Novartis Pharmaceuticals Canada Inc. v. Teva Canada Limited

Novartis Pharmaceuticals Canada Inc. v. Teva Canada Limited
Court (s) Database
Federal Court Decisions
Date
2013-03-19
Neutral citation
2013 FC 283
File numbers
T-1420-11, T-288-12
Decision Content
Date: 20130319
Dockets: T-1420-11
T-288-12
Citation: 2013 FC 283
Toronto, Ontario, March 19, 2013
PRESENT: The Honourable Mr. Justice Hughes
Docket: T-1420-11
BETWEEN:
NOVARTIS PHARMACEUTICALS CANADA
INC.
Applicant
and
TEVA CANADA LIMITED and
THE MINISTER OF HEALTH
Respondents
and
NOVARTIS AG and
BOEHRINGER MANNHEIM GmbH
Respondent Patentees
Docket: T-288-12
AND BETWEEN:
NOVARTIS PHARMACEUTICALS
CANADA INC.
Applicant
and
TEVA CANADA LIMITED and
THE MINISTER OF HEALTH
Respondents
and
NOVARTIS AG and
ROCHE DIAGNOSTICS GmbH
Respondent Patentees
REASONS FOR JUDGMENT AND JUDGMENT
HUGHES J.
[1] These reasons are common to two applications each brought by Novartis Pharmaceuticals Canada Inc. under the provisions of the Patented Medicines (Notice of Compliance) Regulations SOR/93-133 as amended (NOC Regulations). In each application, Novartis seeks to restrain the Minister of Health from issuing a Notice of Compliance to Teva Canada Limited; in one application it is in respect of 4 mg/5 ml strength of zoledronic acid IV infusion (T-1420-11) and in the other it is in respect of 5 mg/100 ml strength of zoledronic acid IV infusion (T-288-12) until the expiry of each of Canadian Letters Patent No. 1,338,895 and 1,338,937. The issues in each application are those of validity of those two patents. Infringement is not an issue in either application. Thus, the two applications proceeded on common evidence and argument and were heard together.
[2] For the reasons that follow, I find that Teva’s allegations with respect to invalidity, on the basis of inutility and lack of sufficiency of the ‘895 patent, claim 14 to be justified thus the application is dismissed with respect to that patent. I find that Teva’s allegations with respect to invalidity of the ‘937 patent are not justified thus the application will be allowed in respect of that patent. The Applicant is entitled to half of its costs at the middle of Column IV.
[3] The following is an Index to these Reasons by paragraph number:
THE PARTIES
Paras 4 to 7
THE '895 PATENT GENERALLY
Paras 8 to 12
THE '937 PATENT GENERALLY
Paras 13 to 17
THE EVIDENCE
Paras 18 to 23
ISSUES
Paras 24 to 27
BURDEN OF PROOF
Para 28
PERSON SKILLED IN THE ART
Paras 29 to 34
THE '895 PATENT IN DETAIL
Paras 35 to 55
THE '895 PATENT – CLAIM 14
Paras 56 to 64
THE '937 PATENT IN DETAIL
Paras 65 to 78
THE '937 PATENT – CLAIMS 1 & 2
Paras 79 to 83
BISPHOSPHONATES – TECHNICAL BACKGROUND
Paras 84 to 95
ZOLEDRONATE
Paras 96 to 99
TESTING FOR POTENCY
Para 100
WHAT DID THE '895 INVENTORS DO?
Paras 101 to 103
WHAT DID THE '937 INVENTORS DO?
Paras 104 to 107
THE CONFLICT – AND RESULTING CLAIMS
Paras 108 to 113
OBVIOUSNESS
Paras 114 to 116
THE '895 PATENT - THE INVENTIVE CONCEPT
Paras 117 to 119
THE '937 PATENT - THE INVENTIVE CONCEPT
Paras 120 to 138
DATE OF THE INVENTION - '895 PATENT
Paras 139 to 142
DATE OF THE INVENTION - '937 PATENT
Paras 143 to 145
WHAT WAS THE “COMMON GENERAL KNOWLEDGE” AND “STATE OF THE ART”
Paras 146 to 162
LACK OF UTILITY – PLEADING
Para 163
UTILITY – CLAIM 14 OF THE '895 PATENT
Paras 164 to 170
LACK OF UTILITY – CLAIMS 1 & 2 OF THE '937 PATENT
Paras 171 to 172
SUFFICIENCY – PLEADING
Para 173
SUFFICIENCY – LEGAL PRINCIPLES
Paras 174 to 175
SUFFICIENCY – DATE FOR DETERMINATION
Paras 176 to 189
CONCLUSIONS AND COSTS
Paras 190 to 193
THE PARTIES
[4] The Applicant Novartis Pharmaceuticals Canada Inc. (Novartis) is the same in each application. It has listed each of the two patents at issue in accordance with the NOC Regulations and has itself obtained Notices of Compliance from the Minister of Health to sell a bone mechanism regulator product in Canada containing zoledronate as an active ingredient. Novartis is a “first person” as described in the NOC Regulations.
