Q: Is it possible to get a patent on a single stereoisomer (e.g., a L-enantiomer) of a compound when the racemate is already known?
A: Yes. It is possible. But claiming a single stereoisomer may be challenging without sufficient supporting experimental details.
Critical support for arguing non-obviousness:
- Difficulties associated with resolving racemic mixtures.
- Unexpected properties.
Leading Supreme Court case on Obviousness: KSR Inter- national Co. v. Teleflex Inc., 127 S. Ct. 1727 (2007)
The Supreme Court rejected a strict teaching, suggestion, or motivation (TSM) test for obviousness. Meanwhile, The Supreme Court carefully noted that KSR simply mandated flexibility and reminded courts that the requisite motivation for the invention need not originate from the words of written references but can arise instead from the application of common sense to an apparent market need (KSR, 127 S. Ct. at 1742).
The Supreme Court stated that: “[W]hen there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product is not of innovation, but of ordinary skill and common sense. In that instance, the fact that a combination was obvious to try might show that it was obvious under §103.”
Q: Is it common sense to separate enantiomers from their racemic mixtures?
A: Not necessarily.
The KSR decision appeared at the time to signal trouble for pharmaceutical patents directed toward single-enantiomer drugs. After all, a racemic mixture of two enantiomers is indeed a a finite number of solutions [compounds]. However, in response, the Federal Circuit has seemingly not departed from its pre-KSR jurisprudence. The Federal Circuit, rather, has established a framework for assessing non-obviousness of enantiomeric pharmaceutical products based on the unpredictability of their properties and success in the separation process itself.
MPEP §2143 – E. “Obvious To Try” – Choosing from a Finite Number of Identified, Predictable Solutions, With a Reasonable Expectation of Success
The USPTO’s Manual of Patent Examining Procedure (MPEP) acknowledges that “some commentators on the KSR decision have expressed a concern that because inventive activities are always carried out in the context of what has come before and not in a vacuum, few inventions will survive scrutiny under an obvious to try standard.” However, the MPEP reassures the commentators saying that the cases decided since KSR “have proved this fear to have been unfounded.” Because courts appear to be applying the KSR requirement for “a finite number of identified predictable solutions” in a manner that places particular emphasis on predictability and the reasonable expectations of those of ordinary skill in the art.”
Case Cited by MPEP
The MPEP further cites the Federal Circuit, in Abbott Labs. v. Sandoz, Inc., 544 F.3d 1341, 1352, 89 USPQ2d 1161, 1171 (Fed. Cir. 2008), in which the opinion cautioned that an obviousness inquiry based on an obvious to try rationale must always be undertaken in the context of the subject matter in question, “including the characteristics of the science or technology, its state of advance, the nature of the known choices, the specificity or generality of the prior art, and the predictability of results in the area of interest.”
The MPEP, however, does describe a case where the Federal Circuit found claims indeed to be obvious over the prior art. Here, the MPEP refers to Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293 (Fed. Cir. 2007), where the Federal Circuit held the claims invalid as obvious in light of the prior art disclosure of a mixture of just two of the thirty-two possible isomers. According to Aventis, the MPEP advises a purified compound is not necessarily prima facia obvious over its mixture. However, “if it is known that some desirable property of a mixture derives in whole or in part from a particular one of its components, . . . the purified compound is prima facie obvious over the mixture even without an explicit teaching that the ingredient should be concentrated or purified.” Aventis, 499 F.3d at 1301.
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Obviousness of Stereoisomers
Court Decisions – Stereoisomer Rendered Obvious
A Substantially Pure Isomer Is Obvious in View of Both a Completely Pure Isomer and an Impure Mixture
Spectrum Pharma. V. Sandoz Inc., 802 F. 3d 1326 (Fed. Cir. 2015) [15-1407]
The Court of Appeals for the Federal Circuit (CAFC) held, in favor of Sandoz, that a “substantially pure” isomer obvious in view prior art disclosing both a “completely pure” isomer and an 50/50 mixture. Spectrum Claimed a “Substantially pure” 6S enantiomer [at least 92-95% pure] of Leucovorin (“Folinic Acid”) in U.S. Patent 6,500,829. Leucovorin is a form of folic acid used to reduce the side effects of methotrexate etc. The prior art taught a 50/50 mixture and “completely” pure 6S enantiomer. But the prior art did not teach a “substantially pure” mixture. Spectrum argued that no one would be motivated to use a “substantially pure” enantiomer because a “completely pure” 6S enantiomer is already known in the art. The CAFC rejected Spectrum’s argument reasoning that no unexpected result justified finding the substantially pure isomer non-obvious because the substantially pure isomer worked identically to the completely pure isomer for treatment purposes. Meanwhile, methods of separating the isomers were also known in the art. The Court therefore ruled that a person of ordinary skill in the art would have been motivated to make the substantially pure [6S] isomer starting with the 50/50 mixture and the completely pure isomer found in the prior art.
