Procter & Gamble Pharmaceuticals Canada Inc. v. Canada (Minister of Health)

Procter & Gamble Pharmaceuticals Canada Inc. v. Canada (Minister of Health)
Court (s) Database
Federal Court Decisions
Date
2004-02-12
Neutral citation
2004 FC 204
File numbers
T-155-02
Notes
Digest
Decision Content
Date: 20040212
Docket: T-155-02
Citation: 2004 FC 204
Ottawa, Ontario, this 12th day of February, 2004
PRESENT: THE HONOURABLE MADAM JUSTICE SNIDER
BETWEEN:
PROCTER & GAMBLE PHARMACEUTICALS CANADA INC.
and THE PROCTER & GAMBLE COMPANY
Applicants
- and -
THE MINISTER OF HEALTH and GENPHARM INC.
Respondents
REASONS FOR ORDER
SNIDER J.
[1] The Applicants (collectively referred to as "P & G") make and sell the only approved etidronate disodium drug product for the treatment of osteoporosis in Canada - the Didrocal® kit. The Didrocal® kit is used in an intermittent cyclical therapy ("ICT") for treating osteoporosis, which consists of three main steps: (1) a low effective dose of etidronate is administered to the patient for 14 days; (2) after the 14 day period, a placebo or a calcium supplement is administered for 76 days; (3) the cycle is then repeated. The Didrocal® kit and ICT are protected by Canadian Patent No. 1,338,376 (the " '376 patent"). The '376 patent, which expires on April 9, 2008, consists of two groups of claims described as the "use" claims and the "kit" claims (discussed below).
[2] Litigation between P & G and Genpharm over the '376 patent has been ongoing since October 1999. Prior proceedings resulted in the issuance of an Order of prohibition, which was affirmed by the Federal Court of Appeal (Procter & Gamble Pharmaceuticals Canada, Inc. v. Canada (Minister of Health) (2001), 15 C.P.R. (4th) 496 (F.C.T.D.), aff'd (2002), 20 C.P.R. (4th) 1 (F.C.A.)) leave to appeal to S.C.C. denied (herein referred to as "P & G 2001").
[3] On December 19, 2001, Genpharm served a Notice of Allegation ("NOA") alleging that its proposed etidronate disodium combination drug product for treating osteoporosis - GEN-ETI-CAL CAREPAC - will not infringe certain claims in the '376 patent and that, in any event, this patent is invalid. In the NOA and the Detailed Statement that forms part of the NOA, as is relevant to the claims in issue in this application, Genpharm alleges that:
· the '376 patent - including both the "kit" claims and the "use" claims - is not valid in that what is claimed therein is not novel, or is obvious or both; and;
· claims 7 to 12 (the "kit" claims) of the patent will not be infringed by the making, constructing, using or selling by Genpharm of its product;
· its product will not infringe any of the "kit" claims, since the calcium tablets (the second phase of the ICT) will be provided loose in a bottle rather than in a blister pack.
[4] Although Genpharm initially alleged that the patent was invalid for reasons of both obviousness and anticipation, it did not pursue the anticipation argument at the hearing. I also note that Genpharm makes no allegation of non-infringement of the "use" claims of the '376 patent.
[5] In this application, commenced by way of Notice of Application dated February 1, 2002, P & G request that an order of prohibition be issued pursuant to section 6(1) of the Patented Medicines (Notice of Compliance) Regulations, SOR93-133 ("Regulations") preventing the Minister of Health ("Minister") from issuing a Notice of Compliance ("NOC") under section C.08.004(4) of the Food and Drug Regulations, C.R.C., c. 870 to the Respondent, Genpharm Inc. ("Genpharm"), for its product GEN-ETI-CAL CAREPAC.
Issues
[6] The parties are agreed that the issues are as follows:
1. Is Genpharm's allegation of patent invalidity due to obviousness justified?
2. Is Genpharm's allegation of non-infringement of the "kit" claims justified?
[7] Genpharm also raises the question of whether the "kit" claims fall outside the definition of "medicine" under section 2 of the Regulations. If they do, Genpharm would not be required to allege non-infringement of these claims. Since I regard this argument to be part of Genpharm's non-infringement argument, I will deal with it when I consider this issue.