[5] The Respondent Teva Canada Limited (Teva) is a “second person” as so described in the NOC Regulations. It seeks to sell generic versions of Novartis’ drug. Application T-1420-11 deals with Teva’s intent to seek a Notice of Compliance to sell such a drug for administration by IV infusion in a 4 mg/5 ml dose and has served upon Novartis a Notice of Allegation dated July 20, 2011 in accordance with the NOC Regulations. Application T-288-12 deals with Teva’s intent to seek a Notice of Compliance to sell such a drug for administration by IV infusion in a 5 mg/100 ml dose and has served upon Novartis a Notice of Allegation dated December 23, 2011 in accordance with the NOC Regulations.
[6] The Respondent Minister of Health is charged with various duties under the NOC Regulations, including the issuance of a Notice of Compliance to a “second person”, such as Teva, in appropriate circumstances. The Minister took no active role in these proceedings.
[7] Novartis asserts, and Teva does not challenge, that Canadian Patent 1,338,895 is owned by the Respondent Boehringer Mannheim GmbH and that Canadian Patent 1,338,937 is owned by the Respondent Novartis AG. Neither of these entities took any active role in these proceedings.
THE '895 PATENT GENERALLY
[8] Canadian Letters Patent No. 1,338,895 (the '895 patent) resulted from an application filed with the Canadian Patent Office on July 29, 1987. Therefore, that patent is governed by the provisions of the “old” Patent Act, RSC 1985, c. P-4, applicable to patents, the application for which was filed in the Canadian Patent Office prior to October 1, 1989.
[9] The '895 patent claims priority from an application filed in the Federal Republic of Germany on August 1, 1986. This is the presumed “date of invention” upon which the issue of obviousness is to be determined provided that the priority document is in the evidence and supports the claimed invention. A different date of invention can also be proved by evidence as to what the inventors did.
[10] The '895 patent was issued and granted to Boehringer Mannheim GmbH on February 4, 1987. The patent is to be construed as of that date. The term of the patent is to be calculated as being seventeen (17) years from the date of grant; thus this patent’s term will expire February 4, 2014.
[11] The '895 patent names Elmar Bosies and Rudi Gall, both of the Federal Republic of Germany, as inventors. The record shows that Bosies is deceased and Gall is “fearful of death”; therefore, we have no evidence from the inventors in these proceedings.
[12] Only claim 14 of the ‘895 patent is at issue in these proceedings.
THE '937 PATENT GENERALLY
[13] Canadian Letters Patent No. 1,338,937 (the '937 patent) resulted from an application filed with the Canadian Patent Office on October 19, 1987. Therefore, that patent, like the '895 patent, is governed by the provisions of the “old” Patent Act, applicable to patents applied for in Canada before October 1, 1989.
[14] The '937 patent claims priority from an application filed with the Swiss Patent Office on November 21, 1986. This is the presumed “date of invention” upon which the issue of obviousness is to be determined based on the evidence as discussed with respect to the ‘895 patent.
[15] The '937 patent was issued and granted to Ciba-Geigy AG of Switzerland on February 25, 1997. The patent is to be construed as of that date. The term of the patent is to be calculated as being seventeen (17) years from that date; thus, this patent’s term will expire February 25, 2014.
[16] The '937 patent names Knut A. Jaeggi and Leo Widler, both of Switzerland, as inventors. One of them, Leo Widler, provided evidence in these proceedings.
[17] The '937 patent contains two (2) claims, claims 1 and 2, both of which are at issue in these proceedings.
THE EVIDENCE
[18] As is usual in these proceedings, the evidence took the form of affidavits, exhibits to affidavits, transcripts of cross-examination, and exhibits to cross-examination. The Court had no opportunity to see or hear the witnesses, or to observe their demeanour.
[19] The Applicants have filed the affidavits, with exhibits, of the following persons:
• Dr. Leo Widler: He is one of the named inventors of the '937 patent. He is a Senior Investigator, Global Discovery chemistry at the Novartis Research Institutes for Biomedical Research in Basel, Switzerland. He provided some history as to bisphosphonates generally, and particular history leading up to the '937 patent. He was cross-examined.
