Tuesday, November 17, 2015

Can a Compound Claim Be Supported by an Inventive Process?

Amgen Canada Inc v Apotex Inc (NOC) 2015 FC 1261 Hughes J
            1,341,537 / filgrastim / NEUPOGEN

In Amgen / filgrastim Hughes J held Claim 43 of the Amgen’s ‘537 patent to be invalid for obviousness, though it survived novelty and utility attacks. This post focuses on Hughes J’s obviousness analysis, which seems to me difficult to reconcile with Sanofi 2008 SCC 61.

Human granulocyte colony-stimulating factor (G-CSF) stimulates the growth of white blood cells. Naturally occurring G-CSF was first isolated and purified in small quantities by Welte and others at Sloan-Kettering Institute [16]. However, Welte had not determined any of the amino acid sequence [18]. If the DNA sequence of the naturally G-CSF could be determined with sufficient precision, G-CSF could be produced in commercial quantifies by recombinant DNA technology. Amgen was ultimately successful in doing so, leading to the invention of filgrastim, sold by Amgen as NEUPOGEN, which is used to boost the production of white blood cells and therefore help prevent infection in people whose immune system is compromised as a result of chemotherapy.

Monday, November 16, 2015

I G Farbenindustrie Strikes Again

Amgen Canada Inc v Mylan Pharmaceuticals ULC 2015 FC 1244 Phelan J
            2,202,879 / cinacalcet / SENSIPAR

In Amgen / cinacalcet Phelan J held the ‘879 patent invalid over the 2,115,828 patent (which shares most of the same inventors). While this conclusion is clearly correct on the facts as found by Phelan J, there were some difficulties along the way which illustrate that the law of selection patents in Canada remains in need of clarification – or, preferably, as I have suggested in a previous post, the concept should be abandoned entirely.

The facts are reasonably straightforward. The parathyroid gland regulates calcium levels in the body through the secretion of parathyroid hormone [6]. At one time it was thought that parathyroid cells respond to calcium through a “calcium channel.” The inventors discovered that the true mechanism was a calcium-sensing receptor. This was a real breakthrough [15]. It lead to the realization that compounds that mimic the effect of calcium at the parathyroid calcium receptor could be effective in treating diseases related to poor calcium regulation [8]. Accordingly, the ‘828 patent claimed a large genus of such compounds [25].

Claim 5 of the subsequent ‘879 patent claims cinacalcet, which falls within the claims of the ‘828 patent. On the evidence, cinacalcet had no particular advantage over any of the other compounds disclosed and claimed by the ‘828 patent [70]. The patentees had initially pursued a different compound, which was specifically disclosed in the ‘828 patent [69], but when that turned out to have toxicity problems, they picked another, namely cinacalcet, with comparable properties [70]. The patentees had no particular reason to believe cinacalcet had any special properties as compared with the other compounds of the genus, as it had not even been synthesized as of the claim date of the ‘879 patent [71].

Saturday, November 14, 2015

Data Protection Regulations Apply to Post-NDS Supplementary Information

Hospira Healthcare Corporation v Canada (Health) and Sanofi-Aventis Canada Inc 2015 FC 1205, 2015 FC 1206 Gagné J
            2,196,922 / oxaliplatin / ELOXATIN

The main decision in these companion cases is the 1205 decision, in which Gagné J held that the data protection provisions of the Food and Drug Regulations (C.08.004.1) apply to supplementary submissions made after the filing of an NDS. In my view this holding was clearly correct, though the unusual facts may illustrate some problems with other aspects of Canada’s drug approval regime.

Oxaliplatin has long been a “standard of care” drug in the treatment of colorectal cancer. Oxaliplatin was discovered in Japan and subsequently licensed to and acquired by Sanofi [14].* However, until 2006 Sanofi did not seek an NOC for its oxaliplatin product, ELOXATIN, which had been sold in Canada since 1999, but only under the Special Access Program [14]. From 2004 to 2006, Hospira sought to file an NDS for its OXALIPLATIN FOR INJECTION product. However, Hospira did not have clinical trial data, and because by that time oxaliplatin was internationally recognized as the most therapeutically effective treatment for colorectal cancer, clinical trials could not ethically be performed. Nor could it file an ANDS referencing Sanofi’s product, because Sanofi had not yet obtained an NOC for sale in Canada. Consequently, in late 2006 Hospira filed its NDS without any clinical data, but only literature references and reports of post-marketing experience.

