Gilead Science Inc. v. Canada (Health)

Gilead Science Inc. v. Canada (Health)
Court (s) Database
Federal Court Decisions
Date
2013-12-20
Neutral citation
2013 FC 1270
File numbers
T-8-12
Decision Content
Date: 20131220
Docket: T-8-12
Citation: 2013 FC 1270
Ottawa, Ontario, December 20, 2013
PRESENT: The Honourable Mr. Justice Barnes
BETWEEN:
GILEAD SCIENCES, INC. AND
GILEAD SCIENCES CANADA, INC.
Applicants
and
THE MINISTER OF HEALTH AND
TEVA CANADA LIMITED
Respondents
PUBLIC REASONS FOR JUDGMENT AND JUDGMENT
[1] This is an application under the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133 as amended (NOC Regulations) for an Order prohibiting the Minister of Health (Minister) from issuing a Notice of Compliance (NOC) to Teva Canada Limited (Teva) for a generic version of the Applicants’ (collectively Gilead) Truvada® medication.
[2] The patents in issue in this proceeding are Canadian Letters Patent No. 2,261,619 (the 619 Patent) and Canadian Letters Patent No. 2,298,059 (the 059 Patent). Teva asserts that both patents are invalid.
[3] The active pharmaceutical agent (API) that underlies both patents is tenofovir or PMPA. Tenofovir disoproxil or bis(POC)PMPA, a prodrug of tenofovir, is claimed by the 619 Patent and its salt form, tenofovir disoproxil fumarate (TDF), is the subject of the 059 Patent.
[4] TDF is indicated for use on its own and in combination with other pharmaceutical compounds for the treatment of HIV/AIDS. Gilead markets two different drugs containing TDF. These are Truvada® and Viread®. Bristol Myers Squibb (BMS) markets Atripla®, which also contains TDF. Each of these products has a different drug identification number and received its own NOC pursuant to Part C, Division 8 of the Food and Drug Regulations, CRC, c 870. Teva served Gilead with a separate Notice of Allegation (NOA) with respect to each of Truvada® and Viread®. Another NOA was served upon BMS with respect to Atripla®. In response, Gilead and BMS commenced three separate applications (Court files T-8-12, T-280-12 and T-1708-12) seeking orders prohibiting the Minister from issuing NOCs to Teva until the expiry of the 619 and 059 Patents.
[5] Although these applications were commenced separately and they remain separate, they raise identical issues and arguments. The parties agreed and the Prothonotary ordered that the Applications would be brought together and the validity issues determined under Court file T‑8‑12. The parties further agreed that my decision and reasons with respect to T-8-12 will apply equally to T‑280-12 and T-1708-12, although separate orders will be issued for each of those applications.
[6] Most of the relevant evidence in this proceeding was provided by expert witnesses. Drs. Ronald Borchardt, Allan Myerson, Richard Elion and Hans Maag gave evidence on behalf of Gilead. Drs. Robert Zamboni, Lawrence Kruse, Larry Sternson, Michael Parniak and Peter Ford gave evidence on behalf of Teva. Fact evidence on behalf of Gilead was also provided by Drs. William Lee and Reza Oliyai. This fact evidence was primarily directed at the history of the development of tenofovir disoproxil. All of the expert witnesses were qualified to opine on the subjects they addressed and no significant credibility issues were raised.
[7] Among other arguments raised, Teva contends that the claimed discoveries of tenofovir disoproxil and TDF would have been obvious to the person skilled in the art and that the patents in suit amount to the “evergreening” of the now expired patent over tenofovir. Teva also argues that the 619 Patent is invalid on the basis that the claimed discovery of tenofovir disoproxil was anticipated by an earlier patent application. Gilead argues that the discovery of a suitable prodrug and a prodrug salt form of tenofovir were delicate, complicated and unpredictable and therefore inventive.
Medicinal Background
[8] Tenofovir was known to be an effective antiviral agent useful to treat HIV/AIDS. It falls within the class of compounds known as acyclic phosphonate nucleotides and its antiviral efficacy arises from its disruption of the process of viral replication (reverse transcriptase) in human cells. In that capacity tenofovir acts as a nucleoside reserve transcriptase inhibitor or NRTI. Although tenofovir had been shown to be a very promising compound for the treatment of HIV/AIDS, it did not receive regulatory approval for medicinal use until it was converted firstly to a prodrug or intermediate form (tenofovir disoproxil) and then to a salt form (TDF).