• Dr. Martin Knauer: of Bensheim Germany He is a Patent Attorney employed by Roche Diagnostics GmbH as Director and Senior Patent Counsel for patent conflicts. He filed two affidavits attaching as exhibits documents of Boehringer Mannheim (acquired by Roche) relating to developments leading to the '895 patent. He was cross-examined.
• Dr. Frank H. (Hal) Ebetino (expert): of Blackrock, Ireland. He is a consultant in drug discovery and development with specific expertise in the bisphosphonate (BP) field. He is a Visiting Scholar at the University of Southern California, and a Visiting Research Professor at Queen’s University, Belfast. He worked with Proctor & Gamble in the early development of BPs. He provided a history of the development of generations of BPs. He dealt with arguments and evidence of Teva as to obviousness and sufficiency of the ''937 patent. He was cross-examined.
• Dr. Mark Lundy (expert): of West Chester, Ohio. He is President of Osteoresearch LLC, a consulting firm for the pharmaceutical industry. He received a PhD I Biomedical Sciences from Albany Medical College and started his courses in the bone field as a post-doctoral fellow in the Department of Medicine and Anatomy at Loma Linda University in California. He joined Proctor & Gamble and did much of the early research into BPs there. He provided a history of the development of BPs and specific opinions respecting the '895 and '937 patents. He reviewed the documents provided by Dr. Knauer as to developments leading to the '895 patent. He addresses in particular statements as to utility made in Dr. Grynpas’ affidavit. He was cross-examined.
• Dr. James J. Benedict (expert): of Aveda, Colorado, Vice-President of Research and Development at Cerapedics, Inc. He received a doctorate from the University of Wisconsin in Transition Metal Organometallic Chemistry. He began his career at Proctor & Gamble dealing with phosphonates and moved on to other organizations engaged in bone metabolism and bisphosphonate research. He gave a history of bisphosphonates and opinions as to inventiveness of the '895 patent and its sufficiency. He rebutted the evidence of some of Teva’s witnesses. He was cross-examined.
• Ejvind Johannes-Christiansen (expert): of Hellerup, Denmark, a European patent attorney. He gave evidence as to when a Danish patent application, 1985 0 5996 was published and actually obtainable by the public. He was not cross-examined. At the hearing, Counsel for Teva advised the Court that Teva was not relying on the Danish application for any purpose in these proceedings.
• Eric McIntomny: a law clerk employed in the offices of the Applicants’ Counsel. He provided, as exhibits, certain correspondence between the firms of Counsel representing Teva. He was not cross-examined.
[20] The Respondent Teva filed the affidavits, with exhibits, of the following persons:
• Dr. Stanley Michael Roberts (expert): of Devon, United Kingdom. He received a doctorate from the University of Salford, and did post-doctorates at the University of Zurich and Harvard University. He was a professor at various English Universities and Head of Chemical Research at Glaxo Group in Greenford, UK. He has received various honours and consults in a variety of areas, including medicinal chemistry, agrochemistry, biotechnology and combinatorial chemistry. He provides opinions as to obviousness respecting the '895 and '937 patents. He was cross-examined.
• Dr. Jouko Vepsalainen (expert): of Kuopio, Finland. He received a doctorate from the University of Joensuu, Finland; his thesis focused on halomethylene bisphosphonation. He worked exclusively in the area of bisphosphonates. He teaches and has written many scientific papers in that area. He submitted an affidavit and rebuttal affidavit directed to the obviousness of the '895 and '937 patents. He was cross-examined.
• Dr. Marc Grynpas (expert): of Toronto, Ontario. He is a Senior Scientist at the Samuel Lunenfeld Research Institute at Mount Sinai Hospital, Toronto; and a Professor in the Department of Laboratory Medicine & Pathobiology at the University of Toronto. He deals principally with utility in respect of the '895 and '937 patents. He was cross-examined.
• Christine Slattery: of Oakville, Ontario. She is fluent in English, French and German and is a freelance translator. She compared a European Patent Application in German, No. 0 170 228, with a United States patent in English 4,687,767. She found them to be almost identical. She was not cross-examined. Her evidence is not contested.
• John Coakley: of Hamilton, Ontario. He is a freelance translator fluent, among other things, in Danish and English. He compared Danish Patent Application No. 168754 with European Patent Application No. 0186405, in English, and found them to be mostly identical. He was not cross-examined. As previously stated, the Danish application is no longer at issue.
• Melissa Marie Dimilta: of Toronto, Ontario. An articling student in Teva’s Counsel’s office. She located and provided a copy of what is called the Schenck article.
• Louise McLean: of Toronto, Ontario. A law clerk in Teva’s Counsel’s office. She provided an affidavit and a reply affidavit. She was cross-examined. Her evidence served to make of record certain documents referred to in the Notices of Allegation and correspondence between the Counsel for the Applicants and Teva.
