Innovator drug companies have been actively wooing generic drug-makers, to have a foot in the innovative and generic segments of the pharmaceutical landscape.

Hailed as the “hybrid model”, this strategy though, may not quite be the right way forward for the long term, observes Mr Murray Aitken, Senior Vice-President with IMS Health, a leading provider of market intelligence
to pharmaceutical and healthcare companies.

The hybrid model may be attractive today, he said, given that drug companies are faced with pricing and  regulatory pressures across different world markets. But it may not be good for the long term, Mr Aitken told Business Line, giving details from an IMS study that reveals an increased pick-up in branded innovative products after 2015 – as the “patent cliff” (where drugs go off-patent) is passed and research pipeline matures.

Off-patent loss-

Company heads will have to “manage” their hybrid models against the backdrop of the optimism that the market reveals in terms of innovative products driving growth, said Mr Sameer Savkur, IMS Managing Director, in India.

Generic medicines are not covered by patents, while innovative drugs enjoy patent-protection, or market exclusivity for 20 years. The next five years will see $ 94 billion impact from the loss of exclusivity, and a $ 89 billion impact from new launches. The next five years will see reduced impact of $ 66 billion due to loss of exclusivity, and an increase of $ 271 billion from the new products launched in the previous five years, the study said.

In the Indian market, the hybrid model is illustrated by Japanese innovative drug-maker Daiichi Sankyo's acquisition of generic drug company Ranbaxy or the more recent acquisition of Piramal Healthcare's domestic  formulations business by Abbott.

Optimistic-

Giving a “more optimistic than expected” outlook – the IMS study projects that the pharmaceutical industry is headed to clock $ 1 trillion in 2020, on the back of a renewed pipeline and growth in the pharma-emerging markets, among other things. The study also shows a healthy pipeline of products across 41 focus categories including oncology, diabetes and HIV, a contrast to the gloomy picture that industry often paints.

The Indian patent office yanked Pfizer's patent on the kidney cancer drug Sutent. The move was a victory for  local drugmakers Cipla and Natco Pharma, which legally protested Sutent's patent protection.

Pfizer plans to appeal the decision. But in doing so, it will join two of its Big Pharma brethren who've so far been unsuccessful. Bayer fought back when India forced it to license its cancer drug Nexavar to Natco, allowing the domestic drugmaker to launch a much cheaper copy. It was the Indian government's first compulsory license, allowed in certain circumstances under World Trade Organization rules.

And Novartis has been fighting for patent protection for its cancer fighter Glivec for years. The case wended its way to the country's Supreme Court.

A recent Federal Court decision highlighted the differences in prohibition proceedings under the Patented Medicines (Notice of Compliance) Regulations (the NOC Regulations) and impeachment actions under the Patent Act. It is yet another example of how every case is to be determined on the specific evidence adduced before the Court.

In Eli Lilly Canada Inc. v. Apotex Inc, the Court dismissed Eli Lilly's application under the NOC Regulations for an order prohibiting the Minister of Health (the Minister) from issuing a notice of compliance (NOC) to Apotex in respect of the medicine atomoxetine until after the expiry of the '735 Patent. However, the dismissal was based on mootness alone, as the Court would have allowed the application had it not invalidated the '735 Patent entirely in a related impeachment action brought by Novopharm. 
 
Proceedings under the NOC Regulations vs.  Actions under the Patent Act

In Canada, in order for a generic manufacturer to get approval to market a generic version of an existing drug product, it must file an abbreviated new drug submission (ANDS) with Health Canada demonstrating that
its product is bioequivalent to the innovator's previously approved drug product. If the Minister of Health (the Minister) is satisfied with the submission, she must issue a NOC allowing the generic drug to be marketed, but
only if the generic manufacturer has first "jumped the hurdles" of the NOC Regulations. 
 
In particular, the Minister is prohibited from issuing a NOC to a generic manufacturer, even if it has satisfied Health Canada as to the safety and efficacy of its drug, until the generic has addressed all of the patents listed against the innovator's drug product under the NOC Regulations. 
 
With respect to each patent listed on this "patent register", the generic must either accept that a NOC will not issue for its drug until the patent expires, or, if it seeks to enter the market before the patent expires, it must allege that the patent is not valid or that no product, use, dosage form or formulation claim of the patent will be infringed by the making, constructing, using or selling of its generic drug. Such allegations must be contained in a notice of allegation (NOA), which is served on the innovator, and includes a detailed statement of the legal and factual basis for the allegations. NOAs are required to be very detailed and are often well over 100 pages in length.