[9] It is undisputed that the discovery of tenofovir in the 1990’s responded to a critical unmet need in the treatment of HIV/AIDS. This point is described in the affidavit of Gilead’s expert, Dr. Elion.
[10] Dr. Elion is a Board Certified Physician who has provided clinical care to HIV/AIDS patients since 1984. Since 2007 Dr. Elion has held the position of Director of Clinical Research at Whitman Walker Health in Washington, D.C. Between 1984 and 2007, he held several positions relevant to his understanding of the historical treatment of HIV/AIDS, including as medical advisor to the New York Department of Public Health (1990-1991) and a member of the protocol development team for the National Institute of Health's Community Research Program on AIDS (1993-1994). Dr. Elion was also principal and co-investigator on several clinical trials involving the treatment of HIV (1998-2007).
[11] According to Dr. Elion, the first commercial test for HIV was approved in 1985, but there was no means of treating the primary cause of AIDS and clinicians were left to treat only the underlying symptoms (Elion Affidavit at paragraph graphs 33-34). Through research, it was learned that:
38. …HIV is a retrovirus whose genetic material is encoded in RNA rather than the customary DNA as for most cells. Upon entering the cell, HIV's RNA is converted by the viral enzyme reverse transcriptase to DNA. The newly transcribed viral DNA integrates into the genetic code of the host cell. The viral DNA uses the host cell's replication machinery to produce copies of the virus. The infected cell then multiplies, creating an incurable and deadly infection.
[12] Researchers sought to develop drugs that would stop the replication process at various points along the replication chain, including reverse transcriptase.
[13] In 1987, the first HIV treatment drug, zidovudine (AZT), received approval from the Food and Drug Administration (the “FDA”). By 1996, the FDA had approved nine drugs for the treatment of HIV. Unfortunately, all of these therapies were associated with toxicity issues that caused unpleasant, and sometimes life-threatening, side effects. Patient adherence to drug regimes was also an issue, as patients were often reluctant to take medication that made them feel sick to treat a virus that was not presently making them feel sick (Elion Affidavit at paragraphs 42-51). Another concern with the available therapies was the ability of the virus to build up resistance to these antiviral agents (Elion Affidavit at paragraphs 52-56).
[14] The regulatory approval of TDF in 2001 represented a significant improvement over previous treatment options as it was dosed once daily, had a better toxicity/side effect profile and was less prone to viral resistance (Elion Affidavit at paragraphs 76-78). Based on his clinical experiences, Dr. Elion believed TDF to be more effective than the previous alternatives (Elion Affidavit at paragraphs 81-82). TDF in combination with other therapies has since become the “gold standard” in HIV treatment (Elion Affidavit at paragraph 85).
[15] The primary medicinal problem presented by tenofovir was its limited bioavailability (the ability to get to the target cell) when taken orally. For long-term treatment of HIV/AIDS, effective oral administration of any drug was considered to be essential and IV administration impractical.
[16] The poor bioavailability of tenofovir is described by Dr. Borchardt at paragraph 65 of his affidavit:
62. PMPA [tenofovir] poorly passes through these cellular membranes because all cell membranes in animals and humans are made up of lipids, which are oily in nature. Charged compounds, like the ionized form of PMPA, associate with water rather than with oily lipids. This causes them to poorly partition into cell membranes and cell interiors. The oral bioavailability of PMPA is low in animals and humans. For this reason, PMPA is of limited use as an orally administered pharmaceutical antiviral agent.
[Footnotes omitted]
[17] Dr. Kruse also confirmed that drugs like tenofovir that contain phosphonates “are very polar, and therefore are unable to cross cell membranes” (Kruse affidavit at paragraph 37).
[18] One well-known means by which the bioavailability of an API can be improved is the development of a prodrug. A prodrug is described by Dr. Borchardt in the following passage from his affidavit:
43. A prodrug is generally defined as a modified drug made by attaching a promoiety to a parent compound. A prodrug is generally pharmacologically inactive. After oral administration, a prodrug is metabolized by a series of enzymes to produce the pharmacologically active parent compound in the body. This was well known prior to July 26, 1996 and is discussed in many references.
