Patent law generally requires that an invention must firstly be new (this is referred to as the “novelty requirement”) and secondly must involve an inventive step (this is referred to as the “non-obviousness requirement”). For example, Section 25 (1) of the South African Patents Act provides that: “A patent may, subject to the provisions of this section, be granted for any new invention, which involves an inventive step...” The inventive step requirement is set out in Section 25 (10) which provides that “... an invention shall be deemed to involve an inventive step if it is not obvious to a person skilled in the art...”. Similar requirements are set out in 35 USC § 102 and 35 USC § 103 of the US Code. In the case of chemical compounds the novelty requirement is generally easy to determine because of the large data bases which cover chemical compounds. However, when is a new chemical compound obvious?

If, for example, chlorobenzene is a known compound but bromobenzene, which differs from chlorobenzene only by one atom is not a known compound, would an organic chemist who synthesises bromobenzene for the first time be entitled to patent protection for bromobenzene or could another organic chemist who is “skilled in the art” argue that bromobenzene is obvious?

Organic chemistry is very versatile and organic chemists can, and have, synthesised literally millions of new compounds and skilled organic chemists can make large, complex molecules. However, the biological properties of molecules with similar structures are generally unpredictable and small changes, such as the removal or replacement of a minor functional group or the reduction of a single carbonyl group in an organic molecule can have dramatic effects. By way of example morphine, which is an alkaloid from the poppy Papaver somniferum, is an addictive and very powerful pain killer, but morphine can be converted to the prescription drug codeine by simply replacing one of its hydrogen atoms with a methyl group. Morphine can also be converted to the highly addictive and dangerous drug heroin by simply replacing two of its hydrogen atoms with acetyl groups. Would the person skilled in the art have predicted this?

It is clearly, on the face of it, difficult to decide if a new compound involves an inventive step if it has a structure which is similar to the structure of a prior art compound. The question of the obviousness of a new compound nevertheless arises in cases dealing with medicinal chemistry and the circumstances are generally similar. A third party infringes a patent for a new compound, the patentee sues the third party for infringement and the third party counterclaims for the revocation of the patent on the grounds that the new compound was obvious and therefore not patentable. However in order to determine obviousness, the new compound is not considered in isolation. Different approaches are followed in different jurisdictions and in the USA the courts have used, amongst others, combinations of the “teaching-suggestion-motivation” test (the prior art must have taught or motivated the inventor), the “obvious to try” test (the inventor chose from a finite number of identifiable, predictable solutions with a reasonable expectation of success), the concept of a “lead compound” and others. This article briefly looks at some of the “lead compound” cases.

Put simply a “lead compound” is a known (or prior art) compound which, the alleged infringer claims, guided or motivated the inventor to synthesise the new compound. The infringer identifies a lead compound and then argues that the inventor simply modified the lead compound to produce the new compound and that the new compound is therefore obvious.

In the Yamanouchi Pharm. Co. vs Danbury Pharmacal, Inc, case Danbury alleged that Yamanouchi’s ulcer medication famotidine was obvious. In this case Danbury took the “lead compound” idea to an extreme. Danbury selected two different compounds from two different prior art references as lead compounds and then argued that the person skilled in the art would have combined one half of the molecule of the first compound and one half of the molecule of the second compound to produce an intermediate molecule and then modified the intermediate molecule further by replacing a carboxamide group with a sulphonamide to produce famotidine. The court held that structural similarity is only one factor and that the prior art must also provide a reason or motivation to make the new compound. The court rejected Danbury’s argument saying that the person of ordinary skill in the art would not have taken any of the three steps let alone the combination of all three. The court said that Danbury’s obviousness objection had “all the earmarks of somebody looking at this from hindsight”.

The Eli Lilly vs Zenith Goldline case dealt with Eli Lilly’s anti-psychotic compound olanzapine. In this case the difference in the structures of the “lead compound” put forward by Zenith (ethyl olanzapine) and olanzapine itself was a difference of only one methyl group. The court found however that ethyl olanzapine had been identified along with more than 100 other compounds and that there was no specific motivation to use ethyl olanzapine (as opposed to any of the other possibilities) as a starting point for further research. The court found that it should be established by clear and convincing evidence that one of ordinary skill in the art would have been motivated to select ethyl olanzapine as a lead compound and that this was not the case. The court found that there were unexpected differences between the properties of olanzapine and the properties of ethyl olanzapine which would not have been expected based on the known properties of ethyl olanzapine. The obviousness claim was accordingly rejected.