The innovator may apply to a Court within 45 days after being served with a NOA for an Order prohibiting the Minister from issuing a NOC until after the expiration of the patent(s) that are the subject of the NOA. This effectively freezes Ministerial action for 24 months unless the application is disposed of by the Court earlier. Such applications are supposed to be summary in nature, as they proceed by way of affidavits and out-of-court
cross-examinations, and hearings occur by way of lawyers presenting the evidence to a single judge of the Court. 
 
The innovator has the burden of proving that each of the generic's allegations of invalidity and non-infringement are not justified on a balance of probabilities. If the innovator does not meet its burden, the application is dismissed and the Minister is free to issue a NOC to the generic for its drug product. If the innovator successfully argues that the generic's allegations are not justified, then the Minister is prohibited from issuing a
NOC until the latest expiry date of the patents at issue. 
 
What is particularly interesting about this procedure is that (because of the supposed "summary nature" of such applications) the innovator's remedies under the NOC Regulations are in addition to its usual remedies for patent infringement under the Patent Act. In other words, a final decision on an application under the NOC Regulations does not prevent a subsequent action for infringement under the Patent Act, and the doctrine of res
judicata does not apply. Thus, the innovator is free (if its application was dismissed under the NOC Regulations) to effectively re-litigate the patent(s) at issue, meaning that the innovator gets a second "kick at the can" regarding the issues of infringement and validity. Similarly, a generic is free to commence an action under the Patent Act seeking impeachment of the patent(s) and/or a declaration of non-infringement even if the prohibition application was allowed. 
 
Unlike applications under the NOC Regulations, final determinations as to validity of a patent in the course of an action under the Patent Act are in rem, meaning the decision is applicable to the patent itself rather than just the parties in the litigation. Moreover, unlike applications under the NOC Regulations, actions under the Patent Act are subject to the full array of legal procedures, including documentary and oral discovery, expert reports, and live fact and expert witnesses before the Court. This generally means that much more significant evidence is placed before the Court in the trial of an action.
 
Novopharm's action against Eli Lilly to impeach the '735 Patent

As previously reported, Novopharm was successful in impeaching the '735 Patent, which claimed the use of the medicine atomoxetine for treating attention deficit hyperactivity disorder (ADHD) in three of its manifestations among all age groups (children, adolescents and adults). In particular, the judge accepted the evidence of Novopharm's experts going to the significant limitations of a study relied upon by Eli Lilly to establish  utility. The study's most critical shortcomings were related to its small sample size, the potential for imperfect patient blinding, and the limited study duration. 
 
The Court found that the study's reported results failed to demonstrate the critical utility of atomoxetine to treat ADHD in adults or children, and that utility had therefore not been demonstrated. Moreover, the Court found that the alleged invention in the '735 Patent was also not soundly predicted on the basis that the patent failed to disclose reference to the findings in the study in the patent disclosure.

Although the two cases were heard back-to-back by the same Federal Court judge, the decision in Novopharm's action was released before a decision was rendered in the Apotex application (discussed below).

Eli Lilly's application against Apotex under the NOC Regulations

Apotex had alleged in its NOA that the disclosure of the '735 Patent failed to provide any information, data or test results purporting to show that the administration of atomoxetine was safe and effective in the sense that treatment of ADHD would result. Apotex further alleged that the first clinical trials or experiments assessing the safety and efficacy of atomoxetine for treating ADHD were not conducted until after the filing of the priority
application. As a result, Apotex asserted that any results or data obtained from those trials could not have formed a sufficient factual basis or sound line of reasoning upon which a sound prediction could be made of the safety and efficacy of atomoxetine for treating ADHD. Alternatively, if the trials were sufficient for these purposes, Apotex alleged that Eli Lilly failed to disclose the results and data from those trials and experiments in the '735 Patent. Eli Lilly answered the NOA with a notice of application that alleged that it had established by virtue of studies that atomoxetine was useful for the treatment of ADHD (i.e. that it had demonstrated utility). 
 
When it came to presenting evidence, Apotex only framed its case around the issue of sound prediction and failed to provide any evidence contesting Eli Lilly's assertions of demonstrated utility. Eli Lilly responded
by producing the study report that was the subject of the Novopharm action. Apotex elected not to challenge this evidence on matters of substance. In particular, Apotex chose not to seek to file reply evidence or to cross-examine Eli Lilly's witnesses to challenge the study's reliability or sufficiency. The only evidence that Apotex put forward in response to the study was that the study and its data were not referenced in the '735 Patent. Apotex asserted that this was enough to put the issue of utility into play. 
 
