Date: 20031003
Docket: T-122-02
Citation: 2003 FC 1145
Ottawa (Ontario) October 3, 2003
Present: The Honourable Mr. Justice Blais
BETWEEN:
H. LUNDBECK A/S and LUNDBECK CANADA INC.
Applicants
and
THE MINISTER OF HEALTH and GENPHARM INC.
Respondents
REASONS FOR ORDER AND ORDER
[1] This is an application by H. Lundbeck A/S and Lundbeck Canada Inc. pursuant to section 6(1) of the Patented Medicines (Notice of Compliance) Regulations [the "PM (NOC) Regulations"] for an order prohibiting the Minister of Health from issuing a Notice of Compliance ["NOC"] to Genpharm Inc. in respect of citalopram hydrobromide in each of the strengths 10 mg, 20 mg and 40 mg until after the expiration of Canadian Patent no. 2,049,368.
FACTS
[2] The applicant H. Lundbeck A/S is a pharmaceutical company focussing solely on the treatment of the central nervous system. Lundbeck Canada Inc. is the Canadian subsidiary of H. Lundbeck A/S ["Lundbeck"].
[3] The respondent Genpharm Inc. is a Canadian generic pharmaceutical company ["Genpharm"].
[4] Lundbeck Canada Inc. is the owner of two Canadian patents relating to citalopram hydrobromide ["citalopram"] : patent no. 1,237,147 ["'147 patent"] and patent no. 2,049, 368 ["'368 patent"]. Only patent '368 is at issue in this case.
[5] Lundbeck filed an application for patent '368 on August 16, 1991; the patent was granted October 23, 2001 and will expire August 16, 2011. It was listed on the Patent Register on November 29, 2001.
[6] On December 11, 2001, Genpharm sent to Lundbeck a Notice of Allegation ["NOA"] concerning both citalopram patents, '147 and '368. In this letter, Genpharm stated that it had filed a submission with the Minister of National Health and Welfare for a NOC in respect of the drug citalopram hydrobromide in three strengths, namely 10 mg, 20 mg and 40 mg.
[7] Genpharm maintained in the NOA that patents '147 and '368 should not be listed on the Patent Register. Patent '147 was subsequently removed from the Register by the Therapeutic Products Directorate ["TPD"], following a request from Genpharm. Genpharm's request to remove patent '368 from the Register is the basis for another proceeding, T-1652-02, to be heard at the same time as this case.
[8] In its NOA, Genpharm argued that even if the '368 patent were not removed from the Register, for Genpharm to produce the drug citalopram would still not constitute infringement, relying on the fact that there would be no infringement as to use. The inclusion of the '368 patent list on the Register seeks to protect the use of the medicine.
The patent
[9] Patent '368 is entitled Treatment of Cerebro-Vascular Disorders. The chemical composition of the drug involves a novel intermediate step, which is the object of the '147 patent. The novelty element in patent '368 is the use of citalopram to treat dementia and cerebro-vascular diseases ["CVD"]. Citalopram is already well-known as an anti-depressant, as the patent itself states.
[10] The '368 patent contains the description of the drug, and a list of 21 claims. The claims that are protected by the inclusion of the drug on the patent list are those claims related to the use of the medicine. Reproduced below are the claims of patent '368; the claims related to use are underlined.
The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. Use of a 1-[3-(dimethylamino)propyl]-1-phenylphthalane of the formula: wherein R1 and R2 each are selected from the group consisting of halogen, trifluoromethyl, cyano and R-CO-, wherein R is an alkyl radical with 1 to 4 C-atoms inclusive, or a pharmaceutically-acceptable acid addition salt thereof, for the manufacture of a medicament for the treatment of cognitive disorders or amnesia associated with dementia and of cerebrovascular disorders.
2. Use according to claim 1, wherein the medicament is for the treatment of cerebrovascular disorder caused by cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, subarachnoid hemorrhage, cerebral thrombosis, or cerebral embolism.
3. Use according to claim 2, wherein the medicament is for the treatment of ischemia.
4. Use according to claim 3, wherein the medicament is for the treatment of amnesia associated with ischemia.
5. Use according to claim 1, wherein the medicament is for the treatment of vascular or multi-infarct dementia.
6. Use according to claim l, wherein the dementia is a dementia of the Alzheimer's type.
7. Use according to any one of claims 1 to 6, wherein the compound of Formula I is citalopram or a pharmaceutically acceptable acid addition salt thereof.
8. A pharmaceutical composition or medicament for the treatment of dementia and cerebrovascular disorders comprising an amount of a 1-[3-dimethylamino)propyl]-1-phenylphthalane of the formula: wherein R1 and R2 each are selected from the group consisting of halogen, trifluoromethyl, cyano and R-CO~; wherein R is an alkyl radical with 1 to 4 C-atoms inclusive, or a pharmaceutically-acceptable acid addition salt thereof, which is effective for such purpose, and a pharmaceutically-acceptable diluent or carrier.
9. Composition according to claim 8, which is for the treatment of cerebrovascular disorders caused by cerebral infraction, cerebral hemorrhage, cerebral arteriosclerosis, subarachnoid hemorrhage, cerebral thrombosis, or cerebral embolism.
10. Composition according to claim 9, which is for the treatment of ischemia.
11. Composition according to claim 9, which is for the treatment of amnesia associated with ischemia.
12. Composition according to claim 9, which is for the treatment of vascular or mufti-infarct dementia.
13. Composition according to claim 8, which is for the treatment of dementia of the Alzheimer's type.
14. Composition according to claim 8, wherein the compound of Formula I is citalopram or a pharmaceutically-acceptable acid addition salt thereof.
