Glaxosmithkline Inc. v. Pharmascience Inc.

Glaxosmithkline Inc. v. Pharmascience Inc.
Court (s) Database
Federal Court Decisions
Date
2008-05-09
Neutral citation
2008 FC 593
File numbers
T-833-06
Decision Content
Date: 20080509
Docket: T-833-06
Citation: 2008 FC 593
Ottawa, Ontario, May 9, 2008
PRESENT: The Honourable Mr. Justice Barnes
BETWEEN:
GLAXOSMITHKLINE INC. and
THE WELLCOME FOUNDATION LIMITED
Applicants
and
PHARMASCIENCE INC. and
THE MINISTER OF HEALTH
Respondents
REASONS FOR JUDGMENT AND JUDGMENT
[1] This application was commenced by Glaxosmithkline Inc. and the Wellcome Foundation Limited (collectively GSK) against the Minister of Health and Pharmascience Inc. (Pharmascience) under the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133 as amended (NOC Regulations). GSK seeks an order prohibiting the Minister from issuing a Notice of Compliance (NOC) to the Respondent, Pharmascience, until the expiry of Canadian Patent No. 1,340,083 (the 083 Patent). GSK asserts that the 083 Patent is a valid selection patent which will be infringed if Pharmascience is permitted to produce the antiviral compound valacyclovir (marketed as Valtrex). The 083 Patent was filed on August 12, 1998 and issued on October 13, 1998. It has a priority date of August 15, 1987 and it will expire on October 13, 2015. The earlier genus patent from which the selection of valacyclovir was drawn was GSK’s European Patent No. 0,099,493 (the 493 Patent) for which the Canadian equivalent is Canadian Patent No. 1,208,637 (the 637 Patent). The 637 Patent expired on July 29, 2003.
[2] Notwithstanding the summary nature of this proceeding, it is worth noting that the argument took place over four and a half days, that the Application Record is made up of 40 volumes containing over 11 000 pages and that the cross-examination transcripts of the five principal expert witnesses comprise over 1700 pages. Counsel are, however, to be commended for having reduced the matters in issue to those which had arguable merit thereby avoiding the full litigation of a number of issues which would not have been determinative.
I. Background
[3] This is a case about selection. It is common ground that GSK’s 493 Patent claimed a monopoly over a class or genus of compounds which included valacyclovir. Pharmascience wants to produce a generic version of GSK’s drug Valtrex but in doing so it will admittedly infringe several claims in GSK’s later 083 Patent for valacyclovir. Pharmascience asserted in its Notice of Allegation (NOA) that GSK’s 083 Patent is invalid for anticipation, obviousness, non-utility, double patenting, lack of invention, insufficiency, disclosure, lack of sound prediction and because that patent does not contain or disclose a valid selection from GSK’s earlier patent over valacyclovir (the EPA 493 Patent). Many of these allegations overlap and for present purposes it is unnecessary to deal with all of them in a discrete way.
Burden of Proof
[4] The parties are in agreement that the ultimate burden of proof on a balance of probabilities rests upon GSK subject to Pharmascience’s intermediate or evidentiary burden to adduce sufficient evidence of invalidity to put its NOA allegations “in play”.
The Person Skilled in the Art and the Expert Witnesses
[5] I can identify no material differences among the expert witnesses’ opinions as to the attributes required of the person skilled in the art in mid-1987 to whom the 083 Patent would be addressed. Such a person would have a combination of specialized education and work experience in the areas of drug discovery and testing with particular exposure to the design, synthesis and evaluation of prodrugs. This would include a capacity to evaluate the drug-like properties (eg. bioavailability) of drug and prodrug candidates using standard in vitro and in vivo studies. The educational attributes of such a person could include a B.Sc. or M.Sc. or equivalent in the fields of pharmacy, chemistry, or an equivalent discipline coupled with considerable employment experience. Such a person might also hold a Ph.D. in a relevant field of expertise such as pharmaceutical chemistry, bioanalytical chemistry, synthetic organic chemistry or medicinal chemistry.