44. To treat an infection, after oral administration a prodrug must remain stable through acidic and enzyme-laden environments as it passes through the gut, crosses the intestinal mucosa into the blood, and penetrates the infected cells. Inside the infected cells, the prodrug must be processed by several enzymes within the infected cell to produce the pharmacologically active drug.
[Footnotes omitted]
[19] Dr. Kruse offered the following description of a prodrug in his affidavit:
24. A prodrug is a drug which is inactive per se but is transformed in the body into the active compound (the “parent compound”). The term “prodrug” was coined by Dr. Adrien Albert in 1958. This transformation may be due to enzymatic activation or may be simply caused by a chemical reaction (for instance, the cleavage of a chemical bond as the prodrug moves into a more chemically reactive environment).
25. A prodrug is used for one or more of the following reasons:
a. to improve the stability and/or solubility characteristics of the parent compound;
b. to improve the bioavailability of the parent compound;
c, to increase the duration of the pharmacological effects;
d. to increase the ability of the compound to target a specific site; and
e. to decrease toxicity and adverse effects associated with the parent compound.
26. A prodrug should have a number of properties, including:
a. adequate chemical stability from a formulation perspective;
b. chemical stability in the pH environment of the gastrointestinal tract;
c. adequate solubility in the gastrointestinal tract;
d. the ability to withstand cleavage by enzymes in the gastrointestinal tract;
e. good cell permeability;
f. the ability to easily revert to the parent compound once absorbed into the blood stream or when it reaches its cellular target; and
g. non-toxic degradation byproducts.
The 619 Patent - Validity
[20] I accept that Teva’s evidence concerning the 619 Patent and the 059 Patent is sufficient to fulfill its obligation to overcome the presumption of validity created by subsection 43(2) of the Patent Act, RSC 1985, c P-4, and the ultimate burden of proof on a balance of probabilities thus falls upon Gilead.
[21] The person of skill to whom the 619 Patent is directed is someone with an advanced degree in biochemistry, pharmaceutical chemistry, medicinal chemistry, organic chemistry or chemical engineering with practical experience in drug development including general knowledge of the design of prodrugs.
[22] Only Claim 32 of the 619 Patent is in issue. It is not disputed that Claim 32 is directed to tenofovir disoproxil and its salts. The inventive concept of Claim 32 is the use of the carbonate promoiety disoproxil with the antiviral compound tenofovir. Teva has acknowledged that it is seeking a Notice of Compliance for a pharmaceutical product containing tenofovir disoproxil and it is common ground that the Teva product will infringe if Claim 32 is valid.
Is Claim 32 of the 619 Patent anticipated by the 214 Application?
[23] In Free Word Trust v Electro Santé Inc., 2000 SCC 66, [2000] 2 SCR 1024 at para 26, the Court applied Hugessen’s J.A.’s classic statement of the disclosure element for anticipation by prior publication from Beloit Canada Ltd. v Valmet OY:
The test for anticipation is difficult to meet:
One must, in effect, be able to look at a prior, single publication and find in it all the information which, for practical purposes, is needed to produce the claimed invention without the exercise of any inventive skill. The prior publication must contain so clear a direction that a skilled person reading and following it would in every case and without possibility of error be led to the claimed invention.
(Beloit Canada Ltd. v. Valmet OY (1986), 8 CPR (3d) 289 (FCA), per Hugessen JA, at p. 297)
[24] The above statement continues to be the legal standard on this issue (see Bell Helicopter v Eurocopter, 2013 FCA 219 at paras 109-110, [2013] FCJ No 1043).
[25] The prior art reference relied upon by Teva to establish anticipation is the 214 Application. The 214 Application was filed by Bristol-Myers Squibb Co. (BMSC) on September 10, 1991. It described the invention of “novel orally active prodrugs of phosphonate nucleotide analogs” and their salts suitable to overcome the bioavailability problems associated “with nucleotides and other ionic organophosphate esters”. Teva’s NOA asserted that the 214 Application “discloses prodrug forms of, inter alia, PMPA and, in particular, prodrugs in which the phosphate functionality had been esterified to improve oral bioavailability” (Applicants’ Record, Volume 1, Tab 1 at p 32).
