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Inventive Concept Redux: Shire’s ADHD Prodrug Patent Upheld By Federal Court

In a decision released publicly on June 21, 2018, the Federal Court dismissed Apotex’s action against Shire seeking a declaration of invalidity with respect to Canadian Patent No. 2,527,646. The case was heard together with an application brought by Shire under the Patented Medicines (Notice of Compliance) Regulations involving the same patent. The Court held that the patent is valid and issued a prohibition order but rejected a counterclaim brought by Shire, finding that capsules made by Apotex for experimental and regulatory purposes did not infringe.

The 646 Patent relates generally to prodrugs of amphetamines and in particular, L-lysine-d-amphetamine (also referred to as LDX), which is used in the treatment of Attention Deficit and Hyperactivity Disorder and is sold under the brand name VYVANSE. The claims are directed to LDX and its pharmaceutically acceptable salts, as well as compositions of LDX and its use in the treatment of ADHD.

Sustained release formulations of amphetamines are susceptible to abuse. By crushing or dissolving sustained release tablets, large amounts of the drug can be released and abused by snorting or injection. According to the patent, prodrugs formed by covalent attachment of a chemical moiety to amphetamine decreased its pharmacological activity when administered by injection or intranasally. When taken orally, the prodrug is metabolized slowly in the body to release the parent compound, resulting in a sustained therapeutic effect.

Apotex unsuccessfully challenged the validity of the patent on four grounds: obviousness, anticipation, overbreadth and insufficiency.

As a preliminary matter, Justice Fothergill rejected Shire’s position that the Court should regard decisions in other jurisdictions in which counterparts of the 646 Patent were upheld to be valid as “instructive”. He agreed with Apotex’s position that the “Court must decide the legal issues raised by these proceedings in accordance with the factual record and Canada’s own laws” and placed no reliance on the foreign decisions.

Anticipation

Apotex asserted that LDX was anticipated by a 1965 Australian patent, AU 168. LDX was not exemplified but was within the disclosed genus of AU 168. Noting that AU 168 did not say anything about the compounds being prodrugs or indicating that any of the compounds provided a sustained release treatment for ADHD or a reduced potential for abuse, Justice Fothergill held that the disclosure element of the test for anticipation was not met.

Obviousness

In assessing obviousness, Justice Fothergill found that there was a single inventive concept: “a sustained release formulation of a therapeutically useful dose of amphetamine that is resistant to abuse.”

Justice Fothergill rejected Apotex’s argument relying on the decision of the Federal Court of Appeal in Ciba v.SNF (see our previous post here), that the “inventive concept  should no longer be pending clarification of its meaning by the Supreme Court.  In discussing Ciba, Justice Fothergill stated:

[115] The Federal Court of Appeal has recently observed that there may be cases in which the inventive concept may be grasped without difficulty; however, because “inventive concept” is undefined, the search for it has brought considerable confusion into the law of obviousness. That uncertainty may be reduced by avoiding the inventive concept altogether, and pursuing the alternative course of construing the claim. This avoids distraction or engaging in unnecessary “satellite debate” …

Justice Fothergill held that Apotex’s position was a “misreading of Ciba” and that “[a]s a matter of stare decisis, Ciba cannot be understood to have overruled Sanofi-Synthelabo.” He then found that the inventive concept in this case could be “grasped without difficulty” and, therefore, that there was “no need to resort to the “alternate course” endorsed by Ciba”.

After reviewing the prior art, Justice Fothergill concluded that the claimed prodrugs were not obvious (or obvious to try), finding that as of the relevant date “formulations were the primary, perhaps the only, method used to reduce a drug’s potential for abuse” and that “no prodrug had yet been developed as a means of reducing abuse potential.” He also noted that:

[131] Without testing, it would be impossible to predict whether any particular conjugate of amphetamine would cleave upon administration, at what rate it would cleave, whether saturation at a desired concentration would occur, or whether active transportation would occur … Furthermore, it was commonly understood that amides were too stable in vivo to be useful prodrug forms for amines… The area was fraught with uncertainty.

[144] The difficulty with Apotex’s analysis is that there was no way of knowing what the properties of LDX might be without testing. LDX could not therefore be “obvious to try”, because it was not more or less self-evident that it ought to work. This is true even if the testing may itself have been routine.

Infringement

Apotex had apparently acquired over 200 kilograms of LDX and had made over 3 million capsules, of which approximately 900,000 remained in inventory. Justice Fothergill accepted the evidence put forward by Apotex that all the LDX had been used for experimental and regulatory purposes and that none of the retained capsules would be sold commercially. All of this material, therefore, was exempt form infringement by s. 55.2(1) of the Patent Act as well as the common law experimental use and fair dealing exemptions “that permit manufacturers to make and use a patented invention in the course of experimental research and development work designed to establish and implement a commercial process or product made in accordance with the patent.”

Justice Fothergill’s Reasons are available here.