[6] Subject to the obvious limitations presented by attempting to evaluate the credibility of any witness based on affidavits and cross-examination transcripts, I can identify nothing which would generally discredit any of the expert witnesses relied upon by the parties or which might cast doubt upon their qualifications to give evidence in the required fields of expertise. Indeed, all of these witnesses appear to be eminently qualified and generally objective in the provision of their opinion evidence. To the extent that I have formed any reservations about the expert evidence on particular points, I have attempted to state them in these reasons.
Acyclovir and Its Prodrug Esters
[7] Acyclovir is an antiviral drug which has been known for some time to be effective in the treatment of a variety of herpes and other viral infections. Although acyclovir is given orally, it presents problems of bioavailability such that only 15% to 20% of any given dosage is actually absorbed into the bloodstream. Acyclovir also has bioavailability limitations for use in aqueous dosage forms such as eye drops and injectable solutions. The primary problem for such aqueous uses was the low solubility of acyclovir. Essentially, not enough acyclovir can be dissolved to obtain a concentration capable of delivering the necessary dose in a formulation such as an eye-drop, which is inherently limited to a very small volume of liquid. These bioavailability limitations led researchers to search for more effective drugs.
[8] One of the known methods for overcoming the bioavailability limitations of a drug like acyclovir was to link the molecule to another compound, referred to as a pro-moiety, (often an amino acid) and to thereby create a prodrug. Valacyclovir is a prodrug formed by the molecular combination of acyclovir with the amino acid, L-valine.
[9] The intended mechanism of action of a prodrug is that the pro-moiety will help deliver the active medicine more effectively to the site of action. In 1987, the improved activity of a prodrug over its constituent medicine was generally attributed to its optimal or more balanced absorption properties. In a 1985 publication by Hans Bundgaard,[1] the feasibility of designing prodrugs to obtain certain desirable absorption properties was canvassed at length including the following discussion about the potential development of prodrugs of acyclovir:
9.3 Enzyme-Specified Prodrugs of Acyclovir
Acyclovir (150) is a clinically useful antiherpetic agent which exhibits great selectivity in its antiviral action through conversion to the active phosphorylated species by virtue of virus-specific thymidine kinase [423 – 425]. It suffers, however, from poor oral bioavailability, only 10 – 20 % of oral dose being absorbed in humans [426 – 429]. This can most probably be ascribed to the poor water-solubility and lipophilicity of the compound. The 6-deoxy-6-amino congener (151) of acyclovir has been studied as a prodrug in an attempt to improve the oral bioavailability [430]. It is deaminated to acyclovir by adenosine deaminase [431], but oral dosing of dogs and rats with the prodrug resulted in only modest increases in acyclovir plasma levels relative to those achieved with acyclovir itself [430]. A far better prodrug may be 6-deoxyacyclovir (152), recently developed by Krenitsky et al. [432]. This compound is 18 times more water-soluble than acyclovir and is oxidized rapidly in vivo by xanthine oxidase to the parent drug. Preliminary studies in rats and in human volunteers showed that 6-deoxyacyclovir is absorbed readily after oral administration (5 – 6 times greater bioavailability relative to acyclovir) [432, 432a]. The compound is also susceptible to oxidation by aldehyde oxidase, to give the inactive 8-hydroxy-6-deoxyacyclovir, but this non-activating oxidation apparently plays only a minor role in comparison to the activating oxidation by xanthine oxidase [432].
[10] Prodrugs are designed such that the pro-moiety (in this case, the amino acid ester) is hydrolyzed, or cleaved, from the active drug compound at an appropriate point after absorption into the body. The evidence before me suggests quite strongly that the prodrug strategy at the time usually employed one of the twenty naturally occurring proteinogenic amino acids as a pro-moiety because the human body was known to have enzymes which could recognize and cleave these amino acids and because the resulting amino acid, once cleaved, would be expected to be non-toxic in humans.
[11] The use of prodrugs was thus known to be a potentially useful strategy for overcoming problems of solubility, stability and permeability associated with a parent compound. It was for the purpose of overcoming the solubility limitations of acyclovir that the amino acid esters of acyclovir were developed by GSK and claimed in its 493 Patent as prodrugs.