[26] All of the witnesses agree that tenofovir disoproxil is not expressly identified in the 214 Application - a point that is acknowledged at page 18 of Teva’s NOA. Dr. Kruse also acknowledged under cross-examination that the 214 Application does not exemplify a carbonate prodrug (see Applicants’ Record, Volume 28, Tab 238 at p 8249). Nevertheless, according to Dr. Kruse the person of skill would read the 214 Application to include tenofovir disoproxil on the strength of the following approach:
56. R4 is defined as a physiologically hydrolyzable ester group and although it gives examples of these groups, a medicinal chemist would understand that R4 is not limited to those groups since the language at page 5, line 1 is “such as”. Further, a medicinal chemist would understand that the exemplified groups are not all traditional esters (i.e., CH2C(O)NR52, which is an ester substituted with an amide). Accordingly, a medicinal chemist would understand that the term is broader and includes all functional groups that will act like an ester. It follows that a skilled person would understand that all of these groups are within the definition of R4 as defined on page 5 of the 214 Application.
[Emphasis added]
According to this view tenofovir disoproxil falls within the class of “functional groups” that act like an ester and is, therefore, disclosed to the skilled reader. Also see Dr. Zamboni’s affidavit at paragraph 58.
[27] Dr. Borchardt answered this evidence in the following way:
96. The definition of R4 in the EP ‘214 Application recites a “physiologically hydrolyzable ester”. A carbonate is not a physiologically hydrolyzable ester as defined in the EP ‘214 Application and would not be understood to be such by a POSITA.
97. In paragraph 56 of his affidavit, Dr. Kruse relies upon the phrase “such as” to read into the definition of R4 of the EP ‘214 Application to expand the definition of “physiologically hydrolyzable ester” beyond the groups it exemplifies to include “all functional groups that will act like an ester”. He then draws on this expanded definition to import compounds that are not specifically disclosed by the EP ‘214 Application. Teva’s interpretation of the definition of R4 would include thousands or millions of compounds.
98. Dr. Kruse provides a table of promoieties that he considers to be “readily hydrolysable esters” following paragraph 56 of his affidavit. Carbonate esters of nucleotide phospohonates [sic] were not known to be “readily hydrolysable esters” in the context of the EP ‘214 Application (i.e., useful as prodrugs). In paragraph 59, Dr. Kruse states that the EP ‘214 Application specifically exemplified 47 compounds, which he set out in Exhibit 2 of his affidavit. Tenofovir disoproxil is not exemplified in the EP ‘214 Application.
99. This same, misunderstanding forms the basis for Dr. Zamboni’s statements in paragraphs 58(c) and 71 of his affidavit that the definition of “hydrolyzable ester group” in the EP ‘214 Application includes carbonates. In fact, Dr. Zamboni later corrects his earlier misunderstanding in paragraph 97, where he distinguishes between an ester and a carbonate on the basis of chemical stability. In his own words, “I have always considered a carbonate to be more stable than an ester.”
100. Tenofovir disoproxil is not anticipated by the EP ‘214 Application. As noted above, the definition of R4 in the EP ‘214 Application does not include a carbonate.
101. “Carbonate” is a clear and unambiguous chemical term, because it represents a unique structure, -OC(O)O-, that was known to POSITAs at the relevant time. If the inventors of the EP ‘214 Application intended to include carbonates, they would have done so explicitly by disclosing that structure and providing an example of a compound containing it (i.e., enabling a carbonate prodrug of a nucleotide phosphonate).
102. Without such a disclosure, a POSITA would not have understood the EP ‘214 Application to disclose carbonates.
[28] Dr. Maag also disagreed with Teva’s witnesses for the reasons set out below:
79. The Kruse and Zamboni analysis of the ‘214 Application and their allegations in respect of novelty hinge on the definition of the R4 group defined at page 5 of the ‘214 Application.
80. Drs. Kruse and Zamboni have misinterpreted the definition of R4 in the ‘214 Application in an attempt to include all functional groups that will act like an ester (including the carbonates disclosed in the ‘619 Patent).
81. This is incorrect. The ester groups defined in R4 of the ‘214 Application do not cover carbonates. Drs. Kruse and Zamboni attempt to extend the definition of R4 because of the phrase “such as” (see for example Kruse affidavit at para. 56). This extended definition would allow the ester groups to include anything, including compounds that are not described. A person skilled in the art would not understand the definition of R4 to include carbonates.
82. Drs. Kruse and Zamboni concede to this fact in their affidavits by relying on “such as” to extend the very specific limited defined ester groups in R4.