[8] From the outset, it is important to be clear about the consequences that will follow if Genpharm succeeds on any of the issues it raises. The critical issue for Genpharm is its allegation of invalidity due to obviousness. If the '376 patent is found to be valid, Genpharm's product will infringe the use claims of this patent. This is because the therapy that Genpharm seeks to market is identical to that which P & G claim in its patent. In a previous proceeding concerning the '376 patent (P & G 2001, supra), the Federal Court of Appeal determined that "if a patient used the Genpharm product for osteoporosis, the use claims of P & G's '376 patent would be infringed". In that case, Genpharm tried to distinguish its product, Gen-etridonate (which contains the same components as the GEN-ETI-CAL CAREPAC kit, the product before me in these proceedings), by arguing that it would not be used for the treatment of osteoporosis, as claimed in the '376 patent, but rather, for the treatment of Paget's disease and hypercalcemia of malignancy. In this case, Genpharm is openly attempting to market its product for the treatment of osteoporosis. There is nothing to distinguish this aspect of the prior decision of the Court of Appeal from the case before me. Accordingly, unless the '376 patent is invalid, Genpharm would be infringing the '376 patent.
[9] It was agreed by the parties that the only claims that are at issue in this application are "kit" claims 7 to 12 and "use" claims 25 to 30 of the patent.
Preliminary Matter
[10] During the preliminary skirmishes leading to this hearing, Genpharm brought a motion before this Court for dismissal of the application of P & G. The basis of the motion for dismissal was that the '376 patent was not submitted to the Minister within 30 days of its issue by the Patent Commissioner and was, accordingly, ineligible for inclusion on the Patent Register. Without a valid registration, Genpharm submitted, there could be no foundation for P & G's prohibition application.
[11] Genpharm's motion was dismissed by Justice Gauthier of this Court. A majority of the Federal Court of Appeal dismissed an appeal of that decision, and held that the eligibility of the '376 patent to be included on the Patent Register could not be raised in these proceedings (Procter & Gamble Pharmaceuticals Canada Inc. v. Canada (Minister of Health), [2003] F.C.J. No. 1805 (C.A.) (Q.L.) (referred to herein as "P & G 2003")).
[12] The majority of the Court based their decision on an application of the doctrine of issue estoppel. The Court found that:
1. The parties to the appeal and to the earlier litigation in P & G 2001, supra were the same.
2. The previous judicial decision was final, as a prohibition order did in fact issue, and an appeal of that order was dismissed by the Federal Court of Appeal.
3. Genpharm had previously raised and argued the issue of ineligibility in the earlier case of P & G 2001 and, although the Court did not explicitly address the eligibility issue in its decision, the decision "must be taken to have implicitly determined that the '376 Patent was eligible for inclusion on the Patent Register" (P & G 2003, supra at para. 21).
[13] Having found that the requisite elements for issue estoppel were present, the Court concluded that Genpharm could not raise the issue of ineligibility in these proceedings.
[14] Since the Reasons for Judgment were only available after the close of this hearing, parties were given an opportunity to provide submissions in respect of their impact.
[15] P & G submit that the practical effect of the decision of the Federal Court of Appeal is that eligibility of the '376 should not be raised in this proceeding. However, I note that the issue of eligibility before me in this proceeding differs from that before either the motions judge or the appeal court. While the issue of ineligibility was the subject of the Court of Appeal's decision, in this case, Genpharm's main argument is that of invalidity due to obviousness. Although Genpharm could have (and likely should have) argued this issue as part of its submissions in P & G 2001, supra, it did not do so. On the other hand, it was open to P & G to argue that Genpharm was estopped from raising the validity of its '376 Patent in these proceedings; it did not do so until these submissions on the impact of the P & G 2003, supra decision. Because of the difference in the issue and in the absence of a full record of argument on the application of estoppel to the arguments in this case, I will proceed to deal with the issue of obviousness on its merits.
[16] It is less clear, however, whether the doctrine of issue estoppel as discussed in P & G 2003, supra applies to the issue raised by Genpharm of whether the "kit" claims fall outside the definition of "medicine" under section 2 of the Regulations. In raising this issue, Genpharm is directly addressing the question of eligibility of the patent, a matter that was implicitly considered by the Court in P & G 2001. This appears to fall squarely within the decision of the Federal Court of Appeal. However, on the basis of the limited arguments before me, I am not satisfied that this particular eligibility argument was considered in the context of P & G 2001. Accordingly, I will consider the merits of the question.
Construction of the Patent
[17] Before turning to the issues of invalidity and infringement, I must identify the essential elements of the invention claimed by P & G in its '376 patent (Whirlpool Corp. v.Camco Inc., [2000] 2 S.C.R. 1067 at para. 43).
[18] The '376 patent contains two types of claims. Claims 17-37 are directed to the use of polyphosphonates, such as etidronate, that inhibit bone resorption. Claims 1-16 cover a kit for the treatment and prevention of osteoporosis.