493 Patent
[12] The 493 Patent claimed a monopoly over a class of "new esters" of 9-(2-hydroxyethoxymethyl)guanine (i.e., acyclovir) of the general formula:
Wherein X represents an oxygen or sulphur atom, R1 represents a hydroxyl or amino group; R2 represents a hydrogen atom or a group of formula –CH2OR3a; and R3 and R3a, which may be the same or different, each represents an amino acid acyl radical.
[13] The invention claimed compounds of the generic formula set out above and acceptable salts thereof "for use in the treatment or prophylaxis of a viral disease in an animal, e.g. a mammal such as man". The Patent specification further described the compounds as follows:
Preferred compounds according to the invention include those wherein R1 represents a hydroxyl group, R2 represents a hydrogen atom and X represents an oxygen atom, i.e. amino acid esters of acyclovir, and their pharmacologically acceptable salts.
With regard to the amino acid acyl radical(s) represented by R3 and/or R3a, such radicals are preferably derived from an aliphatic amino acid, eg, glycine, α – or β alanine.
[14] These new ester compounds were said to "surprisingly have an improved water solubility compared with acyclovir which enables the derivatives to be used to a greater extent than acyclovir in the formulation of aqueous preparations". This solubility characteristic was said to be an improvement over acyclovir which the inventor said "suffers from the disadvantage that it has only a limited solubility in water". The inventor further asserted that this advantageous increase in water solubility over acyclovir is not gained at the expense of antiviral potency. The claimed invention was thus not in finding new antiviral medicaments but in finding prodrug compounds of acyclovir which more effectively delivered acyclovir in aqueous solutions.
[15] Although the 493 Patent describes new esters of acyclovir as being "particularly useful for the formulation of aqueous pharmaceutical preparations such as eye drops and injectable preparations", the specification included a teaching that "the active compounds may be administered by any route appropriate to the condition to be treated... including oral, rectal, nasal, topical …, vaginal and parenteral...” For oral administration of the new ester compounds, the patent specification taught the following:
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
083 Patent
[16] GSK’s 083 Patent claimed the compound valacyclovir (i.e., the L-valine ester of acyclovir) as a selection from the genus of aliphatic amino acids esters of acyclovir claimed in the 493 Patent. The discovery asserted by the 083 Patent was that valacyclovir “surprisingly has improved bioavailability after oral administration compared with alanine and glycine esters mentioned [in the 493 Patent]”. The specification also stated that while acyclovir possessed a potent antiviral activity it was known to be poorly soluble in water and poorly absorbed in the gastrointestinal tract. The inventors acknowledged the utility of the 493 Patent in solving the solubility problem of acyclovir but, by inference at least, they maintained that its oral bioavailability limitations were still unresolved. The Patent specification goes on to offer the following additional inventive findings:
In tests in rats, measuring the urinary recovery as acyclovir (% dose administered) after oral administration, the compounds of the invention show a large increase in absorption from the gut compared with the other esters and compared with acyclovir. This enables less drug to be administered while still providing equivalent drug levels in the plasma after oral absorption. The L-valinate compound is especially preferred by virtue of its particularly good absorption from the gut.
In addition to the relatively high bioavailability, the compound according to the invention possess substantially the same antiviral effect as acyclovir in vitro. The advantageous increase in bioavailability of the compound is thus not gained at the expense of antiviral potency. Indeed, it has been found that in certain clinical applications, e.g. the treatment of stromal keratitis, certain amino acid esters have been found to provide a superior therapeutic effect to acyclovir (EP 99493).
The pharmaceutically acceptable salts of the compounds of formula (I) are preferably acid addition salts derived from an appropriate acid, e.g. hydrochloric, sulphuric, phosphoric, maleic, fumaric, citric, tartaric, lactic, acetic or p-toluenesulphonic acid. A particularly preferred salt is hydrochloride salt of the compound of formula (I).
In experiments in animals, it was discovered that the oral administration of the compounds of formula (I) above produced measurable levels of acyclovir in the plasma. Thus according to another aspect of the invention we provide a means of generating acyclovir in vivo by administration of a compound of formula (I) above or a pharmaceutically acceptable salt thereof to a mammal.