[21] In addition, certified copies of certain patents, including the '895 and '937 patents, as well as others, were filed.
[22] Each of the parties, at the hearing and in their memorandum, tried to marginalize the evidence of the experts of the other. Dr. Roberts, one of Teva’s experts, was said to be too much of a generalist and had not been involved in research respecting bone treatment. He made a search of the prior art, but did not keep his notes, which he described as “hieroglyphics”. Novartis’ experts were said to be “too expert” in that they worked too close to the field at the time and were unable to see the matters clearly as would a “disinterested” scientist.
[23] I am unable to come to any conclusion that would cause me to reject, or give minimal weight, to the evidence of any expert for either party. Dr. Roberts spoke as a generalist; he conducted, in my opinion, a proper prior art search. Novartis’ experts were close to the subject but gave what I find to be fair and disinterested opinions. All of the witnesses for both parties gave useful evidence. I find no reason to reject or be sceptical about any of it.
ISSUES
[24] The main issue is whether or not these applications for prohibition should be granted. That issue depends on whether the Court has been satisfied, or not, that Teva’s allegations as to invalidity of the '895 and '937 patents are justified.
[25] In respect of the '895 patent, Teva’s allegations as to invalidity are based on:
• obviousness
• lack of utility
• insufficiency
[26] With respect to the '937 patent, the allegations as to invalidity are based on:
• obviousness
• lack of utility
• insufficiency
• overbreadth
[27] In its Notice of Allegation, Teva also raised an issue as to double patenting. At a pre-trial conference, Teva’s Counsel advised the Court that this issue would not be pursued.
BURDEN OF PROOF
[28] The issues relate only to Teva’s allegations as to invalidity of the two patents at issue. I recently wrote on that subject in Pfizer Canada Inc v Pharmascience Inc, 2013 FC 120, and I repeat and adopt what I wrote at paragraphs 25 and 26:
[25] There have been many decisions addressing the question of burden when the issue in NOC proceedings is that of patent validity. I refer for instance to Pfizer Canada Inc v Apotex Inc, 2007 FC 26 at paras 9 and 12, and 2007 FCA 195, leave to appeal to Supreme Court refused; Pfizer Canada Inc v Canada (Minister of Health), 2012 FC 767 at para 42, affirmed in the result 2012 FCA 308.
[26] To put the matter briefly, the Patent Act, subsection 43(2) affords a patent a presumption of validity. In NOC proceedings the “second person” must lead some evidence to rebut that presumption. Once such evidence has been led the Court must determine the issue of validity on the usual civil burden of proof having regard to all the relevant evidence.
PERSON SKILLED IN THE ART
[29] The person skilled in the art (PSIA) or person of ordinary skill in the art (POSITA) is the person to whom a patent is directed and through whose eyes many issues respecting a patent are to be considered.
[30] The Applicants, in their Memorandum of Argument, propose the following definition of such a person:
77. Novartis’ position is that a PSIA would be part of a discovery team at a pharmaceutical company looking for a new BP. The PSIA would have a Ph.D. degree with some experience in the BP field or, alternatively, a Master’s or Bachelor’s degree but with more experience investigating BPs. The discovery team would be composed of medicinal chemists, biologists, and sometimes other subspecialists such as physical chemists. However, the medicinal chemist would be the scientist determining which compounds to make and test. Further, the chemist would also have to have specific experience in BP chemistry.
[31] Teva in its Memorandum of Argument proposes the following definition for such a person:
33. The skilled person is a skilled technician who has a mind willing to understand a specification addressed to him, who is “not a dullard, but lacking in imagination” and who is permitted to experiment when assessing obviousness, provided that the testing is routine and does not involve intense investigation. The skilled person “keeps up with the literature and is skilled in reading a patent, not only within the context of its subject matter, but also as a legal document. He reads patents in this and other jurisdictions as if he read them the day they were first made public, casting aside all he has learned since then”.
34. The parties agree that the skilled person for the 895 Patent and the 937 Patent would have had a few years of experience working in the area of drug design or a few years of education at the Ph.D. level in the pharmaceutical area. The skilled person was part of a project team, such as the team tasked with developing a new BP. It included a medicinal chemist who would determine which compounds to make and test. Biologists conducted tests in models to assess activity and completed the team.
[32] The differences between the two are narrow. The Applicants state these differences as follows in their Memorandum:
78. Novartis’ position is, for the most part, consistent with Teva’s position with the exception of two important clarifications. First, the PSIA must have actual experience developing new BPs. Second, to the extent the PSIA includes a researcher from academia, such persons would only fall within the definition of a PSIA if the focus of their research was on drug discovery and if they had experience working with a drug discovery team at a pharmaceutical company in the BP field.
