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Prior art disclosure of compound does not anticipate substantially separated enantiomer

March 23, 2009
Post by Blog Staff

In a recent decision, the Federal Circuit affirmed a district court's determination, after a bench trial, that the asserted claim of a patent had not been proven anticipated or obvious. The district court held that while the prior art showed the chemical structure of the claimed compound, it did not describe the separation of the two enantiomers of the compound, nor did it describe the appropriate salt form to use in tableting the compound. As a result, the claim was not anticipated. Further, the district court held the claim was not obvious, because the separation of the enantiomers had the unexpected effect of separating the beneficial effects of the compound (produced by one enantiomer) with the harmful side effects of the compound (produced by the other enantiomer).The Federal Circuit affirmed. After a detailed analysis of the facts, the court agreed with the district court's analysis that the disclosure of the chemical structure of the compound in the prior art was insufficient to either anticipate or render obvious a claim directed to one of the two enantiomers, given the difficulty and unpredictability in separating enantiomers and the unexpected division of the beneficial and harmful effects between the two enantiomers of this particular compound.More detail of Sanofi-Synthelabo v. Apotex, Inc. after the jump.

Sanofi owns a patent covering a pharmaceutical product that inhibits platelet aggregation and is used to treat or prevent blood-thrombotic events such as heart attacks and strokes. The compound has the common name clopidogrel bisulfate and is sold under the brand name Plavix®. The chemical structure is depicted below:Plavix structure The compound has a single chiral carbon (noted with the asterisk), meaning it has two enantiomers. This same structure was disclosed in an earlier Sanofi patent, however it was disclosed as a racemic mixture, or a mixture of the two enantiomers of the compound. Sanofi scientists discovered that while the racemic mixture inhibited platelet aggregation and had certain neurotoxic effects, those effects were unexpectedly isolated to the two enantiomers individually: the dextrorotatory enantiomer had substantially all of the platelet aggregation inhibitory effect whereas the levorotatory enantiomer had substantially all of the neurotoxic effects. Claim 3 of the patent is directed to the dextro-rotatory isomer of this compound "substantially separated from the levo-rotatory isomer."The defendant, Apotex, filed an Abbreviated New Drug Application (ANDA), stating that it believed the patent was invalid. This certification is defined as an act of infringement under § 271(e), so Sanofi filed suit for infringement. This stayed the FDA's approval of Apotex's ANDA for 30 months. After the 30 month stay expired the FDA approved Apotex's ANDA, and Apotex commenced sales of its generic product. Sanofi moved for a preliminary injunction. Apotex conceded infringement, but asserted the applicable claim was invalid. The district court held the four-factor test favored Sanofi, and thus granted the preliminary injunction. The Federal Circuit affirmed that decision in 2006. A three-week bench trial was held in February 2007, with the district court ultimately ruling that the '265 patent was neither anticipated nor obvious. Specifically, the court held the prior disclosure of the racemic mixture did not anticipate the substantially separated isomers, and the unexpected properties of the dextrorotatory isomer overcame Apotex's prima facie case of obviousness. Apotex appealed.The Federal Circuit affirmed. Apotex asserted the separation of enantiomers is routine, even if time consuming or requiring some experimentation, and thus the separation need not have been performed or described in the prior art reference. Apotex further argued the properties of the enantiomers of the compound are inherently and necessarily present in its known racemate, such that when the enantiomers are separated, the previously observed properties are immediately recognized in one or in the other enantiomer. While Apotex conceded the prior art references did not show any separated enantiomers or describe how to separate them, it argued such detail was not required because persons of ordinary skill in the art would know the existing techniques for separating enantiomers. Apotex thus argued the dextrorotatory enantiomer was not novel as a matter of law. The Federal Circuit disagreed, noting that in order to anticipate, a prior art reference must not only disclose all elements of the claim within the four corners of the document, but must also disclose those elements arranged as in the claim. Here, there was no disclosure of the separation of the enantiomers, and thus there was no anticipation, even if the separation was within the ability of one of ordinary skill in the art.The court then addressed obviousness. Apotex argued the only features of the claim which were not explicit in the prior art required no more than well-known chemical techniques, even if some experimentation was required. Then, upon separation of the enantiomers, routine testing would have revealed the favorable allocation of properties in the dextrorotatory enantiomer isomer. Expert witnesses for both sides agreed that a person of ordinary skill in this field at the time of the invention would have known that enantiomers can exhibit different biological activities. The experts also agreed that it was not predictable whether such differences, if any, would be weak, moderate, or strong, or how they would be manifested, and that weak stereoselectivity of biological properties is more common than strong stereoselectivity, and that absolute stereoselectivity is rare. The experts further agreed that no known scientific principle allows prediction of the degree to which stereoisomers will exhibit different levels of therapeutic activity and toxicity. Based on this evidence, the Federal Circuit held the district court's determination that obviousness had not been proven by clear and convincing evidence was not clearly erroneous. The separation of the enantiomers was not a simple or routine procedure and success in separation, as well as the allocation of properties was unpredictable. A person of ordinary skill in the art could not have reasonably expected the absolute stereoselectivity of these enantiomers, nor could they have reasonably predicted which method would have successfully separated the enantiomers. At the end of the day, the court determined Apotex's obviousness arguments were the application of impermissible hindsight, because the prior art did not suggest this particular dextrorotatory isomer could reasonably be expected to manifest the properties and advantages that were found.Accordingly, the court affirmed the district court's determination that the claim was not proven invalid.To read the full decision in Sanofi-Synthelabo v. Apotex, Inc., click here.


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