15. A method for the production of a pharmaceutical preparation useful in the treatment of dementia and cerebrovascular disorders in a patient in need thereof comprising the step of admixing an amount of a 1-[3-(dimethylamino)propyl]-1-phenylphthalane of the formula: wherein R1 and R2 each are selected from the group consisting of halogen, trifluoromethyl, cyano and R-CO-, wherein R is an alkyl radical with 1 to 4 C-atoms inclusive, or a pharmaceutically-acceptable acid addition salt thereof, which is effective for such purpose, with a pharmaceutally-acceptable carrier or diluent.
16. A method according to claim 15, wherein the preparation is for the treatment of cerebrovascular disorders caused by cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, subarachnoid hemorrhage, cerebral thrombosis, or cerebral embolism.
17. A method according to claim 16, wherein the preparation is for the treatment of ischemia.
18. A method according to claim 16, wherein the preparation is for the treatment of amnesia associated with ischemia.
19. A method according to claim 16, wherein the preparation is for the treatment of vascular or multiinfarct dementia.
20. A method according to claim 15, wherein the preparation is for the treatment of dementia of the Alzheimer's type.
21. A method according to claim 15, wherein the compound of Formula I is citalopram or a pharmaceutically-acceptable acid addition salt thereof.
[11] Citalopram is part of a class of pharmaceutical drugs called Selective Serotonin Reuptake Inhibitors ["SSRI"], a type of drug which has shown itself very useful in the treatment of depression and depressive illness. SSRIs act on the serotonic system, generally linked to mood, feelings of well-being, anxiety, and such. At the present time, Lundbeck is the only manufacturer of citalopram in Canada allowed to sell the product, which is marketed under the registered brand name Celexa®.
[12] The sale of medical drugs in Canada is regulated by the Food and Drugs Act Regulations. Under those Regulations, the manufacturer of a medical drug must obtain a NOC before it can sell the drug. Lundbeck obtained a NOC for its product Celexa® in tablets of 10 mg, 20 mg and 40 mg in February 1999. The NOC issued by the Department of Health specifies that Celexa® is to be used for the symptomatic relief of depressive illness. The NOC does not cover the uses of Celexa® claimed in the '368 patent, i.e., treatment of dementia, CVD or any other disorder named in the patent claims.
[13] Under the PM (NOC) Regulations, a drug manufacturer who holds a patent on a drug, and who has been issued a NOC for the drug, can file a patent list with the Minister in respect of that drug. This patent list appears on a Register maintained by the Minister. From then on, any other manufacturer who applies for a NOC in respect of a drug that is either compared or referenced to the patented drug that appears on the Register must support its application with an allegation that the listed drug patent will not be infringed. The NOA must be served on the patent holder, who has 45 days to dispute and seek an order from the Federal Court prohibiting the Minister from issuing the NOC.
Expert Evidence
[14] Lundbeck presented by way of affidavit and cross-examination two expert witnesses: Dr. Kiran Rabheru and Dr. Serge Gauthier. By their training, attested to by their resumes, they would seem to qualify as expert witnesses.
[15] Genpharm presented two expert witnesses, which appear equally qualified, Dr. Harold Merskey and Dr. Michel Piers Rathbone.
[16] Genpharm's position is fundamentally that by producing citalopram, it would not be infringing Lundbeck's patent, since Genpharm intends to market citalopram solely for the well-known use recognized by the NOC, i.e. depression. Since the patent protects the use of citalopram as a treatment for dementia (of varying types) and CVD (of varying types), including cognitive disorders or amnesia linked to those diseases, Genpharm argues that it will not infringe the uses as stated on the patent list.
[17] Lundbeck presents three basic arguments to counter Genpharm's allegations: nothing prevents off-label use, dementia includes depression, and studies have shown citalopram to be effective in treating dementia, thus the probability of its use as patented and thus the infringement.
Off-label use
[18] Lundbeck maintains that even if Genpharm states that it will market citalopram only for depression, nothing prevents prescribing physicians or patients from using citalopram for dementia or CVD, which would constitute an infringement of the patent, whatever Genpharm's stated intent. Using the medication for uses other than those covered by the NOC is referred to as 'off-label use'.
[19] Little evidence was presented by any of the expert witnesses that citalopram has been used to treat dementia or CVD, or would be the treatment of choice to treat the primary condition associated with these diseases, which is loss of cognitive functions. All seem to agree that citalopram is useful for depression or depressive symptoms.
[20] Both Dr Merskey and Dr Rathbone were questioned in cross-examination on the possibility of off-label use of citalopram, i.e., not as an antidepressant drug according to the NOC but as a drug to treat dementia or CVD, the protected use.
[21] Dr. Merskey : "So I have no hesitation in saying that citalopram is a good drug for depression and that it's a good drug to use in patients with dementia if they have depression. I wouldn't dream in [sic] using it in any other way for dementia". (AR, Vol. III, tab 12, p. 910)
[22] Dr. Rathbone stated that off-label use is generally in the context of large trials, where there is some pharmacological evidence to support trying out the drug for other than the use for which it was approved. Two realities come into play for the prescribing physician : guidelines from the Royal College of Physicians and Surgeons, and, especially for the elderly, the government reimbursement through the Ontario Benefit Plan. The government reimbursement applies only when the drug is prescribed according to its recognized use (in the case of citalopram, for depression, not the patented uses, for which no NOC has been issued). It may happen that a drug will be reimbursed despite the absence of NOC, but only when a great number of clinical trials have taken place and a great deal of evidence supports its off-label use. Experimentation by physicians by way of off-label use is a rare occurrence, according to Dr. Rathbone; it is much more likely that off-label use will happen in the context of large trials based on preliminary pharmacological findings. (AR, Vol III, tab 14, p. 1024-1026)
Dementia (Alzheimer type or cerebro-vascular type) includes depression
[23] CVD (cerebrovascular disorders) is defined in the '368 patent at page 3 as follows:
Brain damage caused by cerebral infarction, cerebral haemorrhage, cerebral arteriosclerosis, subarachnoid haemorrhage, cerebral thrombosis, cerebral embolism, or the like, e.g. ischemia and the psychological and neurological sequelae of such damages. (AR, Vol. I, tab 4b, p.215)
[emphasis added]
[24] Thus the patent includes in the definition of CVD the psychological sequelae of CVD by defining the disorders as brain damage.