In the Janssen vs Mylan case, Mylan argued that the person skilled in the art would have selected pirenperone as a lead compound to produce the patented “compound 11” by converting a benzoyl group to a benzisoxazole group. The court again rejected the argument, saying that the infringer must demonstrate why the hypothetical person would have been motivated to choose pirenperone as a lead compound in attacking the general problem. In KSR International Co. vs Teleflex Inc. the court held that there is no requirement for a “lead compound” to be identified and that the Federal Circuit erred “in its assumption that a person of ordinary skill attempting to solve a problem will be led only to those elements of prior art designed to solve the same problem”.

In the Takeda v Alphapharm and Genpharm case, Takeda had patented the diabetes drug pioglitazone. This compound contains a pyridine ring with an ethyl substituent on the 5-position of the pyridine ring. Alphapharm contended that pioglitazone was obvious in the light of a prior art compound referred to as “compound b” in which the pyridine ring had a methyl group on the 6-position. Alphapharm argued that the changes from “compound b” to produce pioglitazone were “obvious to try” but the court rejected the arguments. The court held that there was no motivation in the prior art to select “compound b” as a lead compound firstly because of the toxicity of “compound b” and the unexpected non-toxic properties of pioglitazone and secondly because of the very large number of different structures which can be obtained by varying the position of the methyl and ethyl groups on the pyridine ring.

In the recent case of Otsuka Pharmaceutical Co Ltd v Sandoz, Inc, Otsuka argued that aripiprazole, which is a carbostyril, was obvious in the light of three prior art carbostyril lead compounds. The court held that it would be necessary to identify a reason that would have led a chemist to modify a known compound in a particular manner. The court found that the question of obviousness follows a two-part enquiry. The first question is whether or not the skilled person would have selected the “lead compound” and secondly whether or not the “lead compound” would have provided the skilled person with a reasonable expectation of success. The court found that the person skilled in the art would not have selected the prior art compounds referred to by Otsuka for use as lead compounds.

These cases show that structural similarity between a new compound and a prior art compound is not enough to support an obviousness rejection. An organic chemist would agree with this view. Using the morphine-codeine-heroin example an organic chemist, tasked with producing a new prescription pain killer and knowing of the pain killing but addictive properties of morphine, would know simply by drawing the structure of the morphine molecule that there are at least 6 obvious positions in which the molecule could be modified. One of these positions is a reactive α,β-unsaturated hydroxyl group and one is a very reactive aromatic hydroxyl group. In a few minutes an organic chemist could write down a list of dozens of substituents which could be used to functionalise these two hydroxyl groups. It is submitted that the person skilled in the art would definitely not be able to predict in advance that methylating the aromatic hydroxyl group (which is one of the dozens of ways in which this group can be modified) and leaving the α,β-unsaturated hydroxyl group untouched would produce the desired prescription pain killer but acetylating both hydroxyl groups (which is a another of the dozens of ways in which these groups can be modified) would produce heroin. In the light of the versatility of organic synthetic procedures and the ability of an organic chemist to synthesise very large numbers of variations of an organic compound it is clear that an obvious objection requires a lot more than structural similarity.

References

1. Obviousness of Chemical Compounds: The “Lead Compound” Concept; by Vincent L. Capuano PhD; Sterne, Kessler, Goldstein & Fox P.L.L.C.: Intellectual Property Today, July 2007.

2. Effect of KSR on Obviousness Analysis of Chemical Compounds; by Pauline Farmer-Koppenol, Fenwick & West LLP: IP Bulletin, Summer 2008.

3. For Chemical Obviousness, Need to Show That Prior Art Suggested Making Modifications to Get Claimed Compound; by Stephen Jenei: Patent Baristas, July 3, 2007.

4. Obviousness and Chemical Compounds; by Jason Rantanen: Patently-O, May 2012.

5. Prima Facie Obviousness of Chemical Compounds; Helmuith A Wegner: Heinonline, 6APLA Q.J. 271 (1978).

6. How to Determine the Obviousness of Chemical Compounds in Patent Applications Dr. MICHAEL A. S. GUTH, Ph.D., J.D.: michaelguth.com/pharmaceuticaleconomics/chemicalcompounds.htm

Written by Mlungiseleli Ganto – Candidate Attorney, Patents Department, Adams & Adams
Verified by – Craig Forbes, Partner, Patents Department, Adams & Adams