83. Clearly, if the inventors had intended to include carbonates, they would have included an appropriate chemical definition for such groups and disclosed and enabled such groups, which they did not.
[29] Teva’s evidence rests heavily on the significance of the words “such as” found in the 214 Application. Drs. Kruse and Zamboni say that the person of skill would interpret the 214 Application expansively in light of that open-ended language and readily conclude that tenofovir disoproxil was included.
[30] The person of skill is “trying to understand what the author of the description [in the prior patent] meant” (see Apotex v Sanofi, 2008 SCC 61, [2008] 3 SCR 265 at para 25). If there is doubt about what the prior art reference includes, it cannot be taken to meet the definition of anticipation. Faced with uncertainty, the person of skill would not be inclined to read up the prior art language or to draw grammatical inferences of the sort made by Teva’s witnesses. Here the uncertainty would be magnified by the absence of any extant prior art describing a carbonate prodrug of a phosphonate nucleotide. I reject the suggestion by Teva’s witnesses and, in particular, by Dr. Kruse at paragraph 56 of his affidavit, that by listing a few compounds preceded by the words “such as” a person of skill would conclude that the reference to “physiologically hydrolyzable ester group” means “all functional groups that act like an ester”. It seems to me that, in the absence of any evidence of bad faith or misrepresentation and in the face of a stark disagreement among the expert witnesses about whether the 214 Application would be read by the person of skill to include tenofovir disoproxil, what is left is uncertainty and not anticipation. Essentially the same point was made by Justice Judith Snider in Merck & Co. Inc. v Apotex Inc., 2010 FC 1265 at para 602, [2010] FCJ No 1646, where she said that “where the existence of the compound alleged to be anticipatory cannot be reasonably or consistently predicted from a large universe of possibilities, I cannot see how this could possibly meet the test for disclosure.” I do not agree that the 214 Application would be read by a person of skill to include tenofovir disoproxil. It teaches nothing about a carbonate prodrug solution to overcome the bioavailability limitations of tenofovir. Gilead has met its burden of proof on this issue.
[31] It necessarily follows from this finding that Claim 32 of the 619 Patent is not a selection of tenofovir disoproxil from the 214 Application and Teva’s selection–related invalidity assertions also fail.
The 619 Patent - Obviousness
[32] The principles of obviousness are set out in section 28.3 of the Patent Act. The parties agree that the relevant date for assessing whether Claim 32 of the 619 Patent was obvious is the claim date of July 26, 1996.
[33] In Sanofi, above, the Supreme Court of Canada set out the following four-part test for determining if a patent claim is obvious:
(a) Identify the notional ‘person skilled in the art’ and the relevant common general knowledge of that person;
(b) Identify the inventive concept of the claim in question or if that cannot readily be done, construe it;
(c) Identify what, if any, differences exist between the matter cited as forming part of the ‘state of the art’ and the inventive concept of the claim or the claim as construed; and
(d) Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to a person skilled in the art or do they require any degree of invention.
The fourth step of an obviousness inquiry may require an “obvious to try” analysis which the Court in Sanofi described in the following way:
(1) Is it more or less self-evident that what is being tried ought to work? Are there a finite number of identified predictable solutions known to persons skilled in the art?
(2) What is the extent, nature and amount of effort required to achieve the invention? Are routine trials carried out or is the experimentation prolonged and arduous, such that the trials would not be considered routine?
(3) Is there a motive provided in the prior art to find the solution the patent addresses?
An obviousness challenge will not succeed if the prior art only establishes that something might work. It also cannot be built upon a selective analysis of the prior art.
[34] As with Justice Roger Hughes in Novartis Pharmaceuticals Canada Inc. v Teva Canada Limited., 2013 FC 283 at para 161, 2013 FCJ No 303 , I endorse the view of obviousness and obvious to try expressed in the following passage from by Kitchin L. J. in MedImmune Ltd. v Novartis Pharmaceuticals UK, [2012] EWCA Civ 1234:
90. One of the matters which it may be appropriate to take into account is whether it was obvious to try a particular route to an improved product or process. There may be no certainty of success but the skilled person might nevertheless assess the prospects of success as being sufficient to warrant a trial. In some circumstances this may be sufficient to render an invention obvious. On the other hand, there are areas of technology such as pharmaceuticals and biotechnology which are heavily dependent on research, and where workers are faced with many possible avenues to explore but have little idea if any one of them will prove fruitful. Nevertheless they do pursue them in the hope that they will find new and useful products. They plainly would not carry out this work if the prospects of success were so low as not to make them worthwhile. But denial of patent protection in all such cases would act as a significant deterrent to research.