[25] Dr Rabheru states in his affidavit that depression and cognitive impairment often co-exist. He relies for this statement on various studies that have been done, included with his affidavit, showing the presence of depression in patients with Alzheimer or CVD. Behavioral and psychological symptoms of dementia ["BPSD"] may be helped with the use of SSRIs such as Celexa, "in the non-cognitive domains such as depression and anxiety" (tab 3, AR, vol 1, p.13). Improvement of cognitive impairment is inconsistent, and remains to be established for cerebro-vascular dementia ["VD"]. Dr. Rabheru goes on to explain that the improvement noted in cognitive function may be due to a relief of the depression.
[26] In cross-examination, Dr. Rabheru expounds further the idea of concomitant dementia and depression:
The cluster of symptoms that make up dementia includes three domains...we think of them as the ABC's of dementia...The "A" refers to the change in functioning or activities of daily living...The second domain involves cognition, and that's the "C"... The third domain is what the "B refers to"...the global term that's now accepted in the literature, is BPSD...behavioural and psychological symptoms of dementia, and they include a whole variety of symptoms, ranging from anxiety to depression, agitation, psychosis, aggression... (AR, Vol. III, tab 15, p.1159-1160)
[27] By assimilating depression and dementia, the risk is to move to the next step, that treating depression in a patient with dementia is really treating dementia. Dr Merskey, in his affidavit, warns against the leap. Depression may be caused by all kinds of physical factors, notably by infections.
Post-influenzal depression is one such form of depression caused by an infection. Relief of that disorder by citalopram would not amount to evidence that citalopram cures influenza in any other respect or that the relief of depression involved a new mechanism.
(AR, Vol. II, tab 9, p. 758).
Studies have shown citalopram to be effective in treating dementia
[28] In his affidavit, Dr. Serge Gauthier indicates that at least four published studies have looked at the effects of citalopram in depressed and non-depressed patients with Alzheimer's disease.
Of particular note is the study of Nyth et al (Acta Psychiatr Scand 1992, 86, 138-145), where 29 patients with dementia were randomized to citalopram (N=15) or placebo (N=8) for 6 weeks, and significant differences in favour of citalopram were found in items of a well validated scale including impairment in orientation to time, impaired recent memory... This pattern of improvement suggests cognitive improvement above and beyond improvement of depression.
[29] A little further he adds, under the heading "Conclusions":
There are sufficient data and biological plausibility to support a broader action of citalopram as an antidementia drug, above and beyond its original use as antidepressant.
(Vol. I, AR, tab 5, p. 293).
[30] Dr. Merskey states in his affidavit that many antidepressants, including SSRIs, improve cognitive functions in patients as the relief of depression occurs. No evidence was offered by the Lundbeck experts to the effect that citalopram performs better in this regard than other comparable antidepressants.
[31] The cognitive improvement above and beyond improvement in depression suggested by Dr Gauthier, according to Dr Merskey, remains speculative. Again according to Dr. Merskey, the lack of further investigation since 1992 "also raises the idea that the current notions put forward with respect to these topics have not been thought worthy of much more attention to date."
(AR, Vol II, tab 9, p. 763.)
[32] Dr Merskey in his affidavit discusses at length the studies cited by Dr Rabheru and Dr Gauthier, and notes that what could have been promising avenues of research (for instance, the interaction of citalopram with the cholinergic system, more directly linked to the cognitive functions) have not been further pursued since 1992 (the Nyth study). Dr. Merskey summarizes thus his clinical experience of the effect of citalopram:
I am familiar with citalopram and indeed it is one of the drugs for depression that I most commonly prescribe. Its "old use" is fully established and relevant to depression whether it occurs with or without any complicating illness. That complicating illness might be kidney disease, heart disease, a painful disorder of some part of the body, or a dementia which has caused alteration in some of the functions of the brain. In all these cases so far as can be determined and in light of present knowledge, and notwithstanding anything I have seen in the documents cited, the effect of citalopram in patients with dementia is parallel to that of citalopram in other cases : to the best of our knowledge it simply relieves depression - rather efficiently. (AR, Vol. II, tab 9, p. 765.)
[33] During the cross-examination of Dr Rabheru, the applicant sought to introduce a new study (Pollock, B.G. et al. "An Open Pilot Study of Citalopram for Behavioral Disturbances of Dementia", American Journal of Geriatric Psychiatry 1997; 5:70-78) which apparently contradicts the statement of Dr Merskey that no further study has been done on the treatment of dementia with citalopram. The respondent objected to the introduction of new evidence during the reexamination of witness, and the evidence was ruled inadmissible by Prothonotary Lafrenière.
[34] From the evidence presented by the expert witnesses, on both sides, I remain unconvinced that citalopram at the present time is used or prescribed for anything else than depression. The fact that it may have positive effects for patients suffering from dementia, Alzheimer's or CVD seems related to the fact that it alleviates depressive symptoms. When depression lifts, cognitive symptoms might improve; the fact remains that it is depression, not anything else, which has been treated.