The research data offered in the 083 Patent to support the oral bioavailability advantage of valacyclovir is set out in the following example from the specification:
Determination of Oral Bioavailability
Long Evans Rats were administered the compound to be tested by gavage at a dose equivalent to 25mg/kg acyclovir. The urine was collected for 24 and 48 hours post-dose, ultrafiltered, and analysed by reverse-phase high-pressure liquid chromatography. The oral bioavailability of the compound was expressed as the percent of the dose excreted in the urine as acyclovir.
Compound
Example 1 [valacyclovir]
Acyclovir (ACV)
Glycyl ester of ACV [glycine ester]
L-alanyl ester of ACV [alanine ester]
Urinary Recovery (% of dose) as acyclovir
63
15
30
34
[17] It is noteworthy that the 083 Patent makes no assertion that valacyclovir has, or could be predicted to have, surprising or unexpected bioavailability advantages over the compounds claimed in the 493 Patent beyond the glycine and alanine esters tested.
II. Issue
[18] Is the 083 Patent for valacyclovir a valid selection patent?
III. Analysis
What is the Scope of the 493 Patent Genus?
[19] It is a well accepted principle of selection law that a selection can be made from a class of two or from a class of thousands. Accordingly, it is not necessary to precisely define the scope of the class of compounds captured by the 493 Patent because it is agreed by the parties that, whatever its size or composition, the 493 Patent covers valacyclovir. Nevertheless, the size of the class of compounds claimed in an originating patent is a factor to consider in determining whether a selection was obvious: see Eli Lilly Canada Inc. v. Apotex Inc. 2007 FC 455, 58 C.P.R. (4th) 353 at para. 306. I would add that the size of the genus may also be relevant to the determination of whether an advantage identified in a compound selected from the genus was surprising or unexpected relative to the other members of the genus. In other words, it may be easier to predict that such an advantage will not be found in a substantial number of other members of the genus where the genus is relatively small and/or where a significant percentage of the genus has been tested. Conversely, a sound prediction may be more elusive where the genus is a large one.
[20] GSK asserts that the class of compounds within the 493 Patent is virtually infinite because it includes all aliphatic amino acids, including synthetics. It says that the person skilled in the art would understand that this class can be expanded by systematically adding CH2 groups to the simplest amino acid, glycine. Pharmascience says that the 493 Patent genus is limited to five naturally occurring amino acids (i.e. glycine, alanine, valine, isoleucine and leucine) which are aliphatic and which are used by the human body to make proteins and one other amino acid that is formed in vivo in humans, namely β-alanine.
[21] I am persuaded that GSK is correct in its interpretation of the scope of the 493 Patent. Claim 1 of that patent refers to compounds of a general formula by which a molecule of acyclovir is linked at the R3 position to “an amino acid acyl radical”. This claim is not further qualified or limited. Upon a literal reading, the reference to “amino acid” would include any organic compound, natural or synthetic, having at least one amine group (-NH2) and at least one carboxylic acid group (-COOH). Although the patent specification describes a preference for derivatives from an “aliphatic amino acid, eg. glycine α- or β-alanine”, I accept GSK’s evidence that the reference to “aliphatic amino acid” did not connote only a subset of 5 of the 20 amino acids which are the building blocks for proteins in the human body, but rather would include any amino acid compound where carbon atoms are linked in open chains rather than rings.
[22] While I agree that a person skilled in the art might be inclined to prefer the 20 human amino acids for use in the construction of a prodrug of acyclovir, the prior art nevertheless taught that effective prodrug strategies were not limited to the use of natural or human amino acids or entirely non-toxic pro-moieties.