[33] Teva argues at paragraphs 35 through 37 of its Memorandum that the Applicants’ definition is too narrow and would have the effect of eliminating persons other than those who were employed by one of the five brand companies working on bisphosphonates at the time; it would include the elimination of Dr. Widler, one of the inventors named in the '937 patent and a witness for the Applicants.
[34] I accept Teva’s definition as the most appropriate and find that the differences with their definition and that of the Applicants’ are few, and that the Applicants’ differences create a PSITA that is too narrowly defined.
THE '895 PATENT IN DETAIL
[35] The '895 patent is titled:
Diphosphonic Acid Derivatives, Processes for the Preparation Thereof and Pharmaceutical Composition Containing Them
[36] It begins at page 1 by stating that the invention concerns “new diphosphonic acid derivatives; how to prepare them, and pharmaceutical compositions containing those derivatives:
The present invention is concerned with new diphosphonic acid derivatives, processes for the preparation thereof and pharmaceutical compositions containing them.
[37] At page 1 from lines 5 to 19, a number of patent applications, all German except for one European, are identified as disclosing certain diphosphonic acid derivatives. At page 23, some of these applications are more particularly identified as issued patents, although there is no particular correlation with those listed at page 1 and at page 23. Counsel for the Applicants could not explain why.
[38] Returning to page 1, commencing at line 20, the '895 patent identifies a particular feature of its diphosphonic acid derivatives that differs from the previously described derivatives; namely, that:
…there is only one carbon atom between this diphosphonate residue and the heterocyclic radical and the heterocyclic radical is not a pyrazole ring…
[39] I digress from the '895 patent for a moment to point out that this feature can be illustrated using the examples found at paragraph 25 of Novartis’ Memorandum of Argument. That example is specific to one of the many compounds embraced by the '895 patent, Zoledronate, but it serves to illustrate what the patent says is the inventive concept:
[40] Returning to the '895 patent, the description at page 1, starting at line 20 and over to page 2, describes the features of this particular composition; namely, that these derivatives are suitable for the wider treatment of calcium metabolism disturbances:
We have now found that analogous derivatives of these compounds in which there is only one carbon atom between the diphosphonate residue and the heterocyclic radical and heterocycle is not a pyrazole ring also display these actions and , in addition, as good calcium complex formers, are suitable for the wider treatment of calcium metabolism disturbances. In particular, they can be very well used in cases in which the bone formation and breakdown is disturbed, i.e. they are suitable for the treatment of diseases of the skeletal system, for example osteoporosis, Bechterew’s disease and the like.
Moreover on the basis of these properties, they can also be used in therapy of bone matastases or urolithiasis and for the prevention of heterotopic ossifications. Furthermore, due to their influencing of the calcium metabolism, they form a basis for the treatment of rheumatoic arthritis, osteoarthritis and degenerative arthrosis.
[41] From the middle of page 2 to page 3, line 18, there is a description of several of the components of the compound.
[42] Commencing at line 24 of page 3 to the end of page 9, several processes for the preparation of the compounds are described.
[43] From the top of page 10 to line 8 of page 11, there is a discussion as to pharmaceutically acceptable salts.
[44] At page 11, lines 9 to 18, there is a discussion as to various forms in which the pharmaceutical may be administered, liquid or solid.
[45] From line 19, page 11, to line 7, page 12, there is a description as to additives, sometimes called excipients.
[46] From lines 8 to 13 of page 12, a general description as to dosages which “can depend on various factors” is given.
[47] At page 13, a test of one of the compounds (not zoledronate) is described with results tabulated on Table 1 appearing on page 14.
[48] At pages 15 through to the middle of page 18, a large number of compounds are particularly identified as being “Preferred in the sense of the present invention”. None of them is zoledronate.
[49] From the middle of page 18 to the end of page 22, a number of examples are provided, which are said to “show some of the process variants which can be used in synthesising the compounds according to the present invention”. Zoledronate is not specifically identified as a compound which can be produced. However, Example 1 is said to produce a compound that would fall within the scope of claim 14 however, that compound is not zoledronate.
[50] Page 23 has already been discussed.
[51] The '895 patent ends with 25 claims. Claim 1 is a very broad claim encompassing a vast number of compounds. Claim 2 claims a narrower range of compounds, as does Claim 3. Claims 4 and 5, 15, 16, 17, and 18 are directed to specific compounds; none of them being zoledronate. Claims 6 and 7 are pharmaceutical composition claims dependent on one or more of claims 1 through 5. Claims 8 to 12 are claims directed to the use of the compounds claimed in one or more of claims 1 through 5. Claims 13 and 20 are directed to a process for making the compounds.