[35] It may be that citalopram would be useful in treating behavioural problems in persons suffering from dementia; however, I find that such an allegation, which scientific research has not established entirely (according to the evidence presented), changes nothing for the matter that occupies us here : whether the allegation of non-infringement is justified. There is nothing in the claims which covers behavioural symptoms. The patent disclosure provides a definition of CVD that includes the psychological and neurological sequelae of brain damage caused by the various manifestations of CVD. Those are not the behavioural symptoms which Dr. Rabheru referred to when he was speaking of dementia or Alzheimer's. Behavioural symptoms are a distressing part of dementia and Alzheimer's, but I do not think that treating them is treating dementia or Alzheimer's, anymore than I think treating depression which occurs with dementia is treating dementia. Nor do the "psychological and neurological sequelae of brain damage "cover, in my opinion, depression as it understood today and as it is understood for the purposes of the NOC. Depression is not a psychological or neurological sequela of brain damage. It may occur in the context of brain damage, but it also occurs absent any brain damage caused by CVD or dementia. It exists as an autonomous disorder, and that is what citalopram purports to treat.
ISSUE
[36] Is Genpharm justified in its allegation that by manufacturing and selling the drug citalopram, it will not infringe the '368 patent?
LEGISLATION
[37] The following sections of the PM (NOC) Regulations (SOR/93-133) apply to this case:
| 5. (...) (1.1) Subject to subsection (1.2), where subsection (1) does not apply and where a person files or has filed a submission for a notice of compliance in respect of a drug that contains a medicine found in another drug that has been marketed in Canada pursuant to a notice of compliance issued to a first person and in respect of which a patent list has been submitted, the person shall, in the submission, with respect to each patent included on the register in respect of the other drug containing the medicine, where the drug has the same route of administration and a comparable strength and dosage form,
(...)
(b) allege that
(...)
(iv) no claim for the medecine itself and no claim for the use of the medicine would be infringed by the making, constructing, using or selling by that person of the drug for which the submission for the notice of compliance is filed.
(3) Where a person makes an allegation pursuant to paragraph (1.1)(b) (...) the person shall
(a) provide a detailed statement of the legal and factual basis for the allegation;
(...)
(c) if the allegation is made under subparagraph (1)(b)(iv),
(I) serve on the first person a notice of the allegation relating to the submission filed under subsection (1) or (1.1) at the time that the person files the submission or at any time thereafter, and
(ii) include in the notice of allegation a description of the dosage form, strength and route of administration of the drug in respect of which the submission has been filed: (...)
6. (1) A first person may, within 45 days after being served with a notice of an allegation pursuant to paragraph 5(3) (b) or (c), apply to a court for an order prohibiting the Minister from issuing a notice of compliance until after the expiration of a patent that is the subject of the allegation.
(2) The court shall make an order pursuant to subsection (1) in respect of a patent that is the subject of one or more allegations if it finds that none of those allegations is justified.(...)
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5.(1.1) Sous réserve du paragraphe (1.2), lorsque le paragraphe (1) ne s'applique pas, la personne qui dépose ou a déposé une demande d'avis de conformité pour une drogue contenant un médicament que l'on trouve dans une autre drogue qui a été commercialisée au Canada par suite de la délivrance d'un avis de conformité à la première personne et à l'égard de laquelle une liste de brevets a été soumise doit inclure dans la demande, à l'égard de chaque brevet inscrit au registre visant cette autre drogue contenant ce médicament, lorsque celle-ci présente la même voie d'administration et une forme posologique et une concentration comparables :
(...)
b) soit une allégation portant que, selon le cas :
(...)
(iv) aucune revendication pour le médicament en soi ni aucune revendication pour l'utilisation du médicament ne seraient contrefaites advenant l'utilisation, la fabrication, la construction ou la vente par elle de la drogue faisant l'objet de la demande d'avis de conformité.
(...)
(3) Lorsqu'une personne fait une allégation visée aux alinéas (1)b) ou (1.1)b) ou au paragraphe (2), elle doit :
a) fournir un énoncé détaillé du droit et des faits sur lesquels elle se fonde;
(...)
c) si l'allégation est faite aux termes des sous-alinéas (1)b)(iv) ou (1.1)b)(iv) :
(i) signifier à la première personne un avis de l'allégation relative à la demande déposée selon les paragraphes (1) ou (1.1), au moment où elle dépose la demande ou par la suite,
(ii) insérer dans l'avis d'allégation une description de la forme posologique, de la concentration et de la voie d'administration de la drogue visée par la demande;(...)
6. (1) La première personne peut, dans les 45 jours après avoir reçu signification d'un avis d'allégation aux termes des alinéas 5(3)b) ou c), demander au tribunal de rendre une ordonnance interdisant au ministre de délivrer un avis de conformité avant l'expiration du brevet visé par l'allégation.
(2) Le tribunal rend une ordonnance en vertu du paragraphe (1) à l'égard du brevet visé par une ou plusieurs allégations si elle conclut qu'aucune des allégations n'est fondée.(...)
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[38] The patent list referred to in subsection 5(1.1) is described in section 4. The patent list appears on a Register maintained by the Minister, as described in section 3; no patent list in respect of a drug may appear on the Register until after the drug has received the NOC allowing its manufacture and sale in Canada. The NOC is issued under section C.08.004 of the Food and Drug Regulations and concerns the safety of the drug.
[39] Subsection 4(7) specifies that the person who submits a patent list must certify that the patents are eligible for inclusion and "relevant to the dosage form, strength and route of administration of the drug in respect of which the submission for the notice of compliance has been filed". Subsection 3(3) states that no information pursuant to section 4 may be included on the Register until after the issuance of the NOC. The NOC, under the Food and Drug Regulations, specifies the use of the medication.
[40] There is no explicit link in the PM (NOC) Regulations between the use specified in the NOC and the uses appearing on the patent list. This issue will be revisited in the companion hearing T-1652-02.
