidavit as Exhibit B). This makes it patently obvious to any person skilled in the art that generating Terazosin hydrochloride in water would lead to the crystallization or precipitation of its less soluble dihydrate form in the same way that it is obtained in a lower alcohol. The use of water is further made obvious because some water is of course required to hydrate the Terazosin hydrochloride into its dihydrate form.

     20.      In my opinion, it would have been quite obvious to a chemist involved in scale-up, to adapt the process in the Patent by forgoing the use of a lower alcohol and carrying-out the reaction in water. It would have been the obvious and logical thing to do when faced with manufacturing it on a large scale, provided the resulting product had the required purity.

     21.      Scaling-up a process (from laboratory to plant) often involves tinkering with minor modifications such as changing the solvent, reducing its volume, operating a different temperature, substituting one acid or base for another, and attempting to minimize production costs by cutting down excess chemicals used in the process, etc. These are all basic techniques known to those skilled in the art.

     In Nu-Pharm's view, the Abbott Patent describes only one process for making the dihydrate. That process utilizes a lower alcohol with a small water content and requires external heat at two stages. Claims 2 and 3 reiterate specifically the use of a lower alcohol such as "ethanol or a denatured alcohol" and a two-stage heating step "to a temperature of about 35C" and "to a temperature of about 70C". No other solvent is suggested in claims 1, 2 or 3. From this, Nu-Pharm concludes that the use of alcohol and heat is an essential feature of the Abbott Patent and that its use of water at room temperature is outside the scope of an obvious chemical equivalent referred to in claim 6.

     In cross-examination, Nu-Pharm confronted the Abbott affiants with: (a) a 1991 article on terazosin authored by Abbott employees which suggested that "... the compound shows degradation in weak aqueous acid at room temperature and rapid degradation in weak aqueous acid and weak aqueous base at elevated temperatures"; and (b) a 1995 Abbott U.S. patent which disclosed that "[t]he acidic cleavage of Terazosin, ... occurs rapidly in aqueous medium." I have reviewed the transcripts. On the basis of this cross-examination, I have not been able to conclude that the inventor of the Abbott Patent did not envisage water as an effective solvent.

     For Abbott, the possible use of water as the solvent in its Patent is obvious. Water must be present to make dihydrate and is the most common solvent used in drug synthesis. The lower alcohol used in the Abbott Patent contains 5% of water. The concentrated aqueous hydrochloric acid (HCl) contains water. Abbott also refers to certain disclosures in its Patent that terazosin hydrochloride is "highly soluble in water" and that the dihydrate form of terazosin hydrochloride is less soluble in water than terazosin hydrochloride.

     Abbott's submission, supported by Mr. Heitmann's affidavit at paragraph 24, is that the required temperature depends on the choice of the solvent in which the dissolution is to be achieved. I accept this proposition. Accordingly, the role of the solvent in the preparation of terazosin hydrochloride dihydrate becomes the pivotal issue.

     During the first and second steps of the process, terazosin free base is suspended in the solvent and then forms terazosin hydrochloride after the addition of concentrated aqueous hydrochloric acid. It is at this stage that the terazosin hydrochloride dissolves in the solvent. In the third step, the molecules of terazosin hydrochloride acquire two additional molecules of water to form terazosin hydrochloride dihydrate. The terazosin hydrochloride dihydrate must then have low solubility in the solvent to facilitate the recovery of the terazosin hydrochloride dihydrate from solution. The solvent, therefore, must be a liquid in which terazosin hydrochloride is highly soluble, but in which terazosin hydrochloride dihydrate is less soluble. I make these findings on the basis of the affidavit of Mr. Heitmann, particularly at paragraphs 15 and 24.