[23] There is another anomaly confronting the construction suggested by Pharmascience which arises from the β-alanine example given by the 493 Patent. While α-alanine is one of the 20 amino acids taken up by the human body to make proteins, β-alanine is not. Although β-alanine is used in the human body, it is just one of several hundred known non-proteinogenic amino acids and its inclusion in the list of patent examples is suggestive that the claimed invention was not limited to those aliphatic amino acids which are a sub-group of the 20 human proteinogenic amino acids. Although I accept that the five human aliphatic proteinogenic amino acids are often listed together as a homologous group for descriptive purposes, that practice does not explain the inclusion of β-alanine or the absence of qualifying language in the patent specification. If the inventor had intended to limit the class of compounds claimed by the 493 Patent, it would have been a rather simple drafting exercise to have obtained that result. It is perhaps noteworthy that when Drs. Mitra and Dordick attempted to restrict the class of compounds claimed by the 493 Patent they frequently resorted to qualifying terms such as “basic,” “simple,” “common,” or “natural.” My review of the relevant text book references submitted as evidence also discloses no consistent nomenclature or scheme of classification for aliphatic amino acids which would be sufficient to displace the unqualified language of claim 1 of the 493 Patent. On this issue, I accept Dr. Borchardt’s reply evidence as set out below:
44. At paragraphs 159 to 162 of his affidavit, Dr. Mitra suggests that in addition to the α-amino acids, glycine, alanine, valine, isoleucine and leucine, there is a β-amino acid, β-alanine, found in the human body. Thus, Dr. Mitra suggests that the person skilled in the art would include this and only this β-amino acid with the 5 α-amino acids included in the “aliphatic amino acid” group, as he defines it. Thus, Dr. Mitra concludes that the person skilled in the art would interpret the term “aliphatic amino acid” as used in the EPA '493 as being limited to now 6 aliphatic amino acids, namely, glycine, alanine (α- and β-), valine, isoleucine and leucine.
45. Similarly, at paragraphs 72 to 77 and paragraphs 120 to 122, as well as Appendix A of his affidavit, Dr. Dordick offers the same rationale for now including β-alanine within the definition of “aliphatic amino acid” referred to in the EPA '493.
46. There is no suggestion whatsoever in the EPA '493 that Dr. DeClercq intended to limit the preferred “aliphatic amino acid” class to those which are found within the group of 20 naturally occurring amino acids which the body uses in the synthesis of proteins, much less to the 5 amino acids which PMS has identified in the NOA, namely, glycine, α-alanine, valine, leucine and isoleucine, or the 6 amino acids identified by Dr. Mitra and Dr. Dordick.
47. First, an amino acid by definition is simply a compound which includes both an amine group (-NH2) and a carboxylic acid group (-COOH). Amino acids can be prepared synthetically as well as naturally. In 1987 there were, for example, known to be approximately 350 aliphatic amino acids found naturally.
48. Further, even within the 20 naturally occurring amino acids used in the manufacture of proteins in the body, glycine, α-alanine, valine, leucine and isoleucine are not the only amino acids which are categorized as being “aliphatic amino acids”. This is clear from many of the references attached as exhibits to Dr. Mitra’s affidavit. For example, the new prior art reference at Tab B37 of Dr. Mitra’s affidavit indicate that 15 of the 20 naturally occurring amino acids used by the body to manufacture proteins are considered to be “aliphatic amino acids”. Furthermore, the reference at Tab B38 includes serine and threonine in the definition of aliphatic amino acids that are found in protein. Pages 90 and 91 of the reference at Tab B38 of the Mitra Affidavit are included at Exhibit “G” of this Affidavit.
49. Dr. DeClercq clearly indicates that the term “aliphatic amino acids” as used in the EPA '493 includes β-alanine. As Dr. Mitra and Dr. Dordick both concede, β-alanine is not among the 20 naturally occurring amino acids used by the body to manufacture proteins. Thus, it is illogical to suggest as both of them do that the term “aliphatic amino acid” as used in the EPA '493 must be limited to glycine, α-alanine, valine, leucine and isoleucine (all of which are selected from the 20 naturally occurring amino acids used by the body to manufacture proteins) plus one β amino acid (β-alanine) which does not fall within this group. At the very least, the position being taken by both Dr. Mitra and Dr. Dordick is a concession that Dr. DeClercq intended “aliphatic amino acid” to include more than the 20 naturally amino acids discussed at pages 2 and 3 of the NOA.