After various exchanges and litigation, Hospira’s NDS was rejected in 2012 because the literature references were not sufficiently robust to establish the clinical safety and efficacy required under C.08.002(2)(g), (h) [31]. Meanwhile, in the fall of 2006, within a month Hospira’s submission, Sanofi also filed an NDS which did include clinical trial data [18]. Sanofi’s submission was given priority status and an NOC was issued for ELOXATIN in 2007 [18], [21]. Hospira responded to the 2012 Notice of Noncompliance with new information, including, ultimately, the ELOXATIN Product Monograph [33], [34]. While this was enough to satisfy the safety and efficacy requirements, Hospira was then informed that because Hospira had made comparisons in its submission to ELOXATIN which was listed on the Register of Innovative Drugs by 2012 (though not in 2006), the data protection provisions Food and Drug Regulations (C.08.004.1) applied and the NOC for OXALIPLATIN FOR INJECTION would not be issued until the expiry of the term of market exclusivity for ELOXATIN [40].

It was uncontested that Hospira had indeed made comparisons in its submission to ELOXATIN [75], but Hospira argued that the data protection provisions, in particular C.08.004.1(3) do not apply to post-filing amendments made pursuant to subsection C.08.004(2), which permits the manufacturer to file additional information. The basic argument was textual: C.08.004.1(3) provides that data protection is invoked if a manufacturer “seeks a notice of compliance” for a new drug on the basis of a direct or indirect comparison with an innovative drug, and para (a) provides it cannot “file a new drug submission” until the data protection period expires. Since Hospira did not originally “seek” its NOC on the basis of a comparison, it was not barred from submitting its NDS and so, argued Hospira, the Minister could not refuse to issue the NOC under para (b), even though the approval would ultimately have been granted on the basis of such a comparison [65], [75].

Gagné J applied the standard approach to statutory interpretation, which requires consideration of the text, context and purpose surrounding the provisions at issue [77]. She noted that the purpose of the data protection provisions is in part to prevent unfair use of undisclosed clinical or other data generated by an innovative manufacturer to support its drug submission [73], [83]. This purpose clearly supports the view that the data protection provisions should apply to supplementary information, and the text was not sufficiently clear to override this purposive analysis, particularly when read in context [79], [83].

Because of the unusual facts, Hospira was in a difficult position, and it does seem problematic that Sanofi enjoyed a de facto market exclusivity under the SAP program from 1999 to 2007, and then obtained an additional 8.5 years of data protection starting from 2007 when its NOC was issued (though I’m not familiar with the background, so perhaps there is some good reason for this). But as a matter of statutory interpretation and the policy underlying the NOC Regulations, Gagné J’s holding is certainly correct.

Note that Gagné J also re-affirmed that the applicable standard of the Minister’s interpretgation of the data protection provisions is correctness [49], relying primarily on Takeda Canada 2013 FCA 13 [26]-[30], and also Pfizer Canada 2014 FC 1243 [57]-[104].

The sister decision 2015 FC 1206 concerned Hosipra’s difficulties with the PM(NOC) Regulations. Injectable oxaliplatin was also covered by the ‘922 patent, and the Minister had required Hospira to address that patent before an SNDS for Hospira’s ready-to-use injectable oxaliplatin solution would be considered [12]. Gagné J held that the refusal was moot issue, as the patent has expired and in any event the Mininster is prevented from issuing the NOC due to the data protection provisions, as discussed above.

*While not specified in the 1205 decision, when Gagné J stated that Sanofi “acquired” oxaliplatin, presumably she meant it acquired the ‘922 patent.

Friday, November 13, 2015

Authorized Generics Are Subject to PMPRB After All

Canada (Attorney General) v Sandoz Canada Inc 2015 FCA 249 Noël CJ: Pelletier, Rennie JJA rev’g 2014 FC 501, 2014 FC 502 O’Reilly J partially aff’g PMPRB-10-D2, PMPRB-08-D3

In this decision the FCA has held that authorized generics fall within the jurisdiction of the Patented Medicine Prices Review Board, reversing O’Reilly J’s decision (blogged here). The FCA also reaffirmed the constitutionality of the provisions of the Patent Act setting up the PMPRB and giving it the authority to regulation prices of patented medicines, affirming O’Reilly J on this point. While the FCA’s ultimate holding is important, the argument turned on points specific to the relevant statutory provisions.