[19] As noted, the '376 patent has already been the subject of litigation between P & G and Genpharm prior to these proceedings. Accordingly, it seems appropriate to consider how this patent was construed in these previous decisions. Indeed,
Where the Court has previously construed the same patent, particularly a construction upheld on appeal, the Court, in another proceeding involving different alleged infringers, would require strong argument to come to a different view. [Roger T. Hughes and John H. Woodley, "Patented Medicines - Notice of Compliance" CD-ROM: Hughes and Woodley on Patents, Release 19, July 2003 (Markham: LexisNexis Canada Inc.) at s. 18A]
[20] Justice McKeown of the Federal Court in P & G 2001, supra at paras. 3-5, cited the summary of the invention in the '376 patent as follows:
The present invention relates to a method of treating or preventing osteoporosis, in humans or lower animals afflicted with or at risk to osteoporosis, utilizing a regimen comprising two or more cycles, whereby each cycle comprises a period of from about 1 day to about 90 days during which a bone resorption inhibiting polyphosphonate is administered daily in a limited and effective amount, and a rest period of from about 50 days to about 120 days during which no bone resorption inhibiting agent is administered.
The present invention further relates to a kit for use in the above-described cyclic regimen, said kit containing the following components: from about 1 to about 90 daily doses, with each daily dose containing a limited and effective amount of a bone resorption inhibiting polyphosphonate; from about 50 to about 120 daily doses of a placebo or a nutrient supplement; and a means for having the components arranged in a way as to facilitate compliance with the regimen.
[21] On appeal, Justice Rothstein, at paras. 30-31, described the invention in the '376 patent as follows:
The invention in P & G's '376 patent includes the use of etidronate disodium in intermittent cycles for the treatment of osteoporosis. P & G calls this product Didrocal. P & G submits that its patent claims in the '376 patent for the use, in intermittent cycles, of a polyphosphonate, i.e. etidronate disodium, for the treatment of osteoporosis would be infringed by Genpharm...
[22] From these decisions, the essential components of the '376 patent can be distilled and summarized as follows:
1. In respect of the "use" claims:
a. Use of etidronate at a limited effective dose ("LED") to treat
osteoporosis;
b. Intermittent administration in a regimen, which consists of two stages:
i) use of etidronate; and
ii) a rest period during which the patient takes a placebo or
nutrient such as calcium.
c. Use on a cyclical basis.
2. In respect of the "kit" claims:
a. A kit for the treatment of osteoporosis:
i) containing components of etidronate and a placebo or nutrient
such as calcium; and,
ii) a means of arranging these components to facilitate
compliance with the regimen.
[23] Genpharm claims that nowhere in the '376 patent is it clearly stated that a bone cell activator is not part of the ICT therapy. For this reason, Genpharm submits that a bone activation compound could form part of the treatment in the '376 patent. I do not accept this argument. In the broadest "use" and "kit" claims in the '376 patent, P & G explicitly define their therapy cycle as consisting of two phases: etidronate and then a rest period where either a nutrient, such as calcium, or a placebo is administered. After this rest period, the cycle is repeated by administering etidronate again. There is no third phase, meaning there is no room in the cycle where a bone activation compound could be administered. For this reason, I do not accept Genpharm's claim that the '376 patent is ambiguous as to whether a bone activation compound forms part of the ICT therapy. It is obvious that it does not.
[24] In its description of the essential elements of the patent, P & G included, under both the "use" claims and the "kit" claims, the essential element that the regimen should be followed for "two or more cycles". However, defining the therapy as intermittent and cyclical necessarily implies that etidronate is not just administered once. Genpharm used the requirement of two cycles to argue that its kit of only one cycle would not infringe. However, the cyclical nature of the regimen is captured not by the "kit" claims, but by the "use" claims. This is evidenced by the wording in the '376 patent, which ties the concept of a cycle to the treatment and not to the definition of the kit itself. For example, claim 1 reads:
A kit for use in the treatment or prevention of osteoporosis, in humans or lower animals afflicted with or at risk to osteoporosis, according to a regimen comprising of two or more cycles ... and a means for having the components arranged in a way as to facilitate compliance with the regimen (emphasis added).
Since the regimen is by definition cyclical in nature, a kit that facilitates compliance with such a regimen will ensure that the patient does not just complete one cycle.
[25] For these reasons, the presence in the kit of enough medicine for two or more cycles is not an essential element of the "kit" claims. So long as a kit facilitates compliance with the ICT therapy, the essential element of the "kit" claims in the '376 patent (assuming their validity) would be infringed.