50. Thus, the person skilled in the art reading the EPA '493 would clearly understand the term “aliphatic amino acid” as encompassing both natural and unnatural amino acids and certainly not just the 6 amino acids which PMS has arbitrarily selected to support its position.
Obviousness and Anticipation
[24] I am satisfied on the evidence presented that the bioavailability advantage that was asserted as the inventive selection of the 083 Patent was neither anticipated nor obvious.
[25] Pharmascience contends that the 083 Patent was anticipated by the prior disclosure of the 493 Patent in which one could find all the information which, for practical purposes, is needed to produce valacyclovir and to appreciate its bioavailability advantage. Pharmascience also argues that the inventive selection of valacyclovir was obvious and that GSK’s attempt to repatent a compound it had already monopolized constitutes double patenting or, as it is sometimes colloquially termed, “evergreening.”
[26] The legal tests for anticipation and obviousness are well-known in patent law. Suffice it to say that neither test is easily satisfied.
[27] A frequent expression of the test for anticipation can be found in the following passage from Beloit Canada Ltd. et al. v. Valmet Oy, (1986) 8 C.P.R. (3d) 289, 64 N.R. 287 (F.C.A.):
It will be recalled that anticipation, or lack of novelty, asserts that the invention has been made known to the public prior to the relevant time. The inquiry is directed to the very invention in suit and not, as in the case of obviousness, to the state of the art and to common general knowledge. Also, as appears from the passage of the statute quoted above, anticipation must be found in a specific patent or other published document; it is not enough to pick bits and pieces from a variety of prior publications and to meld them together so as to come up with the claimed invention. 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. Where, as here, the invention consists of a combination of several known elements, any publication which does not teach the combination of all the elements claimed cannot possibly be anticipatory.
[28] A useful summary of the law dealing with obviousness can be found in the following passage from Janssen-Ortho Inc. v. Novopharm Ltd., 2007 FCA 217, 59 C.P.R. (4th) 116:
23 The accepted legal test for obviousness is stated as follows in the leading case of Beloit Canada Ltd. et al. v. Valmet OY (1986), 8 C.P.R. (3d) 289 (F.C.A.) at page 294, per Hugessen J.A.:
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.
24 The inquiry mandated by the Beloit test is factual and functional, and must be guided by expert evidence about the relevant skills of the hypothetical person of ordinary skill in the art, and the state of the art at the relevant time. The expert evidence must be carefully assessed as to its credibility and reliability. The classic warning from Beloit about hindsight must always be borne in mind (at page 295, per Hugessen J.A.):
Every invention is obvious after it has been made, and to no one more so than an expert in the field. Where the expert has been hired for the purpose of testifying, his infallible hindsight is even more suspect. It is so easy, once the teaching of a patent is known, to say, "I could have done that"; before the assertion can be given any weight, one must have a satisfactory answer to the question, "Why didn't you?"
25 There is no single factual question or a set of questions that will determine every case, or any particular case. Justice Hughes, at paragraph 113 of his reasons, proposes a list of factors to be considered when the validity of patent is challenged on the basis of obviousness. The list is apparently derived from a survey of numerous cases from Canada, the United States and the United Kingdom. In my view, despite the continual debate as to whether the legal test for obviousness is the same in all of those countries, the list of factors proposed by Justice Hughes is helpful to guide the required factual inquiry, and as a framework for the factual analysis that must be undertaken. What follows is an edited version of his list:
Principal factors
1. The invention
What is in issue is the patent claim as construed by the Court.
2. The hypothetical skilled person referred to in the Beloit quotation
It is necessary to identify the skills possessed by the hypothetical person of ordinary skill in the art.
3. The body of knowledge of the person of ordinary skill in the art
The common knowledge of the hypothetical person of ordinary skill in the art includes what the person may reasonably be expected to know and to be able to find out. The hypothetical skilled person is assumed to be reasonably diligent in keeping up with advances in the field to which the patent relates (Whirlpool at paragraph 74). The presumed knowledge of the hypothetical skilled person undergoes continuous evolution and growth. Not all knowledge is found in print form. On the other hand, not all knowledge that has been written down becomes part of the knowledge that a person of ordinary skill in the art is expected to know or find.