[52] Claim 14 is the claim at issue, which I will subsequently discuss in more detail.
[53] Claim 19 claims the composition of claim 14, as well as claims 15, 16, 17 or 18, with a compatible salt.
[54] Claim 21 claims the composition of claim 14, as well as claims 15, 16, 17 or 18, with a salt and carrier.
[55] Claims 22, 23, 24 and 25 are directed to the use of the composition of claim 14, as well as claims 15, 16, 17 or 18, for various medical purposes such as calcium metabolism disturbances, arthritis, diseases of the skeletal system, rheumatic arthritis, osteoarthritis, degenerative arthrosis therapy of bone metastases, and urolithiasis, and prevention of heterotropic ossification.
THE '895 PATENT – CLAIM 14
[56] Claim 14 of the '895 patent is the only claim that is at issue in these proceedings. That claim is an independent claim; that is, it does not incorporate by reference any other claim; it stands on its own. Claim 14 reads:
14. A heteroarylalkane diphosphonic acid of formula I
Wherein R1 is a 5-membered heteroaryl radical selected from imidazolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl and oxadiazolyl, which is unsubstituted or substituted one or more times by lower alkyl, lower alkoxy, phenyl or halogen; R2 is a hydrogen atom, hydroxyl group or an amino group or a salt thereof.
[57] Claim 14 is directed to a class of compounds called heteroarylalkane diphosphonic acids, having the general formula depicted as Formula I, with a number of choices of atoms or combinations of atoms that can be placed at the R1 and R2 positions. The evidence is that a conservative estimate of the number of individual compounds that would be embraced by this claim is 1.2 million.
[58] Any one of a number of chemical structures may be placed at the R1 position, each of which may be generally described as a five-membered heteroaryl radical, with the group within that general description restricted to the following:
…selected from imidazolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl and oxadiazolyl, which is unsubstituted or substituted one or more times by lower alkyl, lower alkoxy, phenyl or halogen;…
[59] At the R2 position, there may be a hydrogen atom, or a group of molecules selected from the hydroxyl group of molecules, or a group of molecules selected from the amino group of molecules.
[60] In the descriptive portion of the '895 patent, R1 is part of a broader class referred to as Het and R2 as X.
[61] Thus, in claim 14, there are a finite number of choices for R1 and a finite number of choices for R2. The total number of choices is calculated as being about 1.2 million.
[62] Among the resulting choices is that where R1 is an imidazole ring joined to the Formula I structure at one of the nitrogen positions in the ring and where R2 is a hydroxyl (OH). The resulting compound may be chemically depicted as follows:
[63] This compound is referred to in the evidence as zoledronate or zoledronic acid. It is the active ingredient in Novartis’ commercial products. Teva wants to receive a Notice of Compliance to sell a generic version of those products, also containing zoledronic acid as the active ingredient.
[64] Thus to construe claim 14 it claims a class of some 1.2 million compounds all sharing a selection of molecules at the R1 and R2 positions placed on a biphosphonic backbone; zoledronate is but one of such compounds.
THE '937 PATENT IN DETAIL
[65] The '937 patent is titled:
Process for the Manufacture of Novel Substituted Alkanediphosphonic Acids
[66] The patent begins at page 1 by stating that it relates to certain novel acids depicted as Formula I:
Novel substituted alkanediphosphonic acids
The present invention relates to novel substituted alkanediphosphonic acids, in particular to heteroarylalkanediphosphonic acids of formula
Wherein R1 is a 5-membered heteroaryl radical which contains, as hetero atoms, 2 to 4 N-atoms or 1 or 2 N-atoms as well as 1 0- or s-atom, and which is unsubstituted or C-substituted by lower alkyl, phenyl or phenyl which is substituted by lower alkyl, lower alkoxy and/or halogen, or by lower alkoxy, hydroxy, di-lower alkylamino, lower alkylthio and/or halogen, and/or is N-substituted at a N-atom which is capable of substitution by lower alkyl, lower alkoxy and/or halogen, and R2 is hydrogen, hydroxy, amino, lower alkylthio or halogen, and to the salts thereof, to the preparation of said compounds, to pharmaceutical compositions containing them, and to the use thereof as medicaments.
[67] There follows at page 1 over to the upper third of page 3 a description of some of the constituents that may be used in creating the compound. This is followed at page 2 over to the first three lines of page 4 by a discussion of the salts that can be formed from the compound.