[41] For greater ease, sections 3 and 4 are reproduced below:
| 3. (1) The Minister shall maintain a register of any information submitted under section 4. To maintain it, the Minister may refuse to add or may delete any information that does not meet the requirements of that section.
(2) The register shall be open to public inspection during business hours.
(3) No information submitted pursuant to section 4 shall be included on the register until after the issuance of the notice of compliance in respect of which the information was submitted.
(4) For the purpose of deciding whether information submitted under section 4 should be added to or deleted from the register, the Minister may consult with officers or employees of the Patent Office. SOR/98-166, s. 2.
PATENT LIST
4. (1) A person who files or has filed a submission for, or has been issued, a notice of compliance in respect of a drug that contains a medicine may submit to the Minister a patent list certified in accordance with subsection (7) in respect of the drug.
(2) A patent list submitted in respect of a drug must
(a) indicate the dosage form, strength and route of administration of the drug;
(b) set out any Canadian patent that is owned by the person, or in respect of which the person has an exclusive licence or has obtained the consent of the owner of the patent for the inclusion of the patent on the patent list, that contains a claim for the medicine itself or a claim for the use of the medicine and that the person wishes to have included on the register;
(c) contain a statement that, in respect of each patent, the person applying for a notice of compliance is the owner, has an exclusive licence or has obtained the consent of the owner of the patent for the inclusion of the patent on the patent list;
(d) set out the date on which the term limited for the duration of each patent will expire pursuant to section 44 or 45 of the Patent Act; and
(e) set out the address in Canada for service on the person of any notice of an allegation referred to in paragraph 5(3)(b) or (c), or the name and address in Canada of another person on whom service may be made, with the same effect as if service had been made on the person.
(3) Subject to subsection (4), a person who submits a patent list must do so at the time the person files a submission for a notice of compliance.
(4) A first person may, after the date of filing of a submission for a notice of compliance and within 30 days after the issuance of a patent that was issued on the basis of an application that has a filing date that precedes the date of filing of the submission, submit a patent list, or an amendment to an existing patent list, that includes the information referred to in subsection (2).
(5) When a first person submits a patent list or an amendment to an existing patent list in accordance with subsection (4), the first person must identify the submission to which the patent list or the amendment relates, including the date on which the submission was filed.
(6) A person who submits a patent list must keep the list up to date but may not add a patent to an existing patent list except in accordance with subsection (4).
(7) A person who submits a patent list or an amendment to an existing patent list under subsection (1) or (4) must certify that
(a) the information submitted is accurate; and
(b) the patents set out on the patent list or in the amendment are eligible for inclusion on the register and are relevant to the dosage form, strength and route of administration of the drug in respect of which the submission for a notice of compliance has been filed. SOR/98-166, s. 3.
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3. (1) Le ministre tient un registre des renseignements fournis aux thermes de l'article 4. À cette fin, il peut refuser d'y ajouter ou en supprimer tout renseignement qui n'est pas conforme aux exigences de cet article.
(2) Le registre est ouvert à l'inspection publique durant les heures de bureau.
(3) Aucun renseignement soumis aux termes de l'article 4 n'est consigné au registre avant la délivrance de l'avis de conformité à l'égard duquel il a été soumis.
(4) Pour décider si tout renseignement fourni aux termes de l'article 4 doit être ajouté au registre ou en être supprimé, le ministre peut consulter le personnel du Bureau des brevets.
4. (1) La personne qui dépose ou a déposé une demande d'avis de conformité pour une drogue contenant un médicament ou qui a obtenu un tel avis peut soumettre au ministre une liste de brevets à l'égard de la drogue, accompagnée de l'attestation visée au paragraphe (7).
(2) La liste de brevets au sujet de la drogue doit contenir les renseignements suivants :
a) la forme posologique, la concentration et la voie d'administration de la drogue;
b) tout brevet canadien dont la personne est propriétaire ou à l'égard duquel elle détient une licence exclusive ou a obtenu le consentement du propriétaire pour l'inclure dans la liste, qui comporte une revendication pour le médicament en soi ou une revendication pour l'utilisation du médicament, et qu'elle souhaite voir inscrit au registre;
c) une déclaration portant, à l'égard de chaque brevet, que la personne qui demande l'avis de conformité en est le propriétaire, en détient la licence exclusive ou a obtenu le consentement du propriétaire pour l'inclure dans la liste;
d) la date d'expiration de la durée de chaque brevet aux termes des articles 44 ou 45 de la Loi sur les brevets;
e) l'adresse de la personne au Canada aux fins de signification de tout avis d'allégation visé aux alinéas 5(3)b) ou c), ou les nom et adresse au Canada d'une autre personne qui peut en recevoir signification avec le même effet que s'il s'agissait de la personne elle-même.
(3) Sous réserve du paragraphe (4), la personne qui soumet une liste de brevets doit le faire au moment du dépôt de la demande d'avis de conformité.
(4) La première personne peut, après la date de dépôt de la demande d'avis de conformité et dans les 30 jours suivant la délivrance d'un brevet qui est fondée sur une demande de brevet dont la date de dépôt est antérieure à celle de la demande d'avis de conformité, soumettre une liste de brevets, ou toute modification apportée à une liste de brevets, qui contient les renseignements visés au paragraphe (2).
(5) Lorsque la première personne soumet, conformément au paragraphe (4), une liste de brevets ou une modification apportée à une liste de brevets, elle doit indiquer la demande d'avis de conformité à laquelle se rapporte la liste ou la modification, en précisant notamment la date de dépôt de la demande.
(6) La personne qui soumet une liste de brevets doit la tenir à jour mais ne peut ajouter de brevets à une liste que si elle le fait en conformité avec le paragraphe (4).