[26] Finally, in construing the '376 patent, it is imperative to remember that the "use" claims cover a regimen that is a combination invention. The ICT regimen does not consist of discrete components that operate independently and are merely juxtaposed. Rather, P & G's osteoporosis treatment results from the synergistic combination of a limited effective dose of etidronate, administered intermittently, and on a cyclical basis. This is the heart of its claimed invention:
It has now been discovered that bone loss can be inhibited and bone mass can be increased if certain polyphosphonates are given, in a limited amount, according to a specific regimen of intermittent, rather than chronic, dosing. This regimen forms the heart of the present invention.
Analysis
Issue #1: Is Genpharm's allegation of patent invalidity due to obviousness justified?
[27] As Justice Binnie for the Supreme Court of Canada stated in Apotex Inc. v. Wellcome Foundation Ltd. (2002), 21 C.P.R. (4th) 499 at para. 37, "The patent monopoly should be purchased with the hard coinage of new, ingenious, useful and unobvious disclosures." Thus, an invention should not be patentable if the subject matter was obvious. A monopoly should not be granted, nor should previous inventions be "evergreened", by the expedient of obvious or uninventive additions (Whirlpool Corp., supra at para. 37).
[28] The parties agree that the date at which to test obviousness is presumed to be the priority filing date of June 6, 1985 (Lubrizol Corp. v. Imperial Oil Ltd. (1992), 45 C.P.R. (3d) 449 at pp. 462-463 (F.C.A.)).
[29] Genpharm alleged in its NOA that, by the mid 1980s, the essential elements of the invention claimed in P & G's '376 patent were not novel and in fact obvious. Genpharm submits that references noted in the '376 patent, such as Chesnut, were all known to a person skilled in the art at the critical date. According to Genpharm's expert witness, Dr. Timothy Chambers, these references were "common general knowledge" in the field of osteoporosis research in the mid-1980s and the teachings contained therein make the invention described and claimed in the '376 patent, obvious.
[30] Before considering the law on obviousness or the specific facts that the parties rely upon, it is helpful to understand the disease that P & G's product treats and Genpharm seeks to treat.
i) Osteoporosis
[31] Osteoporosis produces a decrease in skeletal bone mass and an increase in bone fragility. Net bone loss occurs due to an imbalance within the bone remodelling process, whereby bone loss (resorption) exceeds bone formation. Bone remodelling is a continuous process whereby bone breaks down and reforms. This turnover or renewal is necessary for bones to grow and for minor damage from everyday stress to be repaired. The imbalance in the bone remodelling process is believed to be the cause of osteoporosis.
[32] Dr. Graham Russell in his affidavit provides a useful and succinct summary of the most accepted bone remodelling theory, reproduced below:
a) A BMU [basic multicellular unit] is activated (activation).
b) Cells called osteoclasts are mobilized at the bone surface to breakdown (or resorb) the bone. They resorb a given quantity of bone (resorption) and then move away or disappear.
c) Cells called osteoblasts move into the resorption cavity, build new bone to replace the bone that has been removed and then become inactive (formation). The formation stage involves both the filling in of resorption cavities as well as mineralising the newly deposited bone matrix. Mineralization occurs by the laying down of crystals of hydroxyapatite, which consists primarily of calcium and phosphate ("mineralization") to harden the bone matrix laid down by the osteoblasts during bone formation.
[33] Normally, BMUs are randomly activated and resorption, formation and mineralization occur so that there is no net change in bone quantity. In osteoporotics, osteoclasts resorb more bone than osteoblasts build, thereby yielding net bone loss. Treatments for osteoporosis seek to inhibit bone resorption just enough so as to restore the proper balance between bone resorption and bone formation. The subject matter of this proceeding is a therapy for treating osteoporosis that is claimed by P & G in the '376
patent.
ii) Legal Test for Obviousness
[34] The '376 patent was issued under the prior Patent Act, R.S.C. 1970, c. P-4. No specific section in the Patent Act, as it then existed, set out the requirement of inventiveness or inventive ingenuity. According to Diversified Products Corp. v. Tye-Sil Corp. (1991), 35 C.P.R. (3d) 350 at 365-366 (F.C.A.), however, it is well established that, by use of the words "invention" and "inventor" throughout the Patent Act, inventiveness is required for a patent to be valid.