4. The climate in the relevant field at the time the alleged invention was made
The general state of the art includes not only knowledge and information but also attitudes, trends, prejudices and expectations.
5. The motivation in existence at the time the
alleged invention to solve a recognized problem
"Motivation" in this context may mean the reason why the claimed inventor made the claimed invention, or it may mean the reason why one might reasonably expect the hypothetical person of ordinary skill in the art to combine elements of the prior art to come up with the claimed invention. If within the relevant field there is a specific problem that everyone in the field is trying to solve (a general motivation), it may be more likely that the solution, once found, required inventive ingenuity. On the other hand, if there is a problem that only the claimed inventor is trying to solve (a unique or personal motivation), and no one else has a reason to address that problem, it may be more likely that the solution required inventive ingenuity. However, if commonplace thought and techniques can come up with a solution, there may be a reduced possibility that the solution required inventive ingenuity.
6. The time and effort involved in the invention
The length of time and expense involved in the invention may be indicators of inventive ingenuity, but they are not determinative because an invention may be the result of a lucky hit, or the uninventive application of routine techniques, however time consuming and expensive they may be. If the decisions made in arriving at the solution are few and commonplace, that may indicate that no inventive ingenuity was required to arrive at the solution. If the points for decision were many and choices abundant, there may be inventiveness in making the proper decisions and choices.
Secondary factors
These factors may be relevant but generally bear less weight because they relate to facts arising after the date of the alleged invention.
7. Commercial success
Was the subject of the invention quickly and anxiously received by relevant consumers? This may reflect a fact that many persons were motivated to fill the commercial market, which may suggest inventive ingenuity. However, it may also reflect things other than inventive ingenuity such as marketing skills, market power and features other than the invention.
8. Meritorious awards
Awards directed to the alleged invention may be recognition that the appropriate community of persons skilled in the art believed that activity to be something of merit. That may or may not say anything about inventive ingenuity.
[…]
27 I emphasize that this list is a useful tool, but no more. It is not a list of legal rules to be slavishly followed; nor is it an exhaustive list of the relevant factors. The task of the trial judge in each case is to determine, on the basis of the evidence, sound judgment and reason, the weight (if any) to be given to the listed factors and any additional factors that may be presented.
28 I would also repeat the caution of Justice Hughes that catchphrases derived from this list or from the jurisprudence are not to be treated as though they are rules of law. I agree with the following comment of Justice Hughes from paragraph 113 of his reasons:
In this regard phrases such as "worth a try" and "directly and without difficulty" and "routine testing" have been used by the courts. It is not useful to use such phrases as they tend to work their way into expressions of law or statements of expert witnesses. Sachs L.J. deprecated the coining of such phrases in General Tire & Rubber Company v. Firestone Tyre & Rubber Company Limited, [1972] R.P.C. 195 at pages 211-12.
[29] I have carefully reviewed the 493 Patent and I accept that it does not anticipate the selection of valacyclovir as a medicine that would have improved oral bioavailability.
[30] The 493 Patent taught the use of various esters of acyclovir as prodrugs[2] for achieving improved solubility for use principally in small volume aqueous formulations. Overcoming the solubility problems of acyclovir in such uses was the clear focus of the inventor’s work and the solution taught by the 493 Patent.
[31] On this issue, I accept the following interpretation of the 493 Patent offered by Dr. Borchardt which seems to me to be consistent with the overall position of the scientific evidence:
The strategy employed in EPA '493 to increase the aqueous solubility of acyclovir is identical to the strategy that other medicinal chemists were employing in the 1980s to increase the solubility of other water-insoluble drugs, including metronidazole (Bundgaard et. al., 1984 (NOA, Appendix A, Document 34); Bundgaard et. al., 1984 (NOA, Appendix A, Document 35); Cho and Haynes, 1985), corticosteroids (Kawamura et. al., 1971; Anderson et. al., 1985; Johnson et. al., 1985 (NOA, Appendix A, Document 50)), and paracetamol (Kovach et. al., 1981 (NOA, Appendix A, Document 23)). All of this work was focused on the potential use of esters in topical or injectable formulations, e.g., formulations for delivery by a route other than in or through the digestive system. Improving the aqueous solubility of acyclovir, as with these other water-insoluble drugs, in order to make aqueous formulations to inject or use as eye drops is vastly different from improving oral bioavailability of a drug.