91. For these reasons, the judgments of the courts in England and Wales and of the Boards of Appeal of the EPO often reveal an enquiry by the tribunal into whether it was obvious to pursue a particular approach with a reasonable or fair expectation of success as opposed to a hope to succeed. Whether a route has a reasonable or fair prospect of success will depend upon all the circumstances including an ability rationally to predict a successful outcome, how long the project may take, the extent to which the field is unexplored, the complexity or otherwise of any necessary experiments, whether such experiments can be performed by routine means and whether the skilled person will have to make a series of correct decisions along the way. Lord Hoffmann summarised the position in this way in Conor at [42]:
"In the Court of Appeal, Jacob LJ dealt comprehensively with the question of when an invention could be considered obvious on the ground that it was obvious to try. He correctly summarised the authorities, starting with the judgment of Diplock LJ in Johns-Manville Corporation's Patent [1967] RPC 479, by saying that the notion of something being obvious to try was useful only in a case where there was a fair expectation of success. How much of an expectation would be needed depended on the particular facts of the case."
92. Moreover, whether a route is obvious to try is only one of many considerations which it may be appropriate for the court to take into account. In Generics (UK) Ltd v H Lundbeck, [2008] EWCA Civ 311, [2008] RPC 19, at [24] and in Conor [2008] UKHL 49, [2008] RPC 28 at [42], Lord Hoffmann approved this statement of principle which I made at first instance in Lundbeck:
"The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success."
93. Ultimately the court has to evaluate all the relevant circumstances in order to answer a single and relatively simple question of fact: was it obvious to the skilled but unimaginative addressee to make a product or carry out a process falling within the claim…
Also see Eli Lilly and Company v Janssen Alzheimer Immotherapy, [2013] EWHC 1737 at para 232.
[35] The strength of the ability to predict success is the lynchpin to an obvious to try analysis and not necessarily whether the means or methods employed to arrive at the result were well-known. This point was recently emphasized by Pelletier J. A. in the following passage from Apotex Inc. v Sanofi-Aventis, 2013 FCA 186, [2013] FCJ No 856:
78 As a result, the Trial Judge found himself in exactly the same position as did the Supreme Court when it decided Plavix, cited above. The focus of the obviousness analysis in Plavix was not the difficulty in seperating [sic] the racemates covered by the '875 genus Patent - which included PCR 4099 - but the unknown properties of the resulting enantiomers. :
The method to obtain the invention of the '777 patent were common general knowledge. It can be assumed that there was a motive to find a non-toxic efficacious product to inhibit platelet aggregation in the blood. However, it was not self-evident from the '875 patent or common general knowledge what the properties would be and therefore that what was being tried ought to work.
Plavix, cited above, at paragraph 92
79 The reasons of the Trial Judge make it clear that, as was the case in Plavix, it was not possible to predict the properties of the separated enantiomers: Reasons, at paragraphs 673 and 676. The lack of knowledge as to these properties is precisely what led the Supreme Court in Plavix, cited above, to hold that it was not self-evident that what was being tried ought to work (Plavx [sic], at paragraph 92, quoted above). Simply put, the person skilled in the art would not think of separating PCR 4099 and testing its enantiomers in order to obtain the benefit of its properties when the existence and nature of those properties were unknown.
80 It follows that although the resolution of PCR 4099 was part of the common general knowledge, nothing turns on this as it is the unknown nature of the properties of the enantiomers which explains why the invention was not "obvious to try".
81 Given that the Trial Judge applied the test for obviousness set out in Plavix, and given that he applied it to the same material facts as the Supreme Court, he ought to have come to the same conclusion. His error lay in failing to recognize that the unknown nature of the properties of the enantiomers of PCR 4099, or of any of the other compounds of the '875 Patent, was fatal to the "obvious to try" analysis. Put another way, the distance between the common general knowledge and the inventive concept of the '777 Patent could not be bridged by routine experimentation since the results to be obtained were unknown. On the facts, this was confirmed by the fact that the inventors, who had more knowledge that the person of ordinary skill in the art, attempted to resolve a number of other compounds before finally trying PCR 4099: see Reasons, at paragraphs 752-759.