[68] From the first full paragraph on page 4 to the first three lines of page 5, there is a description of the “valuable properties” of the compounds embraced by Formula I:
The compounds of formula I and salts thereof have valuable pharmacological properties. In particular, they have a pronounced regulatory action on the calcium metabolism of warm-blooded animals. Most particularly, they effect a marked inhibition of bone resorption in rats, as can be demonstrated in the experimental procedure described in Acta Endrocinol. 78, 613-24 (1975), by means of the PTH-induced increase in the serum calcium level after subcutaneous administration of doses in the range from about 0.01 to 1.0 mg/kg, as well as in the TPTX (thyroparathyroidectomised) rat model by means of hypercalcaemia induced by vitamin D3 after subcutaneous administration of a dose of about 0.0003 to 1.0 mg. Tumor calcaemia induced by Walker 256 tumors is likewise inhibited after peroral administration of about 1.0 to 100 mg/kg. In addition, when administered subcutaneously in a dosage of about 0.001 to 1.0 mg/kg in the experimental procedure according to Newbould, Brit. J. Pharmacology 21, 127 (1963), and according to Kaibara et al., J. Exp. Med. 159 1388-96 (1984), the compounds of formula I and salts thereof effect a marked inhibition of the progression of arthritic conditions in rats with adjuvant arthritis. They are therefore eminently suitable for use as medicaments for the treatment of diseases which are associated with impairment of calcium metabolism, for example inflammatory conditions in joints, degenerative processes in articular cartilage, of osteoporosis, periodontitis, hyperparathyroidism, and of calcium deposits in blood vessels or prothetic implants. Favourable results are also achieved in the treatment of diseases in which an abnormal deposit of poorly soluble calcium salts is observed, as in arthritic diseases, e.g. ancylosing spondilitis, neuritis, bursitis, periodontitis and tendinitis, fibrodysplasia, osteoarthrosis or arteriosclerosis, as well as those in which an abnormal decomposition of hard body tissue is the principal symptom, e.g. hereditary hypophosphatasia, degenerative states of articular cartilage, osteoporosis of different provenance, Paget’s disease and osteodystrophia fibrosa, and also osteolytic conditions induced by tumors.
[69] From the first full paragraph at page 5 through to the middle of page 7, a large number of compounds are identified specifically as being to which the invention “relates” or “relates more particularly” or “preferably relates” or “relates firsts and foremost”. Zoledronate is not specifically named, but does fall within the broad range of the compounds so identified.
[70] At the middle of page 7, this paragraph appears:
The invention relates specifically to the compounds of formula I and the salts thereof, especially the inner salts and pharmaceutically acceptable salts thereof with bases mentioned in the Examples.
[71] There are about thirty two compounds specifically named in Examples 1 to 20 which are the Examples for the preparation of compounds, omitting repetitions. Zoledronate, written as:
2-(imidazol-1-yl)-1-hydroxyethane-1, 1 diphosphonic acid
is one of them. It appears in two of the examples; Example 11 and Example 13:
Example 11: The procedure of Example 1 is repeated, starting from 1-imidazoleacetic acid hydrochloride, 1-(1H-1,2,4-triazole) acetic acid hydrochloride, 1-pyrazoleacetic acid hydrochloride, and 3-pyrazoleacetic acid hydrochloride, to give the following compounds:
2-(imidazol-1-yl)-1-hydroxyethane-1, 1-diphosphonic acid, m.p. 239°C (dec.),
2-(1H-1,2,4-triazol-1-yl)-1-hydroxeyethane-1, 1-disphosphonic acid, m.p. 255°C (dec.),
2-(pyrazol-1-yl)-1-hydroxyethane-1, 1-diphosphonic acid, m.p. 234°C (dec.), and
2-(pyrazol-3-yl)-1-hydroxyethane-1, 1-disposphonic acid, m.p.
(Emphasis added)
. . .
Example 13: With stirring and under reflux, 8.6 g (0.053 mole) of imidazol-1-ylacetic acid hydrochloride, 7.1 ml of 85% phosphoric acid and 25 ml of chlorobenzene are heated to 100°C. Then 13.9 ml of phosphorus trichloride are added dropwise at 100°C, whereupon evolution of gas occurs. Over the course of 30 minutes a dense mass precipitates from the reaction mixture. The batch is heated for 3 hours to 100°C and the supernatant chlorobenzene is removed by decantation. The residual viscous mass is heated for 3 hours to the boil, with stirring and under reflux, with 40 ml of 9N hydrochloric acid. The batch is then filtered hot with the addition of carbon and the filtrate is diluted with acetone, whereupon the crude 2-(imidazol-1-yl)-1-hydroxyethane-1, 1-diphosphonic acid precipitates. This product is recrystallised from water. Melting point: 239°C (dec.). Yield: 41% of theory.