(7) La personne qui soumet une liste de brevets ou une modification apportée à une liste de brevets aux termes des paragraphes (1) ou (4) doit remettre une attestation portant que :
a) les renseignements fournis sont exacts;
b) les brevets mentionnés dans la liste ou dans la modification sont admissibles à l'inscription au registre et sont pertinents quant à la forme posologique, la concentration et la voie d'administration de la drogue visée par la demande d'avis de conformité.
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GENPHARM'S ALLEGATIONS
[42] According to Genpharm's submission to the Minister of National Health and Welfare, the only use for the medicine it proposes to manufacture and sell is the symptomatic relief of depressive illness. No use as claimed in any of the 21 claims of the '368 patent will be indicated. Therefore, Genpharm argues, no claim for the use of the medicine will be infringed by Genpharm.
LUNDBECK'S SUBMISSIONS
[43] Ljundbeck submits that given the considerable overlap of patients which suffer from both depression and dementia or CVD, it is inevitable that Genpharm's tablets will be prescribed to patients suffering from dementia or CVD. Lundbeck argues that this will mean that citalopram will treat their dementia or CVD. In the patent description, on p. 3, CVD (cerebrovascular disorders) are defined as including "psychological and neurological sequelae" of brain damage caused by various cerebrovascular diseases such as cerebral infarction or cerebral hemorrhage. Therefore the use according to the patented claim of treating CVD covers the treatment of depression, which could qualify as one of the psychological sequelae of brain damage.
[44] The argument by Genpharm that this is not its intent is immaterial to the determination of infringement. Moreover, any evidence of inefficacy is inadmissible because it is beyond Genpharm's NOA.
ANALYSIS
[45] In Merck Frosst Canada Inc. v. Canada (Minister of National Health and Welfare)(1994), 55 C.P.R. (3d) 302 (F.C.A.), affirming 53 C.P.R. (3d) 368, Hugessen, J.A., writing for the Court, defined as follows the burden of proof in a case under the PM (NOC) Regulations:
As I understand the scheme of the regulations, it is the party moving under s. 6, in this case Merck, which, as the initiator of the proceedings, has the carriage of the litigation and bears the initial burden of proof. That burden, as it seems to me, is a difficult one since it must be to disprove some or all of the allegations in the notice of allegation which, if left unchallenged, would allow the Minister to issue a notice of compliance. There may, of course, be some presumptions (such as for example the statutory presumption of validity of a patent) (Patent Act, s. 43) which may help the moving party and have the effect of displacing the burden of proof. The presumption enacted by s. 55.1, however, is not one of them. The proceedings are not an action and their object is solely to prohibit the issuance of a notice of compliance under the Food and Drug Regulations. Manifestly, they do not constitute "an action for infringement of a patent": see Bayer, supra.
Furthermore, since the regulations clearly allow the Minister, absent a timely application under s. 6, to issue a notice of compliance on the basis of the allegations in the notice of allegation, it would seem that on the hearing of such an application, at least where the notice has alleged non-infringement, the court should start from the proposition that the allegations of fact in the notice of allegation are true except to the extent that the contrary has been shown by the applicant. In determining whether or not the allegations are "justified" (s. 6(2)), the court must then decide whether, on the basis of such facts as have been assumed or proven, the allegations would give rise in law to the conclusion that the patent would not be infringed by the respondent. [p.319]
[emphasis added]
[46] Lundbeck must thus discharge its burden of proving that Genpharm's allegations of non-infringement are without merit. It must prove that the use that Genpharm's drug would be put to would infringe the use protected by virtue of the fact that patent '368 is listed on the Register.
[47] What Lundbeck must establish is that the Genpharm tablets will be used for the protected use (as listed on the Register) as opposed to the unprotected use, as enunciated in the NOC. At most, Lundbeck's experts have stated that citalopram could be effective in treating behavioural problems linked to dementia or Alzheimer, and even that use has not been fully established by medical literature.
[48] Lundbeck argues that Genpharm cannot present evidence of inefficacy as this is beyond its detailed statement in the NOA. In the case cited, AB Hassle et al. v. Minister of National Health and Welfare et al.(2000), 7 C.P.R. (4th) 272 (F.C.A.), the Federal Court of Appeal ruled that additional evidence could not be provided by the respondent beyond the evidence listed in the detailed statement. The rationale appears to be that the purpose of the NOA is to allow the patentee the opportunity to decide whether or not to react to the NOA, by framing the allegations which it must answer.
[49] In the instant case, the affidavits submitted by Genpharm were in answer to the affidavits submitted by Lundbeck. Genpharm's allegation is simple: the citalopram it would produce would not be used to treat any of the diseases enumerated in the patent claims. The evidence presented by Genpharm was two-fold: depression is not dementia or CVD, and thus treating the former is not treating the latter; and there is little likelihood that citalopram would be prescribed for the uses which the patent protects. This evidence, I find, serves to support its allegation of non-infringement. The matter of inefficacy was not aimed at the validity of the patent, but rather, at the probability that the generic citalopram would be used or prescribed in a way that infringed the patent claims. There was nothing unexpected in this strategy, and it was up to the applicant to show that the generic citalopram would be prescribed for the uses that were protected by the patent list.
[50] In Pfizer Canada Inc. v. Nu-Pharm Inc. (1998), 83 C.P.R. (3d) 1, the Federal Court stated at p. 3:
It is well established that in order to grant a prohibition order, the Court must find that the patentee has established, on a balance of probabilities, that a second person's allegations are not justified. In determining the nature of the burden to be met by the applicants, it is important to remember that the proceeding under subsection 6(2) is not an ordinary infringement action. Rather, it is a summary proceeding intended to allow a patent owner to protect its patent rights where the generic's allegations of non-infringement or invalidity have no merit. Accordingly, if a patent owner cannot establish that the generic's allegations have no merit, the prohibition application should be dismissed and the issue left to be resolved by more conventional measures.