82 As a result, the Trial Judge erred in finding that the invention of the '777 Patent was obvious.
[Emphasis in the original]
[36] Tenofovir disoproxil was the first example of a carbonate prodrug on a phosphonate nucleotide. Because there were no direct comparators, Teva’s case is built primarily around the person of skill drawing several inferences from the prior art dealing with prodrugs of other parent compounds where some success had been achieved.
[37] In their application of the prior art to the discovery of tenofovir disoproxil, Drs. Kruse and Zamboni essentially isolated each choice that the person of skill would face and, in doing so, they failed to view the problem in context. By proceeding in this way they fail to recognize that if at the junction of each investigatory pathway or choice an element of uncertainty arises, the cumulative level of uncertainty must be taken into account. In considerable measure, the Teva witnesses made untenable extrapolations by glossing over or ignoring the degree of scientific uncertainty that would have confronted the person of skill and the inventors at several points along the pathway to tenofovir disoproxil. I do not agree that the prior art illuminates that pathway as clearly as the Teva witnesses suggest. In my view, the evidence from these witnesses is selective and reflects a classic hindsight analysis.
[38] I am satisfied from the evidence that a person of skill would have considered tenofovir to be a worthy candidate for development as a prodrug and in the search for promoiety options that person would have looked, at some point, at the carbonates. However, I do not agree with Teva that the carbonates or the carbomates would be considered by the person of skill to be the only reasonable or viable options. I also do not agree that a person of skill would have predicted directly and without difficulty that any of the potential promoiety options would work. Indeed, the history of prodrug development described in the prior art included many failures and unpredictable outcomes.
[39] Dr. Kruse was questioned during cross examination (Applicants’ Record, Volume 28, Tab 238) about the properties that were required for the development of a successful prodrug and, in particular about paragraph 26 of his affidavit. His responses reflect the general complexity of the problem facing the person of skill:
199 Q. I think you start that around paragraph 24. You have some pictorials there, and you set out in paragraph 25 some of the kinds of things where a prodrug might have an implication, but I am looking at 26, and you say that a prodrug should have a number of properties. I think you have seven of them there. Do you see that?
A. Yes.
200 Q. Am I correct in my understanding that what you are saying here is that for a prodrug to be practically successful, it would have to, for example, have adequate chemical stability when you make the thing?
A. For a prodrug to be successful, it would have to have enough of the properties on the list that it actually gets into the target in the body.
201 Q. Right. You put them, I think, kind of in this order, so the first step would be that, chemically, it has to be stable enough that you can make it into a formulation that will remain in the chemical state you want it to remain in?
A. Yes.
202 Q. If you have achieved that, now it goes into the body if we are dealing with an oral, and now it goes into the stomach and the lumen, and now it is exposed to the gastric juices and whatnot. I think the second one is it needs to be stable in that environment?
A. It is going to vary from compound to compound, depending upon where the drug is absorbed, but presumably, it would need to navigate the acid pH of the stomach,
203 Q. Right, because if it got into the stomach, and at that pH it lost its stability and broke up at that point, you wouldn’t have the prodrug anymore.
A. That’s right.
204 Q. You would now be back to the active - -
A. That’s right.
205 Q. Am I correct in my understanding that when we speak of prodrugs, we generally have a component which I am going to call the “active moiety”?
A. Yes.
206 Q. That active moiety, scientists know will have some desirable properties if it got to a cell and did something. Is that generally what happens?
A. Yes.
207 Q. For some reason, that active moiety chemically can’t be made adequately or won’t go through the body or won’t stay in the plasma but ultimately can’t get to the cell for some reason?
A. For some reason; correct.
208 Q. Some of these reasons are what may lead a scientist to say, “Maybe we can use a prodrug approach to bring this thing which itself isn’t going to get into where we want it, but somehow we will get it in.”
A. Yes.
209 Q. We were, say, at (b), so we needed this prodrug that you made to be at least stable enough to survive the pH environment of the stomach and the GI, otherwise it would be broken down right there. You would be back to your active moiety, which the scientist knows isn’t getting in somehow?