Two appeals were heard together. In the first case, ratiopharm sold an anti-asthmatic medicine called ratio-salbutamol HFA, which is the generic equivalent of the Ventolin HFA, a patented medicine manufactured and sold in Canada by GlaxoSmithKline (GSK). GSK sold ratio HFA to ratiopharm and granted ratiopharm an exclusive licence to set the price and sell ratio HFA in Canada without any right to sub-licence [6]. The second case involved Sandoz, a wholly owned subsidiary of Novartis. Sandoz sold medicines covered by patents owned by Novartis, which allowed Sandoz to sell the generic version and to refer to those medicines in obtaining the required NOCs. There was, however, no express licensing agreement [9].

The Board requested information from both ratiopharm and Sandoz pursuant to ss 80, 81 and 88 of the Act, which require a “patentee” to provide pricing information. The Board also held that ratiopharm had sold ratio HFA at excessive prices, contrary to s 83 of the Act which applies to a “patentee.” Sandoz and ratiopharm appealed the Board decisions, primarily on the basis that they were not “patentees” within the meaning of the provisions. The constitutionality of the provisions was also challenged, as trenching on provincial jurisdiction over property and civil rights, and Sandoz also argued that the Board erred in finding that it had an implied licence.

The main question turned on the definition of “patentee” in s 79(1), which applies to the relevant sections (my emphasis):

“patentee”, in respect of an invention pertaining to a medicine, means the person for the time being entitled to the benefit of the patent for that invention and includes, where any other person is entitled to exercise any rights in relation to that patent other than under a licence continued by subsection 11(1) of the Patent Act Amendment Act, 1992, that other person in respect of those rights;

The Board noted that the definition does not on its face require ownership, and in light of the purpose of the provisions, which is to protect consumers from unreasonable pricing, the definition should be interpreted to include licensees. Applying a deferential standard of review of the Board’s interpretation of its home statute [63], the FCA upheld as reasonable both the Board's understanding of the purpose of the provisions [67], and its determination that both ratiopharm and Sandoz, as licensees, were "patentees" within the meaning of s 79(1) [91]. The FCA also re-affirmed the constitutionality of the relevant provisions, essentially on the basis of well-established precedent [116], and affirmed the Board’s finding that Sandoz was an implied licensee as being a factual determination which was supported by evidence and therefore entitled to deference [108].

In the result, it is clear that authorized generics will fall under the jurisdiction of the Board. However, neither the Board nor the FCA provided an explicit definition of the scope of the provision. The Board’s key reasoning in ratiopharm [08-D3, 42] is as follows:

The Agreements gave ratiopharm the exclusive right to set the price of and to sell ratio HFA and to obtain the necessary regulatory approvals to do so. Absent the licence granted, these acts would have violated rights held exclusively by GSK pursuant to section 42 of the Act.

In Sandoz, after reviewing the facts, the Board concluded [10-D2, 57], that “Sandoz is a patentee, within the meaning of subsection 79(1) of the Act, of any patent owned directly or indirectly by Novartis AG, where that patent is for an invention pertaining to a medicine that Sandoz is authorized by its parents to sell in Canada.” The FCA concluded that the Board correctly held that including persons "who exercise selling rights under a patent" is within the ambit of subsection 79(1) [122]. The FCA also made it clear that in order to be a licensee it is not necessary that a party’s products would actually infringe the patent but for the licence; it is enough that a licence agreement exists which would protect the party if infringement were alleged [103]. 

The parties raised a variety of arguments as to why a narrower interpretation was warranted. I will not review these arguments in detail, as most were not particularly powerful, in my view. The most interesting was that the Board's definition would capture wholesalers, retailers and pharmacies [79]. This argument was rejected by the Board, on the basis that “subsection 79(1) only captures persons who sell to consumer classes protected by the Board, and wholesalers, hospitals and pharmacies do not come within that class.”* The FCA affirmed this point as well, saying "The fact that the respondents operate under a licence to sell the patented medicine whereas wholesalers, retailers and pharmacies derive their right qua owners of the products which they purchase for re-sale provides a principled basis for the distinct treatment" [79].