The Court, however, disagreed. Where a patentee relies on demonstrated utility, its disclosure obligation is limited to the provision of a full description of the invention and the means to work it. It is only where the patentee relies upon a sound prediction of utility that it is required to disclose in the patent both the factual data on which the prediction is based and the line of reasoning to support it. Therefore, because Eli Lilly was relying upon an assertion of demonstrated utility, it was under no obligation to disclose the study or its
findings in the '735 Patent. 
 
As a result, Apotex's evidence, which simply pointed to the absence of proper disclosure in the '735 Patent, was not even capable of rebutting the statutory presumption of validity. As stated by the Court: I am accordingly bound on this record to reject Apotex's allegation of inutility  because it has failed to satisfy its initial evidentiary burden ... For this issue, the statutory presumption of validity prevails.

This is, of course, a surprising result in the face of my earlier finding in Novopharm Limited v. Eli Lilly and Company, 2010 FC 915, that the MGH Study was not sufficient to demonstrate utility. But in that case the
issue was addressed by the parties on the strength of considerable evidence that went to the merits of the MGH Study. Here, Apotex took a different approach and elected not to meet Lilly's assertion of demonstrated utility head-on. In the result, its allegation of inutility fails. 
 
In the result, the Court would have allowed Eli Lilly's application to prohibit the Minister from issuing a NOC to Apotex since Apotex's allegations were not justified. However, because of the intervening determination that the '735 Patent was invalid in the Novopharm action (an interim decision), Eli Lilly's application against Apotex was dismissed on the basis of mootness. Apotex was therefore still able to receive a NOC to market its generic version of atomoxetine.

On August 3, 2010, the Federal Court released reasons in Novo Nordisk Canada Inc. et al. v. Cobalt Pharmaceuticals Inc. et al. (2010 FC 746; "Novo Nordisk")) finding Cobalt's allegation of obviousness justified with respect to Canadian Patent No. 2,111,851. The patent covers repaglinide (an (S) enantiomer), its use for the treatment of Type 2 Diabetes, and processes to make it. 
 
Novo Nordisk is an important case both from legal development and commercial perspectives. The Federal Court has made clear that scientific knowledge evolved after 1987, the date considered by the Supreme
Court of Canada ("SCC") in Sanofi and that by 1991 it was the state of the art to separate and test enantiomers of racemic potential drugs. This decision refines the obvious-to-try test set out by the SCC and suggests a review of all enantiomer patents applied for in or after 1991.

The Decision in a Nutshell

The patent involved in this proceeding (the "851 Patent") essentially covers the enantiomer repaglinide. Repaglinide is sold under the brand name GLUCONORM".

Enantiomers are mirror image molecules that cannot be superimposed on each other (think of right and left hands). They are normally synthesized together, as a "racemate", and one cannot know how each of the two
enantiomers comprising the racemate (denoted (S) and (R)) will act in the body until it has actually been made and tested. Activity and toxicity can be different as between the racemate, the (S) enantiomer and the (R) enantiomer. 
 
Unlike other recent cases, the racemate comprising repaglinide was never approved or marketed as a drug product, although the racemate had been identified in a previous "genus" patent covering numerous
compounds, as well as a patent covering new solid forms of the racemate. Nonetheless, Cobalt alleged repaglinide to be obvious, and the 851 Patent to be invalid on this and other grounds. The Court agreed and
found the 851 Patent obvious to try.

This is only the second decision known to the author in which the Court found allegations of invalidity of an enantiomer patent justified.
 
Refining the Obvious-to-Try Test

In the Sanofi case, the SCC dealt with an enantiomer patent and in that context, set out the obvious to try analysis applied by the Court to repaglinide in this case. The obvious to try factors include asking whether it
is more or less self-evident that what is being tried (i.e. the invention) ought to work.
 
In answering this question, the SCC stated:

As I have observed earlier, Shore J. found that the skilled person would not know, before separating this particular racemate into its isomers and then testing the separated isomers, that the properties of the
dextro-rotatory isomer [(R) enantiomer] would be different from the properties of the racemate or the levo-rotatory [(S) enantiomer] isomer (para. 81).  Similarly, he found that the person skilled in the art would not know before trying the different salts in combination with the dextro-rotatory isomer what the bisulfate salt's beneficial properties would be (para. 82).

Just because there are known methods of separating a racemate into its isomers does not mean that a person skilled in the art would necessarily apply them. The fact that there are such known methods of separation
will be of no account if the evidence does not prove that it was more or less self-evident to try them. It is true that at the relevant time there was evidence that a skilled person would know that the properties of a racemate and its isomers might be different. However, a possibility of finding the invention is not enough. The invention must be self-evident from the prior art and common general knowledge in order to satisfy the "obvious to try" test. That is not the evidence in this case. 
 