[35] A helpful description of the skilled technician that this Court and experts giving evidence in this proceeding must contemplate when considering Genpharm's allegation of obviousness was provided by Justice Hugessen for the Federal Court of Appeal in Beloit Canada Ltée/Ltd. v. Valmet Dy (1986), 8 C.P.R. (3d) 289 at 294 (F.C.A.):
The test for obviousness is not to ask what competent inventors did or would have done to solve the problem. Inventors are by definition inventive. The classical touchstone for obviousness is the technician skilled in the art but having no scintilla of inventiveness or imagination; a paragon of deduction and dexterity, wholly devoid of intuition; a triumph of the left hemisphere over the right. The question to be asked is whether this mythical creature (the man in the Clapham omnibus of patent law) would, in the light of the state of the art and of common general knowledge as at the claimed date of invention, have come directly and without difficulty to the solution taught by the patent. It is a very difficult test to satisfy.
This test has been widely mentioned and followed by this Court.
[36] The Supreme Court of Canada (Farbwerke Hoechst Aktiengesellschaft v. Halocarbon (Ontario) Ltd. (1979), 42 C.P.R. (2d) 145 at 155 (S.C.C.)) and Federal Court of Appeal (Reading & Bates Construction Co. v. Baker Energy Resources Corp. (1987), 18 C.P.R. (3d) 180 at 188 (F.C.A.)) have cautioned lower courts not to engage in an exercise of hindsight, as very few inventions are unexpected discoveries. The solution to the problem posed must be "plain as day" or "crystal clear" (Bayer Aktiengesellschaft v. Apotex Inc. (1995), 60 C.P.R. (3d) 58 at 80-81 (Ont. Gen. Div.), aff'd (1998), 82 C.P.R. (3d) 526 (Ont. C.A.); leave to appeal dismissed). This Court must determine whether a mythical skilled technician would be led, based on the state of the art, to the claimed invention without conducting further experiments, serious thought or research (Farbwerke, supra; Diversified Products Corp., supra; SmithKline Beecham Pharma Inc. v. Apotex Inc. (2001), 14 C.P.R. (4th) 76 at 99-101 (F.C.T.D.), aff'd (2002), 291 N.R. 168 (F.C.A.)). Further, "[i]t is well-established that evidence of a "mere scintilla of invention" is sufficient to support the validity of a patent." (Diversified Products Corp., supra). Therefore, the simplicity of an invention is not a bar to patent validity.
[37] In these proceedings, there is a rebuttable statutory presumption that P & G's patent is valid (Lubrizol Corp., supra; Bayer Inc. v. Canada (Minister of National Health and Welfare) (2000), 6 C.P.R. (4th) 285 (F.C.A.)). There is also, however, a rebuttable presumption that the facts alleged by Genpharm in its NOA are true (Merck Frosst Canada Inc. v. Canada (Minister of National Health and Welfare) (1994), 55 C.P.R. (3d) 302 at 319 (F.C.A.), aff'd (1994), 53 C.P.R. (3d) 368). Ultimately, P & G have the burden of proving, on a balance of probabilities, that the allegations of invalidity and obviousness in Genpharm's NOA are not justified (H. Lunkdeck A/S v. Canada (Minister of Health) [2003] F.C.J. No. 1481 at para. 50 (T.D.) (QL) citing from Pfizer Canada Inc. v. Nu-Pharm Inc. (1998), 83 C.P.R. (3d) 1 at 3).
[38] Thus, as stated in Bayer, supra at para. 9 the presumption of validity only takes P & G so far:
...The operation of the statutory presumption in the face of evidence of invalidity depends upon the strength of the evidence. If the evidence proves on a balance of probabilities that the patent is invalid, the presumption is rebutted and is no longer relevant: Diversified Products Corp. v. Tye-Sil Corp. (1991), 35 C.P.R. (3d) 350 (F.C.A.) at 359.
[39] Given the legal test for obviousness, it is necessary to canvass the relevant art that existed prior to June 6, 1985.
iii) Prior Art
[40] In the late 1960s and early 1970s, it was discovered that certain compounds within the classes of polyphosphonates or bisphosphonates are able to inhibit bone resorption.
[41] In the mid 1980s, only three bisphosphonates were used for the treatment of bone disorders such as Paget's disease and osteoporosis: clodronate, etidronate and pamidronate. Although the '376 patent claims the use of several polyphosphonates, this proceeding is concerned with the use of etidronate to treat osteoporosis.
[42] Studies conducted prior to this date and that are relied upon by Genpharm in its NOA are as follows:
1. Jowsey J. et al, "The treatment of osteoporosis with disodiumethane-1-hydroxy-1, 1-diphosphonate" (1971) Journal of Laboratory and Clinical Medicine, 78:574-584 ("Jowsey").