Thus even though a patent confers an exclusive right to make, sell and use the invention (s 42), the "benefit of the patent" in s 79(1) encompasses only a restricted subset of those rights, namely the right to sell to persons selling to consumer classes protected by the Board. It does not encompass the right to use, or even the right to sell to the public generally. This is certainly an awkward distinction to draw on the basis of the text of the provision, as "benefit" is prima facie a broad term, as the Board emphasized. I am not really persuaded by the FCA's reasoning that there is a principled distinction between a licensee and a party having rights as an owner of the tangible embodiment of the patented invention, as ownership of the tangible embodiment does not in itself give any rights under the patent, unless by express licence, implied licence or exhaustion. With that said, the distinction is sound on a purposive interpretation of the provision, and given that a purposive analysis informs and can even dominate the textual analysis (Canada Trustco 2005 SCC 54 [10]), I do agree that the distinction is sound. This is a case in which text itself is not ideally drafted, but the interpretation given by the Board and FCA best accords with the purpose of the provision. 

I must say that I am very skeptical of the basic mandate of the PMPRB, which strikes me as antithetical to the purpose of the patent system. But the legislature was evidently of a different view, as the provisions setting up the Board are in the Patent Act itself. And if we accept that policy decision, as we must (at least for the purposes of statutory interpretation), it seems to me that the FCA decision is clearly correct. 

* The FCA cited the Board’s decision [08-D3, 15, 16] as stating that [21], but the cited paragraphs are not to that effect, and while that position is certainly consistent with the Board’s reasoning, I was unable to find any express statement to that effect in the Board decision.

Friday, November 6, 2015

Inventorship Not Material for Purposes of S 53

Gilead Sciences, Inc v Idenix Pharmaceuticals, Inc 2015 FC 1156 Annis J
            2,490,191 2,527,657 / sofosbuvir / SOVALDI

Previous posts have discussed Gildead’s utility and sufficiency attacks on Idenix’ 191 patent. This post deals primarily with Idenix’ s 53 attack on Gilead’s 657 patent. Section 53 provides that a patent is void if “any material allegation” in the application is untrue and wilfully misleading. Annis J’s decision adds to the growing body of case law holding that an error in inventorship is not a “material” allegation giving rise to invalidity under s 53. While we are still not at the point of a per se rule that errors in inventorship can never be material, we are getting close.

Idenix argued that the ‘657 Patent was invalid under s 53 for knowingly omitting naming Dr Lieven Stuyver as inventor [877]. The first question was whether he was an inventor at all. The argument failed on the facts on this point, as Annis J held that it had not been established that Dr Stuyver contributed to the inventive concept [904], [916]. 

Annis J nonetheless went on to consider whether the omission would have been material if Dr Stuyver had been an inventor. He noted that “a fair reading of Corlac [blogged here] indicates that the Court very much minimized the impact of improperly omitting a co-inventor on the determination of materiality in section 53(1)” [919] He also pointed out that the FCA in both Corlac and in Wellcome /AZT [2001] 1 FC 495, had noted that it would illogical to hold a patent invalid for failure to name an inventor, because that would deprive that inventor of any effective remedy [921], [922]. Annis J summarized the FC and FCA decisions in Corlac as being to the effect that failure to name an inventor will only be material for the purposes of s 53 if that failure affects “the term, substance or ownership of the ‘657 Patent, or the public’s ability to use the invention” [923] (and there was no such detriment in this case). That is, there must be some detriment to the public to warrant invalidating the patent. That strikes me as a sound view of this provision.

Thursday, November 5, 2015

"Retrosynthetic Analysis" Fails to Establish Sufficiency

Gilead Sciences, Inc v Idenix Pharmaceuticals, Inc 2015 FC 1156 Annis J
            2,490,191 2,527,657 / sofosbuvir / SOVALDI

Yesterday’s post provided an overview of the facts in Gildead v Idenix and dealt with Gilead’s successful utility attack on Idenix’ 191 patent. Today’s post deals with Gilead’s sufficiency attack, which was also successful.