At its broadest, this holding would mean that – in the case of an enantiomer or other selection patent – the discovery of advantageous properties could be the foundation of a valid patent, as long as the properties
were not predictable in the particular selection of compounds. Given that routinely-identified properties (such as toxicity, solubility, pharmacokinetic profile, etc.) are often unpredictable, it was unclear how this holding would be reconciled with previous jurisprudence suggesting that routine testing may not qualify as an inventive step.

Novo Nordisk addresses this seeming tension by clarifying that unpredictable but unsurprising properties are not necessarily a bar to a finding of obviousness.

The Court found that an enantiomer claim can be obvious even if the enantiomer's advantages were unknown. In addition, the Court held that it was impossible to predict what the differences in the pharmacokinetic profiles of enantiomers would be before actually separating and testing them. Nevertheless, as of 1991, it was known that these differences could well exist, and that it was, therefore, important to test for them.

The Court held Cobalt's allegation of obviousness justified even though the Court found that there was no clear preference for one enantiomer or the other expressed in the prior art, and that the advantages of the (S) enantiomer were not previously identified. The basis of this finding was that pharmacokinetic properties that differ between enantiomers would inevitably have been discovered as a result of testing that was a routine part of the state of the art in 1991.

The Evolution of Enantiomer Science

In addition to refining the obvious to try test, this decision should make all patentees ask the question: "Are enantiomers patentable after 1991?"

In Sanofi, the SCC found that as of 1987 there was little motivation to pursue enantiomers. The relevant date in Novo Nordisk is in 1991. The Federal Court found it clear on the evidence that by 1991:

• the world had evolved and it was now the state of the art to separate and test enantiomers;
• techniques for separating racemates into their isomers were generally known; and
• testing enantiomers for differences in pharmacokinetic properties was a routine matter.
 
The evidence in this case included the fact of an enantiomer policy approved in 1989 by Dr. Karl Thomae GmbH – the patent owner – which confirmed that "A forced move towards the development of enantiomer-pure active substances results out of the necessity to minimize development time and costs, as well as in order to comply with the current state of the art. The development of racemates will thus only still be justifiable in exceptional
circumstances".

This decision also highlights the importance of strong evidence of how drug development was actually undertaken at the relevant time. The Court specifically contrasted the evidence presented by Cobalt in this case to that presented in the recent Lundbeck case, where the evidence was found to be "appallingly thin". 
 
References:
 
1. Sanofi-Synthelabo Canada Inc. v. Apotex Inc., 2008 SCC 61.
2. Cobalt asserted a number of grounds of invalidity, though only the anticipation, obviousness and void pursuant to s. 53 of the Patent Act were dealt with by the Court, and only the obviousness ground was successful.
3. The first decision was with respect to the drug levofloxacin. Despite allegations of invalidity being found justified in the context of a NOC proceeding, the enantiomer patent was upheld as valid at trial and appeal.
4. Lundbeck Canada Inc. v. Canada (Minister of Health), 2009 FC 146.

On October 20, the Federal Court of Appeal put an end to the disparity in the jurisprudence surrounding whether a patentee could obtain a patent to a medicine subsequent to obtaining a patent to a process for producing the medicine by dismissing Bayer's appeal in the case of Bayer Schering Pharma Aktiengesellschaft v. The Attorney General of Canada. The case stems from May 2008, when the Commissioner of Patents refused to grant Bayer a patent to a pharmaceutical compound per se because a previous patent had already been issued
to it for the same compound when made by a particular process (product-by-process patent). After Bayer's appeal to the Federal Court was dismissed, it appealed to the Federal Court of Appeal.

Bayer argued that "obviousness-type" double-patenting didn't apply to the situation at hand. However, the Federal Court of Appeal disagreed and dismissed the appeal, stating that: There is nothing inventive or "patentably distinct" in a claim for a product that is the subject of a previous process-dependent patent. On the other hand, a process-dependent patent may be granted, even though a patent has already been issued for the
product itself, if the process claimed and described for making the product exhibits inventive ingenuity. 
 
... Consequently, the Commissioner correctly denied the Application on the ground of "obviousness" double patenting because the patent would have disclosed no new invention. For her to have granted a patent for the
compound would have improperly "evergreened" the parent patent, now expired, by creating a second monopoly in the use of the compound running from the date when the Application was approved.

This decision puts an end to any disparity in the jurisprudence, as the Federal Court of Appeal effectively overruled the decision in Aventis Pharma Inc. v. Mayne Pharma (Canada) Inc., 2005 FC 1183, 42 C.P.R.
(4th) 481, rev'd. on other grounds, 2008 FCA 21, 380 N.R. 35.