     Abbott submits that the solubility characteristics of terazosin hydrochloride and terazosin hydrochloride dihydrate in water were at least inferred, if not disclosed, by the Patent. In any event, however, this information was readily available to chemists through the Merck Index, which shows to persons skilled in the art that terazosin hydrochloride is soluble in water and that terazosin hydrochloride dihydrate could readily be recovered from water due to its low solubility in water. As noted at paragraph 16 of Mr. Heitmann's affidavit: "The Merck Index states that Terazosin hydrochloride is about 31 times more soluble in water than Terazosin hydrochloride dihydrate (761.2 mg/ml versus 24.2 mg/ml)." This data from the Merck Index was available prior to the publication of the two documents relied upon by Nu-Pharm in its cross-examination of the Abbott affiants.

     Dr. James B. Hendrickson, one of Nu-Pharm's affiants, expressed surprise at the positive results obtained by the Nu-Pharm process. In his words:

     "[Y]ou put in the free base and in order to get the hydrochloride dihydrate you must add the HCl which they did first, then it dissolved and then it must not crystallize out with two moles of water ... dihydrate and this apparently takes a slow time to form up and then come out a solution. I think it's quite a discovery. I have never seen anything work so beautifully as that, work that way, that you dissolve it and in a while, twenty-four hours, it comes back out again." (Applicant's Record, p. 480)

I have not been able to reconcile Dr. Hendrickson's surprise at the success of the Nu-Pharm process with the data disclosed in the Merck Index.

     It is on the basis of the data in the Merck Index, which was readily available to persons skilled in the art, that I conclude that the use of water in the Nu-Pharm process is an obvious chemical equivalent of the Abbott Patent. Of interest, the relevance of the Merck Index in this case is analogous to Mr. Justice Richard's reference to an introductory undergraduate textbook in organic chemistry in his disposition of Eli Lilly and Co. v. Novopharm Ltd. (1995), 60 C.P.R. (3d) 417. In concluding that Novopharm's process was the obvious chemical equivalent of the one disclosed in the Eli Lilly claims, Mr. Justice Richard stated at page 439:

     I am satisfied, on the basis of the evidence before me and in the circumstances of this proceeding, that the ether formation process employed in the Fermion process is an obvious chemical equivalent to that claimed in the Lilly Patent. The purpose of both reactions is the formation of a -C-O-C- bond. Both the hydroxyl and the chlorine compounds are present in the reaction, but their placement is reversed. In both reactions the hydroxyl is part of the attacking group and the chlorine is part of the leaving group (second affidavit of Dr. Schmiegel at pp. 208-10). I am in agreement with Lilly's experts that the ether formation step in the Fermion process is a Williamson synthesis and that this alternative mechanism was sufficiently known at the time of the issuance of the patent as to be "obvious". Specifically, the two alternate reactions are set out and described in a chapter of Organic Chemistry (R.T. Morrison and R.N. Boyd, 2nd ed. (Boston: Allyn and Bacon, Inc., 1965), pp. 562-5; see also second affidavit of Dr. Fallis at p. 456), the leading introductory undergraduate textbook during the 1970s. This textbook makes it clear that at the time that the patent was issued there were two alternative methods of making an ether linkage using the Williamson synthesis: using either an alkyl halide ion or an aryl halide ion. With respect to the bonds broken and made by both reactions, Novopharm's expert, Dr. Hendrickson, initially indicated that the bonds broken in both processes had totally different properties (cross-examination of Dr. Hendrickson at pp. 879-81), but upon further cross-examination he confirmed that the bonds broken and made were in fact the same (at pp. 795-9).

     For these reasons, on the basis of the evidence in these summary proceedings, the application will be granted. Abbott has established, on a balance of probabilities, that Nu-Pharm's allegations of non-infringement of the claims of the Abbott Patent are not justified. Accordingly, an order will issue prohibiting the Minister from issuing a Notice of Compliance to Nu-Pharm in connection with the drug in issue until after the expiration of the Abbott Patent. There will be no order as to costs unless counsel, in written submissions filed within one week, can establish special reasons within the meaning of Rule 1618.

                         "Allan Lutfy"        

                         Judge

Ottawa, Ontario

June 9, 1997

__________________

¹      SOR/93-133 (March 12, 1993)