This interpretation was also borne out by Dr. Borchardt’s cross-examination testimony in the following passage:
Q. But insofar as the modes of absorption that you’ve described here, when you’re applying a topical treatment, would the same principles apply here that we see here in 84, some would go by way of transcellular diffusion, paracellular diffusion? Would that apply to the eye and the skin?
A. Again, there are significant differences between these barriers in terms of, for example, the number of layers of cells, the lipid composition of those cells, the metabolic capability of those cells, the junctions, tight junctions associated with those cells.
Q. Perhaps you can answer the question. I take it that when we look at applying a topical treatment that we would have the same issues that we see here in paragraph 84. We’re going to have paracellular division, we’re going to have fatty layers and water channels, correct?
A. Again, I think there are very significant differences and one cannot generalize about the barrier properties of intestinal mucosa versus the skin.
[32] While I accept that the 493 Patent also recognizes the use of the esters of acyclovir for oral use, there is nothing else to indicate to a person skilled in the art that those compounds would have improved oral bioavailability over acyclovir. To apply the current legal test, I do not accept that the 493 Patent contains 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 promise of improved oral bioavailability made by the 083 Patent.
[33] Although they alleged it in their NOA, Pharmascience did not spend much time asserting that the Canada Patent No. 1,258,149 (the 149 Patent) was anticipatory or that it was relevant prior art. The 149 patent claimed a very broad class of compounds, but was not directed at prodrugs, let alone amino acid esters of acyclovir. While a person skilled in the art might, by chance, find valacyclovir among the thousands of compounds included in the 149 Patent genus, that patent offered nothing to such a reader about the prospects for improved oral bioavailability of valacyclovir. Needless to say, having come to the conclusion that the 493 Patent did not anticipate the claimed advantage of the 083 Patent, it follows that the 149 Patent does not assist Pharmascience. On this point, I agree with the evidence of Dr. Borchardt found at paras. 158 to 165 of his affidavit that the 149 patent did not disclose the subject matter of the 083 patent.
[34] With respect to the issue of obviousness, the parties have adopted positions at opposite edges of interpretation of the prior art. Pharmascience says, as it must, that the prior art and common general knowledge would easily lead the person skilled in the art to the solution taught by the 083 Patent, that is, that valacyclovir would have improved oral bioavailability over the two other esters of acyclovir tested. GSK maintains the opposite view that the prior art and common general knowledge not only made the oral bioavailability benefits of valacyclovir unpredictable but actually taught away from such a prediction. As with many cases of this kind, the truth seems to me to lie somewhere between these positions.
[35] The circumstances of this case are complicated somewhat by the fact that current scientific knowledge bearing on the issue of the oral bioavailability of valacyclovir disproves much of what was believed in the 1980s. In 1987, it was believed that the permeability of such molecules was dependant entirely upon passive transcellular and paracellular transport (i.e. diffusion through or between cells). However, it is now understood that the valacyclovir and a number of other drugs are actively transported through the cellular membrane of the intestine and do not rely upon passive transport. This change in scientific understanding placed all of the expert witnesses in the somewhat difficult position of describing the belief of a notional person skilled in the art who was later proven to be wrong. Needless to say, this current knowledge had the potential to permeate or colour the expert testimony from all of the witnesses and to some extent it did.
[36] GSK argues that it would not have been obvious to a person skilled in the art to look at the amino acid esters of acyclovir to overcome the oral bioavailability limitations of acyclovir. It makes this assertion based on its characterization of those compounds as being known to be poor candidates for passive transport across the intestinal wall. GSK says that no one would be motivated to examine these compounds as the means of overcoming the poor absorption of acyclovir.
[37] The evidence before me indicates, however, that there were some good reasons for GSK to look at the potential of valacyclovir and the other esters of acyclovir for improving the oral bioavailability of acyclovir. For instance