(Emphasis added)
[72] Returning to page 7 and through to the top of page 14, there is a discussion of the various processes by which the compounds may be produced.
[73] From the second paragraph at page 14 to the first paragraph of page 16, there is a description of the various forms and formulations that a pharmaceutical, including the compound, may take.
[74] The second paragraph at page 16 speaks to the use of the compound:
The present invention also relates to the use of the compounds of formula I and salts thereof preferably for the treatment of inflammatory conditions, primarily to diseases associated with impairment of calcium metabolism, e.g. rheumatic diseases and, in particular, osteoporoses.
[75] From the middle of page 16 over to the top of page 17, dosage regimens are described.
[76] From the top third of page 17 to the top of page 24, there are twenty Examples directed to the preparation of the various compounds, including, as previously discussed, Examples 11 and 13, which describe the preparation of several specific compounds, one of which is zoledronate.
[77] From pages 24 to 27, Examples 21 to 25 are provided, in which various tablets, lozenges, capsules and injection liquids are discussed. None of them mention zoledronate specifically.
[78] Two claims follow: claims 1 and 2.
THE '937 PATENT – CLAIMS 1 & 2
[79] The '937 patent contains only two claims – claims 1 and 2 – both of which are at issue in these proceedings. Those claims read:
a. 2-(imidazol-1-yl)-1-hydroxyethane-1, 1-diphosphonic acid, or a pharmaceutically acceptable salt thereof.
b. A pharmaceutical composition containing a compound as claimed in claim 1 together with conventional pharmaceutical excipients.
[80] Claim 1 relates to a single specific compound:
2-(imidazol-1-yl)-1-hydroxyethane-1, 1-diphosphonic acid
or a pharmaceutically acceptable salt of that compound.
[81] This formula is yet another way that claimants could write the formula for zoledronate or zoledronic acid, which was one of the 1.2 million or so compounds falling within the number of compounds encompassed by claim 14 of the '895 patent as previously discussed.
[82] Claim 2 simply claims that this chemical compound is made into a pharmaceutical composition by mixing it with “conventional pharmaceutical excipients”.
[83] No complex construction of claims 1 and 2 is needed. Claim 1 claims a single compound-zoledronate. Claim 2 is a mixture of zoledronate and pharmaceutical excipients.
BISPHOSPHONATES – TECHINICAL BACKGROUND
[84] Both Novartis and Teva have provided, through their expert witnesses, as well as the assistance of Counsel at the hearing, considerable information as to the technical background respecting bisphosphonates and their use in treating certain bone diseases.
[85] Bones in the human body, as well as in other mammals, are comprised of various materials; including collagen, calcium, andphosphates. Some of this material is, in a continuing process, released into the body – a process called bone resorption – and new material is retrieved from the body. This process continues during a person’s lifetime and provides for bone growth as well as repair to cracked and damaged bone material. Due to aging and some diseases, this process may become unbalanced. In particular, more bone resorption than is desirable may occur, resulting in conditions such as osteoporosis.
[86] In the late 1960’s, researchers, particularly Dr. Fleisch, determined that a class of compounds known generally as bisphosphonates were useful in controlling the level of bone resorption. The general structure of a bisphosphonate can be depicted as follows:
[87] The PO3 H2 molecules are the phosphonates; the C in the middle is sometimes referred to as the geminal carbon a name derived from the term Gemini (the astrological twins) since there are twin phosphonates attached. At the positions noted as R1 and R2 a number of different atoms or molecules may be attached by a “linker” molecule or molecules.
[88] One of the earliest bisphosphonates (or BPs, as they are called in these proceedings), is one known as etidronate, which had some commercial success. It can be depicted chemically as:
[89] Etidronate had been in existence since the late 1800’s and was used, for instance, to prevent mineral build-up inside pipes. Its use as a bone resorption inhibitor was a new use that came about in the late 1960’s and early 1970’s when it was determined that it would bind to bone mineral surfaces and inhibit bone resorption.
[90] Another early bisphosphonate used to control bone resorption was clodronate. It can be depicted as :
where each of R1 and R2 is chlorine (Cl).
[91] Development of what is known as second generation bisphosphonates followed. Work was done with respect to the “linkers” between the geminal carbon and the R1 molecule. Up to nine (9) linkers being carbon containing molecules (CH2) were investigated. In paragraph 67 of his affidavit, Dr. Benedict provides illustration of such linkers.
[92] Work also continued in the selection of suitable candidates for the atoms or molecules to be placed in the R1 and R2 position. Among the leading candidates for the R1 position were molecules containing nitrogen (N), including ring-structured molecules having five or six sides.
[93] Examples of rings having five sides (heterocycles), and tho