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Federal Circuit: test for obviousness of structurally similar compounds is unchanged post-KSR
June 29, 2007
At the Federal Circuit, it appears that everything old is new again. In a case applying the new obviousness framework from KSR to structurally similar chemical compounds, the court affirmed a district court decision that claimed compounds would not have been obvious in light of the prior art. The court lauded the district court's "extensive findings of fact and conclusions of law as to the four Graham factors," and noted that:
in cases involving new chemical compounds, it remains necessary to identify some reason that would have led a chemist to modify a known compound in a particular manner to establish prima facie obviousness of a new claimed compound.

The decision provides some guidance as to how the Federal Circuit will apply KSR v. Teleflex when dealing with the question of obviousness in structurally similar chemical compounds, and it appears that the previous Federal Circuit law on the issue has survived KSR. More details on Takeda Chem. Indus. Ltd. v. Alphapharm Pty., Ltd. after the jump.Takeda is the owner of patent 4,687,777, directed to thiazolidinedione derivatives, or "TZD" compounds, including pioglitazone. These can be used as antidiabetic agents. Pioglitazone is the active ingredient in ACTOS®, which is used to control blood sugar in patients who suffer from Type 2 diabetes. The claimed compounds include:

1. A compound of the formula:
claimed structure

or a pharmacologically acceptable salt thereof.

The relevant portion of the structure is the left moiety, the ethyl-substituted pyridyl ring. As shown in the claim, the ethyl group (C2H5) may be at any of the four available positions on the pyridyl ring. Pioglitazone is the compound where the ethyl group is at the 5-position, depicted below:pioglitazoneThe appellant, Alphapharm, filed an Abbreviated New Drug Application (ANDA) seeking FDA approval to manufacture and sell a generic version of pioglitazone. In response, Takeda sued Alphapharm, along with three other drug manufacturers who sought FDA approval to market generic pioglitazone.Before beginning its analysis of the particular claims at issue, the Federal Circuit recounted its pre-KSR precedents relevant to obviousness of structurally similar chemical compounds. The court noted that its prior cases held that while "structural relationships may provide the requisite motivation or suggestion to modify known compounds to obtain new compounds," in order to make out a prima facie case of obviousness in such circumstances, there must be "a showing that the prior art would have suggested making the specific molecular modifications necessary to achieve the claimed invention."Turning to KSR, the court held that its pre-KSR framework, outlined above, "is consistent with the legal principles enunciated in KSR." Latching on to the Supreme Court's statement that there was "no necessary inconsistency between the idea underlying the TSM test and the Graham analysis," the Federal Circuit held that:

in cases involving new chemical compounds, it remains necessary to identify some reason that would have led a chemist to modify a known compound in a particular manner to establish prima facie obviousness of a new claimed compound.

The only real change appears to be substitution of the "reason" language from KSR in place of the old TSM language.Turning to the specific facts here, the court found no such reason to modify the prior art to produce pioglitazone. Alphapharm argued that it would have been obvious to modify a prior art compound denoted as "compound b" to produce pioglitazone by two common procedures in drug optimization, homologation, changing a side chain from one group to a similar group, and "ring-walking," or moving the side chain to a different position on the ring. Compound b is depicted below:

Compound bTo change compound b to pioglitazone, the methyl group at the 6-position on the ring must be changed to an ethyl group and moved to the 5-position. Alphapharm asserted that this type of experimentation is commonplace, and thus the claimed compounds were obvious. Based on these arguments, the Federal Circuit centered on whether the prior art would have led to compound b being selected as a lead compound. By "lead compound" the court meant a compound that was the most promising to modify in order to improve its antidiabetic activity and obtain a compound with better activity, in this case pioglitazone. If compound b would not be a compound selected for further experimentation, Alphapharm's obviousness argument fails, because without compound b as the starting structure, homologation and ring-walking would not result in pioglitazone. Essentially, the court noted that there must be a "reason" to select compound b as the starting point. This determination was framed in the "differences between the prior art and the claimed invention" prong of the Graham analysis.In applying these standards, the court agreed with Takeda that one of ordinary skill in the art would not have selected compound b as the lead compound. Rather, the prior art disclosed a broad selection of compounds that could have been selected as a lead compound for further modification. The court also found significant that compound b exhibited negative properties that would have led one of ordinary skill in the art away from that compound, and as such was not "obvious to try." The court ultimately concluded that Alphapharm failed to prove that the prior art would lead to the selection of compound b as the lead.The court also rejected Alphapharm's reliance on the Federal Circuit's recent Pfizer case, where a particular pharmaceutical salt was found to be obvious based on an earlier disclosure of a genus of acceptable anions that could be used to form acceptable salts, combined with other references discussing the properties of the particular claimed salt. As described by the court, in Pfizer, there was "ample motivation to narrow the genus of 53 pharmaceutically-acceptable anions disclosed by [one prior art reference] to a few, including" the claimed compound. Here, however, one of ordinary skill would not have chosen among the 90 compounds disclosed in a prior art reference one which exhibited several negative side effects as a starting point.Also important to the court was the evidence of unexpected results. Particularly, pioglitazone was unexpectedly nontoxic, particularly in light of the toxicity of compound b, the closest structural analog in the prior art. Judge Dyk, in concurrence, would hold that unexpected results, such as shown here, are required in order to validly claim a particular species of a previously disclosed genus of compounds, or in the related instance of claiming a subset of a previously-disclosed numerical range.In short, it appears that the Federal Circuit's pre-KSR jurisprudence regarding structurally similar chemical compounds is substantially unchanged, just framed in the context of Graham and discussed as a "reason" to modify the prior art rather than a "teaching, suggestion, or motivation" to modify the prior art.

To read the full decision in Takeda Chem. Indus. Ltd. v. Alphapharm Pty., Ltd., click here.

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