2. Russell R.G.G. et al, "Diphosphonates in Paget's disease" (1974) Lancet; 1:894-898 ("Russell").
3. Heaney R.P., Saville P.D., "Etidionate disodium in postmenopausal osteoporosis" (1976) Clin. Pharmacol Ther.; 20(5):593-604 ("Heaney").
4. Khairi M.R.A., Altman R.D., De Rosa G.P., Zimmerman J., Schenk R.K., Johnston C.C., "Sodium etidronate in the treatment of Paget's disease of bone" (1977) Annals of Internal Medicine; 87:656-663 ("Khairi").
5. Canfield R. et al "Diphosphonate therapy of Paget's disease on bone" (1977) Journal of Clinical Endoctrinology and Metabolism; 44:96-106 ("Canfield").
6. Parfitt A.M., "Quantum concept of bone remodelling and turnover; implications for the pathogenesis of osteoporosis." (1979) Calcif. Tiss. Int.; 28:1-5 ("Parfitt").
7. Frost H., "Treatment of osteoporosis by manipulation of coherent bone cell populations." Clinical Orthopaedics and related research. 1979; 143:227-244 ("Frost").
8. Siris et al, "Long term therapy of Paget's disease of bone with EHDP." (1980) Arthritis and Rheumatism; 23(10):1177-1184 ("Siris").
9. Rasmussen H. et al., "Effect of combined therapy with phosphonate and calcitonin on bone volume in osteoporosis". (1980) Metabolic Bone Disease and Related Research; 2:107-111("Rasmussen").
10. Harris S.T. et al, "Secondary hyperparathysoidism associated with dischloromethane disphosphonate treatment of Paget's disease". (1982) Journal of Clinical Endocrinology and Metabolism. 1982; 55:1100-1107 ("Harris").
11. Anderson et al, "Preliminary observations of a form of coherence therapy for osteoporosis" (1984) Calcif. Tissue Int.; 36:341 ("Anderson").
12. Chesnut III., "C.H. Synthetic salmon calcitonin, disphosphonates and anabolic steroids in the treatment of post-menopausal osteoporosis" (1984) Proceedings of the Copenhagen International Symposium on Osteoporosis; 549 (Chrislianson et al. ed., 1984) ("Chestnut").
[43] I will now consider the evidence submitted by both parties related to Genpharm's allegation of obviousness.
iv) Affiants
[44] P & G and Genpharm each produced an expert to assist this Court in determining the obviousness, or lack thereof, of the "invention" claimed in the '376 patent. Each expert reviewed the scientific literature that preceded P & G's '376 patent claim (listed above) and rendered opinions as to whether essential elements of the "use" and "kit" claims in the '376 patent would be obvious to a skilled technician in the field by the determinative date of June 6, 1985.
[45] Dr. Graham Russell, expert for P & G, is the Norman Collisson Professor of Musculoskeletal Sciences at Oxford University and Director of the Oxford University Institute of Musculoskeletal Sciences. For nearly 40 years, he has studied the biological effects of bisphosphonates and the treatment of bone disorders. He is a leading expert on bisphosphonates and clinical bone diseases and was so in the mid-1980s. This was acknowledged absolutely and without question by Dr. Chambers, expert for Genpharm. He was an "eye witness" to the evolution of treatment for osteoporosis and, in particular, to the emergence of the therapy in issue in these proceedings.
[46] Dr. Timothy Chambers is Professor of Cellular Pathology and head of the Department of Cellular Pathology at St. George's Hospital Medical School, University of London, England. He is a histopathologist by training. Dr. Chambers is an expert in the cell biology of the bone and has conducted research in this field for more than 20 years.
[47] Genpharm alleged in its NOA the obviousness of the following:
i) The administration of bisphosphonates in limited amounts;
ii) The administration of bisphosphonates intermittently rather than chronically;
iii) The omission of a bone activation compound; and
iv) A kit that facilitates compliance by arranging the components of the regimen within it.
v) Evidence and Analysis
a) Limited Effective Dose (LED)
Evidence
[48] The '376 patent claims the use of etidronate in daily dosage amounts ranging from about 0.25 x LED to about 4 x LED. This is equivalent to 1 mg/kg to about 16 mg/kg of etidronate. All of the dose ranges appear to have been established by testing the bone resorption potency of each bisphosphonate through experiments with male rats using the Schenk and TPTX models. It is possible to extrapolate human dosages from these experiments, as human dosages are proportionally related to the LEDs in the TPTX rat model.