[51] Possible infringement because of physicians prescribing or patients using an "old" drug for a "new" protected use was dealt with in two decisions of the Federal Court of Appeal.
[52] In Genpharm Inc. v. Procter & Gamble Inc. (2002), 20 C.P.R. (4th) 1 (FCA), Genpharm had applied for a NOC to produce tablets of etidronate disodium for the treatment of osteoporosis. Procter & Gamble ["P & G"] had invented a new use for a known product, by introducing an intermittent regimen which would encourage bone recovery. Etinodronate disodium is used in 200 mg tablets to treat Paget's disease and hypercalcimia of malignancy. P & G produced 400 mg tablets for the osteoporosis treatment. Genpharm was seeking an NOC for 400 mg, but arguing that they would be marketed for Paget's disease and hypercalcimia, not as treatment for osteoporosis. The Federal Court of Appeal held that the confusion between P & G's patented drug and Genpharm's proposed drug would be such that infringement would result.
[53] That case is distinguishable because the use for osteoporosis was not at issue; the intermittent use of the 400 mg tablets was approved, patented and protected and could be infringed. As a NOC had been issued for that use, issuing a NOC to Genpharm for similar tablets was likely to give rise to infringement. In this case, the use of citalopram for CVD and dementia has not been established, and no NOC has issued for these uses.
[54] The second case from the Federal Court of Appeal, AB Hassle et al. v. Minister of National Health and Welfare et al. (2002), 22 C.P.R. (4th) 1 (F.C.A.), bears more directly on the issue in this case. Curiously, the applicant has chosen to rely on another decision, A.B. Hassle and Astrazeneca Canada Inc. v. Rhoxalpharma Inc. and Minister of Health [2002] FCT 780 (Gibson J.), which dealt with the same issue but came to a different conclusion.
[55] The issue concerned the manufacture of a known compound, omeprazole. The claim for use in the patent related to the treatment of Campylobacter infections. In its NOA, the generic manufacturer (Apotex in the F.C.A. case, Rhoxalpharma in the Gibson J. decision) alleged that no claim for the medicine or the use of the medicine would be infringed, since its product would not be made, used or sold for the treatment of Campylobacter infections.
[56] At trial, Gibson J., hearing the Rhoxalpharma case, held that since it was probable that physicians would prescribe the generic form of omeprazole for Campylobacter infections, there would be indirect infringement, although direct infringement had not been made out; he therefore issued a prohibition order for the duration of the patent.
[57] In his decision, Gibson J. referred to the trial decision by Justice O'Keefe, AB Hassle et al. v. Minister of National Health and Welfare et al. (2001), 16 C.P.R. (4th) 21 (FCTD) which was later affirmed by the Federal Court of Appeal, precisely the case mentioned above. The fact situation was identical. Justice O'Keefe refused to issue the prohibition order because he was not satisfied that infringement, direct or indirect, had been established.
[58] Justice Gibson's decision has no known history and has not been followed. Justice O'Keefe's decision, as stated above, was affirmed by the Federal Court of Appeal. The Federal Court of Appeal ruled that the decision of the trial judge had been reasonable, given his factual findings:
There was no evidence that Apotex intended to make, use or sell the drug for the specific patented use.
There had to be a connection between the second person (the generic manufacturer) and an infringement by a third party. The second person had to be involved in the infringement, either directly or indirectly, through inducement or procurement. Apotex had neither induced nor procured any infringement.
Hassle had to prove that 1) physician would prescribe medicine by generic name to treat Campylobacter 2) pharmacist would dispense lowest cost generic product, which would result in infringement of '668 patent. This had not been established. Justice O'Keefe found that Hassle had failed to show on a balance of probabilities that Apotex would infringe Hassle's patent.
[59] Infringement can be direct or indirect. In the case at bar, the applicant has not established, on the balance of probabilities, that Genpharm intends to make, use or sell its generic form of citalopram for any other purpose save the old, approved use. Nor has the applicant convinced me that citalopram would be used or prescribed by third parties for uses other than the approved use. I have seen no evidence of citalopram being recognized by the medical profession as a promising medication for any of the patented uses claimed in the patent list.
[60] In Procter & Gamble, supra, the Federal Court of Appeal found that use by patients of the medicine for the uses protected by patent would result in an infringement, and thus NOC should not issue for the generic manufacturer. However, in that case, "the evidence overwhelmingly demonstrated that the actions and intentions [of the generic manufacturer] would inevitably lead to an infringement". [Procter & Gamble, supra, para. 56]
[61] In AB Hassle, supra, the Federal Court of Appeal provides, I believe, a fitting conclusion for our case:
¶ 57 Thus Apotex cannot be prevented from obtaining a NOC solely on the basis that it will sell omeprazole. If it were otherwise, then serious policy issues would arise. If there was any likelihood that a patient would consume a generic product for a patented use, then the generic product would not be approved. This would prevent new uses from being approved for existing drugs because there is always the possibility that someone somewhere will use the drug for the prohibited, patented purpose. This would result in a real injustice: since a generic company cannot possibly control how everyone in the world uses its product, the prevention of the generic from marketing the product would further fortify and artificially extend the monopoly held by the patent holders. The patent holder would, therefore, effectively control not just the new uses for the old compound, but the compound itself, even though the compound itself is not protected by the patent in the first place. The patent holders, as a result, would obtain a benefit they were not meant to have. In the end, society would be deprived of the benefit of new methods of using existing pharmaceutical medicines at a lower cost.
(...)