Recall that as of the filing date Idenix had not made any of the 2’-C-Me/F compounds which it claimed, and the disclosure dealt primarily with 2’-C-Me/OH compounds, which had been synthesized. Consequently, Gildead argued straightforwardly that the disclosure was not sufficient to allow a skilled person to make any of the compounds falling within the claims [413]. This is a classic "how to make" attack, which was perhaps the most common reason for invalidating a patent in the early days of UK patent law, but which we don’t often see anymore. As with utility, the result turned on the facts. This case does provide a good illustration of the point that making the invention may be insufficient as requiring “undue experimentation” even if the effort exercised by the skilled person does not rise to the level of invention. Annis J’s restrained interpretation of the SCC’s Viagra 2012 SCC 60 decision is also of interest, as are his comments on the proper approach to experiments intended to simulate the efforts of a skilled person.

Gilead v Idenix Table of Contents

Gilead Sciences, Inc v Idenix Pharmaceuticals, Inc 2015 FC 1156 Annis J
            2,490,191 2,527,657 / sofosbuvir / SOVALDI

Gilead v Idenix does not contain the Table of Contents which was recently been a welcome feature in longer FC decisions. I have compiled one which is available here (though it is not hyperlinked to the decision itself).

Wednesday, November 4, 2015

Gilead v Idenix: Overview and Utility

Gilead Sciences, Inc v Idenix Pharmaceuticals, Inc 2015 FC 1156 Annis J
            2,490,191 2,527,657 / sofosbuvir / SOVALDI

In his first outing as a judge in a patent case, Annis J has delivered a decision of Arnoldian proportions (outstripping Arnold J’s own effort in the parallel UK case by 313 paragraphs). The case turned largely on the facts, with the bulk of the decision taken up with a meticulous review of the evidence on each point. The decision is primarily concerned with Gilead’s attack on the validity of Idenix’ 191 patent, which was held to be invalid for lack of utility and insufficiency (though Annis J did hold the 191 patent would have been infringed by Gilead’s product SOVALDI (sofosbuvir) had it been valid). Idenix’ counter-claim challenging Gilead’s 657 patent for lack of novelty and wilful misleading was dismissed. This post provides background and discusses the utility attack on the 191 patent. Legally the most interesting point is that Annis J followed Rennie J’s holding in Apotex / esomeprazole 2014 FC 638 (blogged here), that the requirement to disclose the basis for a sound prediction in the patent itself applies only to claims for a new use, and not to compound claims.

In the early 2000s both Idenix and Pharmasset (which was subsequently bought by Gilead), were working on nucleosides for the treatment of the Hepatitis C virus. Idenix discovered that some known nucleoside analogues with a 2’-C-Me/OH structure had activity in in vitro assays against the HCV class of viruses [27]. In 2002 and 2003 Idenix filed the US applications which were the priority documents for Idenix’s 191 patent [18]-[21]. Despite having only synthesized and tested compounds with a 2’-C-Me/OH structure, Idenix’ application also claimed compounds with a 2’-C-Me/F structure. CIPO objected to the application for lack of unity of invention, with the examiner having identified 15 different genera encompassed by the 23 “Forumlas” identified in the application. Indenix responded by narrowing the scope to the class of “Formula IX” compounds, claiming the 2’-C-Me/F genus. However, the disclosure was not amended [22]-[24]. (Presumably these compounds were selected because by that point – 2009 – it was apparent that the flouro compounds had the most promise.) The application was then granted as the 191 patent. The important point to take form this history is that none of the compounds claimed by the 191 patent had even been synthesized, much less tested, by Indenix as of the priority date, and they were barely discussed in the disclosure. Idenix started trying to synthesize the 2’-C-Me/F nucleosides in early 2002, but did not clearly succeed until March of 2005.

In the meantime, Pharmasset, having spotted an apparent gap in an earlier Idenix application, also set about synthesizing a 2’-C-Me/F nucleoside in early 2003 and succeeded a few months later (in May 2003) [42]-[43]. In the same month, Pharmasset filed the US application which ultimately matured to the 657 patent (now owned by Gilead after its acquisition of Pharmasset). Gilead subsequently commercialized SOVALDI, which is covered by the 657 patent. Anticipating an infringement action by Idenix based on the 191 patent, Gilead sought a declaration under s 60(1) that the 191 patent was invalid on the basis of lack of utility, overbreadth and insufficiency. Idenix counterclaimed for infringement and for a declaration that Gilead’s 657 patent is invalid.