[49] According to Dr. Chambers, the studies of Siris, Heaney, Khairi, Russell, and Canfield do not teach the dose of bisphosphonate for use in osteoporosis treatment, but warn a person who is skilled in the art that he or she should limit the dose of bisphosphonate to one that prevents resorption yet avoids unwarranted side-effects. Dr. Chambers believes that these studies established the philosophy of administering the LED to a osteoporotic patient so that a person skilled in the art would choose assays such as the Schenk model and the TPTX model, which are mentioned in the '376 patent, to identify the range of doses likely to be effective. Dr. Chambers points out that Heaney suggested the use of 5 to 10 mg/kg/day to treat osteoporosis. These dosages fall within the range of doses described in the '376 patent.
[50] Dr. Chambers states that Anderson used dosages within the range proposed by the '376 patent to prevent bone loss. These dosages were, therefore, in his view, obvious to a person skilled in the art. He further remarks that he is not aware of any reason why the presence or absence of a bone cell activator, which was used by Anderson, should affect the dose of bisphosphonate that one chooses to use.
[51] It is Dr. Chambers' contention that Chesnut makes obvious to a person skilled in the art that the limited clodronate dosage regimen he uses is effective and that the equivalent dose for etidronate can easily be obtained using assays such as the Schenk or TPTX models. Chesnut teaches that a bisphosphonate should be administered in limited effective dosages and, since the inventions claimed in the '376 patent refer to the use of bisphosphonates generally, this prior art made the LED for etidronate obvious.
[52] According to Dr. Russell, although Heaney, Khairi, Russell and Canfield indicate that one would be drawn to the LED to avoid the negative side-effects that accompany the use of etidronate at high dosages, in reality there is a range of doses that might be effective by extrapolating from studies of Paget's disease. Within the range of 1 to 7.5 mg/kg/day, there are four doses, 1, 2.5, 5 and 7.5 mg/kg/day that were studied and all of them avoided the side effect of inhibiting mineralization (bone formation). If a skilled technician were to extrapolate from these studies, he or she would have no reason to pick one dosage over the others.
[53] In Dr. Russell's view, Dr. Chambers implies that 5 mg/kg/day is the only dose consistent with the definition of LED, meaning a dose that is effective without having significant side effects. However, there are a range of options available and the optimal dose for treating osteoporosis rather than Paget's disease would need to be defined. It would not be obvious to the skilled technician because there is no precedent from the studies on etidronate in osteoporosis that could be used to predict effective doses.
[54] As well, one ought not to extrapolate from Paget's disease to osteoporosis because early studies in Pagetic patients were directed at determining the maximum tolerated dose of bisphosphonate that could be administered. The approach taken was to treat Pagetic patients aggressively over the short term, whereas the objective in osteoporosis treatment is to increase net bone mass over the long term. For these reasons, the dosages of bisphosphonates used in Paget's disease studies would not be extrapolated by a skilled technician to treat osteoporosis.
[55] Dr. Russell disagrees with Dr. Chambers that Siris teaches a general approach for altering dosages to maximize effectiveness and decrease side effects. In the Siris study, side-effects were accepted as part of the treatment as were high doses of etidronate. Siris attempted to obtain an optimal response with high doses of etidronate administered in the short term and counterbalanced this with an off-drug interval to allow the body to repair the damage caused by side effects. Dose-related experimentation would still, therefore, be necessary to determine the effective dose of etidronate, free of side effects, for osteoporotic patients who would be treated over several years, and not just in the short term.
[56] Contrary to what Dr. Chambers states, Dr. Russell asserts that the Schenk and TPTX assays are first line assays and, therefore, would define only the range of doses that might be effective in animals, not the LED for treating humans under disease conditions.
[57] Dr. Russell contends that Heaney only studies a dose of 20 mg/kg/day of etidronate and concluded that etidronate is not likely to be of therapeutic benefit in osteoporosis. Heaney went on to speculate that a dose of 5 to 10 mg/kg/day of etidronate might be effective but does not suggest a regimen. According to Dr. Russell, it was by no means obvious what would happen if this dose of etidronate was administered intermittently to treat osteoporosis. Dr. Chambers admitted on cross-examination that, although Heaney suggested a lower dose of etidronate might be worth trying, he does not say that it will work.
[58] Dr. Russell distinguishes Anderson's use of the dose of etidronate used in the '376 patent by pointing out that this dose was used in the context of Anderson's protocol, the coherence theory, which includes use of a bone cell activator. According to Dr. Russell, it was not known in the mid 1980s whether this dose would work outside of the coherence theory. As well, the coherence theory at this time had not been investigated in detail and so the role of each factor was not known.