¶ 59 The Appellants have not proved that, if a NOC were issued to Apotex and it were to sell omeprazole, patients or other third parties would infringe the Appellants' use patent. If a first person cannot prove in prohibition proceedings that future infringements will occur if a NOC is issued, it cannot obtain a prohibition by relying on subparagraph 5(1)(b)(iv), however the required nexus between the generic and the infringement is defined.
[62] The American case Warner-Lambert Co. v. Apotex Corp., Apotex Inc., and Torpharm, Inc., 2003 U.S. App. Lexis 594 (U.S. Ct. App. Fed. Cir.), is of interest for the succinct statement by the U.S. Court of Appeal (Federal Circuit) of the reasons why a patentee should not be allowed to use a new claim for an old medicine as a means of preventing the generic manufacturer from producing the medicine altogether. Although of course American caselaw is not binding, the two legislations are sufficiently similar to make the quote relevant to our purposes:
Warner-Lambert's proposed interpretation is inconsistent with both of the stated purposes of the Hatch-Waxman Act, and would confer substantial additional rights on pioneer drug patent owners that Congress quite clearly did not intend to confer. If Warner-Lambert's interpretation were correct, for example, an NDA holder [a NOC holder in Canadian terms] would be able to maintain its exclusivity merely by regularly filing a new patent application claiming a narrow method of use not covered by its NDA. It would then be able to use § 271(e)(2)(A) as a sword against any competitor's ANDA seeking approval to market an off-patent drug for an approved use not covered by the patent. Generic manufacturers would effectively be barred altogether from entering the market. That would certainly not advance the purpose of making available "more low cost generic drugs," and was not what Congress intended. Moreover, although Warner-Lambert argues that our affirming the district court's decision would be a disincentive for research and development by innovators, Congress explicitly stated that the incentive created by the Act was patent term restoration. There is no evidence that Congress intended to enable an innovator to extend its exclusivity merely by asserting patents on unapproved uses. [para. 38]
[63] In Apotex Inc. v. Wellcome Foundation Ltd, [2001] 1 F.C. 495 (FCA), one of the issues was whether AZT, a well-known pharmaceutical compound, could be patented because a new use, as prophylaxis of HIV, had been found for it. What was patentable, according to the Federal Court of Appeal, was the new use, and only the new use.
When a new compound is invented, the inventor is entitled to a patent over that compound for all uses. However, where the compound is not new, the patent will be limited to the new use invented for the compound. [para. 81]
[64] In the case at bar, the new use is for dementia, CVD or Alzheimer. Depression is not a new use, and trying to include it in the treatment of those diseases does not make it a new use.
CONCLUSION
[65] The claim for use relates to the treatment of dementia, CVD, Alzheimer or ischemia. The use of citalopram for depression is an old use, and is not claimed by the patent. The use that the NOC has been issued for in the case of Lundbeck's drug Celexa is depression, not any of the diseases for which there is a patent claim listed. The patent makes no claim as to depression, since that use is well-established and thus cannot be patented. It stands to reason that if the use cannot be patented, it cannot be infringed.
[66] Lundbeck argues that the treatment of depression is subsumed in the treatment of dementia or CVD. But even with the statement in the patent description which includes "psychological and neurological sequelae" of brain damage as a form of CVD, there is nothing in the expert evidence whatsoever that establishes on a balance of probabilities that treating depression is treating dementia or CVD. Depression may well accompany various dementia and cerebrovascular disorders, but it exists as a distinct disorder. Treating it is not treating some other disorder, whether it be cancer, influenza or brain hemorrhage, all of which may or may not be present in cases of depression. I would submit that the inclusion of "psychological and neurological sequelae" in the definition of CVD is too vague and unspecific to even begin to address Genpharm's allegation of non-infringement.
[67] Lundbeck has not convincingly established that Genpharm's citalopram would be prescribed for anything else but depression. It seems entirely unreasonable to think that depression will always present alone. Citalopram, as all the experts called on as witnesses have testified, is the drug of choice to treat depression in older people, given its low toxicity and rather benign side effects. Older people are more subject to a host of diseases, including diseases related to dementia, Alzheimer and CVD. That fact alone is not sufficient to show infringement of patent '368, which deals with the treatment of CVD, dementia and Alzheimer, not depression.
[68] No convincing evidence was presented that citalopram would be of any use to treat CVD, dementia or Alzheimer as such. Research as to the treatment of behavioural problems is still very sketchy. The fact is that citalopram offers an effective remedy against depression, and that use is not protected. All other uses of citalopram have so far been in isolated experiments which have not shown much promise of generating more research.
[69] The applicant has not established, on the balance of probabilities, that issuing a NOC to the respondent for the manufacturing and marketing of citalopram would result in the infringement of patent '368.
[70] Accordingly, the application should be dismissed.
O R D E R
THIS COURT ORDERS THAT:
- This application for judicial review be dismissed;
- Costs in favour of the respondent Genpharm.
Pierre Blais
J.F.C.
FEDERAL COURT OF CANADA
TRIAL DIVISION
NAMES OF COUNSEL AND SOLICITORS OF RECORD
DOCKET: T-122-02
STYLE OF CAUSE: H. Lundbeck A\S et al.
v.
Minister of Health et al.
PLACE OF HEARING: Montreal
DATE OF HEARING: September 17, 2003
REASONS FOR ORDER Blais J.
AND ORDER :
DATED: October 3, 2003
APPEARANCES:
Me Marie Lafleur FOR APPLICANTS
Me Roger Hugues FOR RESPONDENT
Me Kamleh Nicola "Genpharm"
SOLICITORS OF RECORD:
FASKEN, MARTINEAU,
DUMOULIN LLP
Montreal, Quebec FOR APPLICANTS
SIM, HUGHES,
ASHTON & McKAY FOR RESPONDENT
Toronto, Ontario "Genpharm"
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