Utility of the 191 Patent
It was common ground that utility of the patent had not been demonstrated as Idenix admitted that it did not test any compound falling within the scope of the claims of the ‘191 Patent until March 2005. Idenix therefore relied on sound prediction [221].

Annis J began the utility analysis by noting if the patent contains a promise, utility will be measured against that promise, though he noted that such a promise must be clear and unambiguous [227]. I must admit, though, that it is not entirely clear to me what standard for utility was actually applied. The parties agreed that the 191 patent contained a promise that the compounds “are useful” in the treatment HCV infections, in humans and other hosts [231], and this is evidently higher than the minimum scintilla necessary to establish utility in the absence of a promise (potential use against HCV would likely suffice). Annis J also held that the patent promised a satisfactory therapeutic index [238], and effectiveness in combination with low toxicity [240]. All of this suggests that utility was assessed against a standard which is higher than the minimum which would otherwise be necessary. But Annis J then stated explicitly that “the ‘191 Patent makes no promise of any specific result or level of treatment,” and “Gilead must therefore, prove that Idenix has not demonstrated or soundly predicted a scintilla of utility” [241].

In any event, this point was moot because Annis J concluded on the facts that there was no basis for a sound prediction of any antiviral activity in a 2’-C-Me/F nucleoside prior to its synthesis [255]; the patent would therefore lack utility whether the standard for utility was a mere scintilla or something higher.

The key question on the facts is whether the activity of the 2’-C-Me/F compounds could be predicted from the known activity of the 2’-C-Me/OH compounds [253]. The evidence was “overwhelming” that the answer was no, largely because the 2’ down position was recognized as a highly conserved and selective position, and fluoride is an unpredictable substituent particularly regarding potential toxicity [284], [376]. This case illustrates that the fact that a particular candidate compound is worth trying does not amount to a sound prediction of success [319].

More interesting in terms of the development of the law is that Annis J, following Rennie J’s holding in Apotex / esomeprazole 2014 FC 638 (blogged here), held that the requirement to disclose the factual basis and line of reasoning for sound prediction in the patent itself applies only to “new use” inventions [378]-[381]. Because the claim in the ‘191 patent was to a compound, the heightened disclosure requirement did not apply [380]. (Annis J went on to hold that if he was wrong, and there was such a requirement, the disclosure in the 191 patent was not adequate to support a sound prediction of utility [412].) The holding that there was no such disclosure requirement was strictly obiter (as was Rennie J’s), as Annis J had already determined there was no factual basis at all, disclosed or not. Nonetheless, while Annis J’s discussion was brief, he did not adopt Rennie J’s position out of comity, but because he agreed with the reasoning [380]. This adds to the weight of authority, though the point will ultimately have to be decided by the FCA.

Sunday, November 1, 2015

FC Has Authority to Vary Ownership When Uncontested

Imperial Oil Resources Ltd v Canada (Attorney General) Exxonmobil Upstream, 2015 FC 1218 LeBlanc J

This was an uncontested application by Inperial Oil and Exxonmobil Upstream, as listed co-owners of the ‘481 patent, to amend inventorship and ownership. The application for the patent listed11 inventors. During prosecution, the scope of the claimed subject-matter was restricted, and only three of the 11 inventors contributed to the elected subset of claims and in consequence of the change in inventorship, Upstream should not have been listed as owner. The patent was issued without the proper modifications. This was all uncontested, and the only question was whether the court had jurisdiction to order the amendment pursuant to s 52. The application was not opposed by the Commissioner.

LeBlanc J noted that “This Court has interpreted the word ‘title’ in section 52 of the Act broadly to include ‘matters relating to the root of title’ such as inventorship” [12] and consequently the court had jurisdiction to amend the inventorship. On the issue of ownership, LeBlanc J noted that while the court does not have jurisdiction under section 52 of the Act to determine ownership of patents, as this would require the application and interpretation of the provincial law on contracts, in this case there was no substantive issue as to ownership, and therefore the Court had jurisdiction to vary the ownership of the ‘481 Patent as a consequence of correcting inventorship [18].