[59] Chesnut is distinguished by Dr. Russell on several grounds. First, Dr. Russell asserts that Chesnut does not disclose the optimal clodronate dosage regimens contained in the '376 patent and, therefore, Dr. Chambers incorrectly compares clodronate and etidronate. Dr. Chambers claims that the optimal etidronate dosage can be extrapolated from a possibly non-optimal (mid-range) dose of clodronate. Chesnut's mid-range dosage of clodronate would not directly lead a person skilled in the art to the limited dosage of etidronate. Chesnut's dosage would also not suggest any predictable results with etidronate, given that these compounds have different potencies.
[60] Dr. Chambers admitted on cross-examination that clodronate is a more potent bone resorption inhibitor than etidronate, meaning that one can administer more of it without side-effects. He further admitted that Chesnut used a dose of clodronate that is 8 times the LED claimed in the '376 patent. He did not consider this as a barrier, however, to arriving at the LED for etidronate based on Chesnut's findings.
Analysis
[61] I accept Dr. Russell's evidence that the LED of etidronate claimed in the '376 patent would not have been "crystal clear" or "plain as day" to a skilled technician at the critical date.
[62] Dr. Chambers' evidence, even if sound, misses the point of the legal exercise that this Court must engage in. Dr. Chambers seems to contemplate an inventor rather than a mythical uninventive skilled technician. Dr. Chambers essentially claims that the etidronate dosage range that is claimed in the '376 patent is obvious because one can extrapolate and infer it from an array of studies. Simply put, Dr. Chambers is telling this Court that a skilled technician would infer the following:
1) from Siris, Khairi, Russell, Canfield (Paget's disease studies), and Heaney (osteoporosis study), that treatment of osteoporosis is achieved by administering the LED of a bisphosphonate and then either,
2a) from Anderson, that the same dosage used by Anderson, which is claimed in the '376 patent, can be used even without a bone cell activator, or
2b) from Chesnut, that the dosage of clodronate can be extrapolated to arrive at the dosage for etidronate.
[63] Genpharm claims that P & G draw an artificial distinction between Paget's disease and osteoporosis to argue that studies of the former cannot inform a skilled technician in the field of the latter. This argument is directed at proving the validity of inference (1) mentioned above but does not take Genpharm far at all. This is because, even if I accept the first inference set out above, I take issue with inferences 2(a) and 2(b). The inferences that Dr. Chambers claims that a skilled technician would draw from Anderson and Chesnut's studies would require at least a scintilla of invention.
[64] Anderson's study was premised upon Frost's coherence theory, meaning he used a bone cell activator in his study. I accept Dr. Russell's comments that, in the mid-1980s, it was not clear which factors of the coherence theory were effective and which were not. Given this uncertainty, I find it difficult to accept that a skilled technician, at that time, would think it obvious that the dosage used by Anderson in his study would be effective or appropriate without the use of a bone cell activator.
[65] Dr. Chambers deposed that he sees no reason for a skilled technician not to take an element of the coherence theory and apply it outside of that context. This is not the same as saying that it would be obvious to do just that at that time. Since it was not clear which elements of the coherence theory were effective, the dosage used by Anderson would have to be tested to see if it is effective without an activator. This moves Dr. Chambers skilled technician away from being one that applies mechanistic skill to one that innovates. Such a technician falls outside the scope of the legal test for obviousness. I must be mindful of how obvious a thing may appear in hindsight, once it is disclosed clearly in a patent. Dr. Russell's comments on this issue seem to be more situated in the context in which this Court must conduct its analysis, that being what was actually known at the time.
[66] As for Chesnut's study, I accept the evidence of both experts that clodronate and etidronate have different potencies. I further accept Dr. Russell's comments that etidronate has a relatively strong tendency to inhibit bone mineralization. As well, both Drs. Russell and Chambers agree that Chesnut's study used a dose of clodronate that was 8 times the LED of clodronate claimed in the '376 patent. For these reasons, the dosage of clodronate used by Chesnut cannot be extrapolated to arrive at the etidronate dosage range claimed in the '376 patent. Even Chesnut himself distinguished between the two bisphosphonates by concluding with a proposal that a study be carried out using etidronate in conjunction with a bone cell activator. In his 1984 study, Chesnut stated:
Whether other disphosphonates (EHDP [etidronate], APD) share in this apparent beneficial effect on bone is unproven.
[67] This suggests that, although similar, prior art still treated clodronate and etidronate as possessing distinct properties. Dr. Chambers admit