A. Yes.
210 Q. In (c), for instance, when you say, “Adequate Solubility,” I guess that is a sine qua non because it has no solubility. I think the expression is it is “brick dust,” and it just goes through the GI?
A. You have been hanging with scientists too long. That’s the exact slang, exactly; yes.
211 Q. It has to be sufficiently soluble so that it can somehow at least have a shot at getting through into the intestine?
A. Yes.
212 Q. Then, of course, when you say, (e), by “Permeability” - - I just want to make sure I understand - - you mean permeability through the intestinal wall which, I guess, would be the endothelium?
A. Yes. I mean it could be any cell permeability. It could be the intestinal wall; it could be the target cell; it could be the nucleus of the target cell. If it is the central nervous system, it could be the blood-brain barrier. So this is kind of a wish list, and a successful prodrug should have a number of these properties. It is almost like a menu that several are probably going to be necessary for any particular drug, but they may differ depending upon the target and so on and so forth.
213 Q. Just on the permeability, I think you are right because to get in through the endothelium into the intestine, it has to get into the cells that are in the intestine. So it has to be permeable at that level, right?
A. Yes.
214 Q. Then, as you mentioned, if it ultimately gets into circulation and is exposed to the target cell that you are interested in, it is now facing another membrane.
A. There are plenty of cases where cleavage of the prodrug occurs in the plasma or even fairly fast in the intestine, and it is still a pretty good prodrug. Enough of it gets into the plasma, or sometimes, the parent that the prodrug is cleaved - - parent in plasma, and it still gets to the target cell.
215 Q. I think, just going back to your original point, that when you get to the target cell, you have another membrane that has to be crossed, generally. Right?
A. That’s correct.
216 Q. Then, you mentioned the nucleus, and it too has a - - am I correct calling it a membrane - - around the nucleus?
A. Correct.
217 Q. So if this particular drug needs to intervene in the nucleus for whatever reason, it would have another barrier to cross?
A. Yes.
218 Q. So when you say “permeability” in (e), it could be permeability at a number of levels - -
A. - - or only one.
219 Q. Right; depending on the drug and where it needs to be active in the body?
A. Yes.
[40] When he was later asked about the ability to predict efficacy with phosphonates by extrapolation from prodrug strategies utilized with carboxylic acids, he responded that he would not be able to do so without experimentation (see Applicants’ Record, Volume 28, Tab 238 at p 8225 and pp 8252-8253). This evidence does not differ materially from that of Dr. Borchardt at paragraph 148 of his affidavit:
Needless to say, this complex interplay of opposing chemical and metabolic properties makes for a process that defies rational drug design in that it is entirely unpredictable and completely empirical.
Also see the Maag affidavit at paragraph 100.
[41] Notwithstanding the above evidence, Dr. Kruse makes several material extrapolations in concluding that the discovery of tenofovir disoproxil was obvious (see paragraph 124 of his affidavit). For instance, Dr. Kruse surmises that the person of skill would understand from the 214 Application that a prodrug strategy for phosphonate nucleotide analogs would include “a carbonate”. Dr. Kruse also assumes that prodrug strategies used with adefovir would be interchangeable with tenofovir. Because carbonate promoieties had been successfully used to mask the hydroxyl group of carboxylic acids, Dr. Kruse similarly surmises that they could be successfully employed with phosphonic acids. Despite acknowledging the structural differences between the POM and POC prodrug moieties, Dr. Kruse maintains that the skilled person would expect them to behave in the same way. These assumptions are summarized at paragraph 138 of Dr. Kruse’s affidavit:
138. The skilled person would anticipate, based on the prior art, that the [(alkoxycarbony1)oxy]alkyl prodrug moiety would break down in a similar manner as the acyloxyalkyl prodrug moieties and at about the same rate of hydrolysis. In addition, the skilled person would expect that an [(alkoxycarbonyl)oxy]alkyl prodrug would work with a phosphonate by reference to the antibiotic prior art. Specifically, considering that (1) both acyloxyalkyl and [(alkoxycarbonyl)oxy]alkyl prodrug groups were successfully used with antiobiotics, and (2) the acyloxyalkyl prodrug group was known to work successfully with adefovir and tenofovir (phosphonates), it follows that the [(alkoxycarbonyl)oxy]alkyl group should also work with tenofovir.
[42] It is unnecessary to deal with all of the points of d