Stereoisomer obvious in light of the prior art disclosure of a mixture of just two of the thirty-two possible isomers.
Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293 (Fed. Cir. 2007) [06-1530]
The Federal Circuit held the claims invalid as obvious in light of the prior art disclosure of a mixture of just two of the thirty-two possible isomers.
A purified compound is not necessarily prima facia obvious over its mixture according to Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293 (Fed. Cir. 2007). However, “if it is known that some desirable property of a mixture derives in whole or in part from a particular one of its components, . . . the purified compound is prima facie obvious over the mixture even without an explicit teaching that the ingredient should be concentrated or purified.” Aventis, 499 F.3d at 1301.
CAFC distinguished the Aventis case from Forest Laboratories, Inc. v. Ivax Pharmaceuticals, Inc., 501 F.3d 1263 (Fed. Cir. 2007), which had been decided one week earlier, and where the prima facie case of obviousness was rebutted because the particular enantiomer at issue showed unexpected benefits and evidence indicated that the racemic mixture would have been difficult for a person of ordinary skill in the art to separate.
Court Decisions – Stereoisomer Rendered Non-Obvious
Stereoisomer non-obvious in view of unexpected results and separation difficulties
Forest Laboratories, Inc. v. Ivax Pharmaceuticals, Inc., 501 F.3d 1263 (Fed. Cir. 2007) [2007-1059]
Claims were non-obvious because the claimed enantiomer showed unexpected benefits and evidence indicated that the racemic mixture would have been difficult for a person of ordinary skill in the art to separate.
Ortho-McNeil Pharmaceutical, Inc. v. Mylan Laboratories, Inc., 520 F.3d 1358, 1364 (Fed. Cir. 2008)
The Federal Circuit affirmed a district courts decision holding that Ortho-McNeil’s patent covering Levaquin® (levofloxacin), which is the (S)-enantiomer of the racemic antibiotic ofloxacin (Floxin®). Levofloxacin, the (S)-enantiomer, was not obvious because Ortho-McNeil presented two main unexpected and superior properties of the (S)-enantiomer over the racemate. Firstly, single-(S)-enantiomer is approximately ten times more soluble than the racemic mixture. And secondly, perhaps more importantly, the (S)-enantiomer is less toxic than the racemate, which contradicted the conventional scientific wisdom in the art. That is, the prior-art taught away from using the (S)-enantiomer – typically a powerful argument.
Early Appellate Decisions Validating Stereoisomers as Non-Obvious
In re Williams, 36 C.C.P.A. 756; 80 U.S.P.Q. (BNA) 150 (C.C.P.A. 1948); 171 F.2d 319
Court of Customs and Patent Appeals (C.C.P.A.) held that “[t]he existence of a compound as an ingredient of another substance does not negative novelty in a claim to the pure compound although though it may, of course, render the claim unpatentable for [obviousness].” <Note that the C.C.P.A. was the predecessor to the Court of Appeals for the Federal Circuit.>
In re May, 574 F.2d 1082, 1090 (C.C.P.A. 1978)
(“The novelty of an [enantiomer] is not negated by the prior art disclosure of its racemate.”).
Brenner v. Ladd, 247 F. Supp. 51, 56 (D.D.C. 1965)
(“[I]t should be noted that plaintiffs’ [enantiomer] is not considered by this court to be anticipated by the solution of [the racemate] disclosed in [the prior art].”).
Sterling Drug Inc. v. Watson, 135 F. Supp. 173, 176 (D.D.C. 1955)
(“[I]t matters not that [the enantiomer] in some form in combination may exist in nature, if it cannot be reduced to a form in which it can be used. It is this product which has been so reduced or resolved that it can be used that is here claimed.”).
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Top Chiral Drugs (2021)
Source: “The top 20 drugs by worldwide sales in 2021” – Fierce Pharma, May 31, 2022
- #7 – Imbruvica® – (Ibrutinib)
- #10 – Biktarvy® – (Bictegravir/emtricitabine/tenofovir alafenamide)
- #12 – Xarelto® – (Rivaroxaban)
- #16 – Trikafta® [U.S.A.] /Kaftrio [Europe] – (Combo: elexacaftor/tezacaftor/ivacaftor)
- #19 – Veklury® – Remdesivir
