On September 1, 2010 the USPTO issued an update to the Obviousness Examination Guidelines that were promulgated after the Supreme Court’s 2007 KSR decision. The new Guidelines are intended to supplement, not replace, the 2007 Guidelines, and extract teaching points from Federal Circuit decisions addressing obviousness in the wake of KSR. I was surprised by the number of pharmaceutical cases discussed in the Guidelines—out of 24 decisions, 13 relate to chemical, biotech or pharmaceutical inventions.
The Guidelines emphasize that the factual inquiries set forth in Graham v. John Deere, 383 U.S. 1 (1966), remain the starting point of every obviousness analysis:
The Guidelines recognize seven approaches to obviousness—the teaching-suggestion-motivation (TSM) test that was at issue in KSR, and six others:
(1) Combining prior art elements according to known methods to yield predictable results
(2) Simple substitution of one known element for another to obtain predictable results
(3) Use of a known technique to improve similar devices, methods, or products in the same way
(4) Applying a known technique to a known device, method, or product ready for improvement to yield predictable results
(5) Obvious to try (choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success)
(6) Known work in one field of endeavor prompting variations for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art
The Guidelines focus on approaches (1), (2) and (5), and discuss specific cases falling under each category. To evaluate the legal merits of the guidelines, one would have to review each decision and compare the court’s discussion and holding to the USPTO’s “teaching point.” While that would be a valuable undertaking, for this article I focus on the USPTO’s characterizations of the pharmaceutical cases.
Teaching point: Even where a general method that could have been applied to make the claimed product was known and within the level of skill of the ordinary artisan, the claim may nevertheless be nonobvious if the problem which had suggested use of the method had been previously unknown.
The patent at issue was directed to omeprazole tablets coated with two enteric coatings. The subcoating was used to protect the omeprazole from the outer coating, which degraded the drug. The use of two coatings generally was known in the art, but the problem of the degradation of omeprazole by the prior art outer coating—which led to the invention—had not been recognized. Thus, there was no reason to modify the prior art coated omeprazole tablet to arrive at the claimed tablet.
The Guidelines place particular emphasis on the fact that the invention involves “an extra process step” that “amounted to extra work and greater expense” to improve an already successful product.
This case is interesting because when I have pointed out that an invention solves a problem that the prior art did not even recognize, examiners have responded that the prior art need not suggest the “same reason” as the invention. For example, on facts similar to this case, an examiner might have cited whatever reason(s) were used in the prior art that taught the use of two coatings, although the Guidelines state that adding a subcoating “would not have been expected to confer any particular desirable property.”
Compare this case to Bayer Schering Pharma A.G. v. Barr Labs., Inc., 575 F.3d 1341 (Fed. Cir. 2009) (discussed below), where claims to a micronized drug were determined to be obvious.
Teaching point: A chemical compound would have been obvious over a mixture containing that compound as well as other compounds where it was known or the skilled artisan had reason to believe that some desirable property of the mixture was derived in whole or in part from the claimed compound, and separating the claimed compound from the mixture was routine in the art.
The claims at issue were drawn to the 5(S) stereoisomer of ramipril. There was evidence that “multiple S stereoisomers” of drugs similar to ramipril were known to have therapeutic effect, and that conventional methods could be used to separate the stereoisomers of ramipril. Although the district court upheld the claims, the Federal Circuit reversed, citing the expectation of efficacy provided by experience with other multiple S stereoisomers of similar compounds.
Comparing this case to Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d 1075 (Fed. Cir. 2008) (discussed below), underscores the fact-specific nature of an obviousness inquiry and the importance of developing a favorable factual record.
Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353 (Fed. Cir. 2008)
Teaching point: A claimed compound would not have been obvious where there was no reason to modify the closest prior art lead compound to obtain the claimed compound and the prior art taught that modifying the lead compound would destroy its advantageous property. Any known compound may serve as a lead compound when there is some reason for starting with that lead compound and modifying it to obtain the claimed compound.
The obviousness argument was based on “the structural similarity between rabeprazole and lansoprazole, which was identified as a ‘‘lead compound’’ and differed by having “a trifluoroethoxy substituent at the 4-position of the pyridine ring, while rabeprazole has a methoxypropoxy substituent.” Because the trifluoro substituent “was known to be a beneficial feature because it conferred lipophilicity to the compound,” modifying that compound to arrive at the claimed compound “would have destroyed an advantageous property of the prior art compound,” and there was no other reason to modify lansoprazole to obtain rabeprazole.
This case is a good reminder to consider the features of the prior art, and what advantages might be lost (from the prior art perspective) when making the modifications necessary to arrive at the claimed invention.
Further USPTO commentary on this case is concerning. The USPTO draws a line between the concept of a “lead compound” as it may pertain to a pharmaceutical chemist and the concept of a “lead compound” in the context of obviousness, with the latter being much broader (of course!). The guidelines assert that a “lead compound” can be “an inactive compound” and that “the reasons for modifying a prior art compound to arrive at the claimed compound [may] have nothing to do with pharmaceutical activity.” The USPTO asserts that although such a compound would not be considered a “lead compound” by pharmaceutical chemists, it “could potentially be used as such when considering obviousness.
I don’t know how the USPTO can reconcile this position with the “person of ordinary skill in the art” standard for evaluating obviousness, as its seems to hold that even if a person of skill in the art would not consider Compound X to be a lead compound, it can be deemed so to support an obviousness rejection!
Teaching point: It is not necessary to select a single compound as a ‘‘lead compound’’ in order to support an obviousness rejection. However, where there was reason to select and modify the lead compound to obtain the claimed compound, but no reasonable expectation of success, the claimed compound would not have been obvious.
Claims to risedronate were alleged to be obvious in view of “2-pyr EHDP, which is a positional isomer of risedronate.” In reaching its decision, “[t]he district court found no reason to select 2-pyr EHDP as a lead compound . . . and no reason to modify it so as to obtain risedronate,” and also noted evidence of “unexpected results as to potency and toxicity.” The Federal Circuit affirmed on the basis that “there was no evidence that the necessary modifications would have been routine, so there would have been no reasonable expectation of success.”
I am bothered by the first “teaching point” that the USPTO draws from this case, because the court here found that the compound at issue was not obvious. The fact that the court focused on the shortcomings of a different aspect of the obviousness rejection does not mean that identification of a lead compound is not an important step of this type of obviousness rejection—but I said I was not going to critique the guidelines . . . .
Teaching point: Obviousness of a chemical compound in view of its structural similarity to a prior art compound may be shown by identifying some line of reasoning that would have led one of ordinary skill in the art to select and modify a prior art lead compound in a particular way to produce the claimed compound. It is not necessary for the reasoning to be explicitly found in the prior art of record, nor is it necessary for the prior art to point to only a single lead compound.
Claims to pantoprazole were alleged to be obvious in view of “compound 12” of the patentee’s earlier patent, which disclosed eighteen compounds. The choice of compound 12 as a lead compound was supported by teachings in the prior art patent that the disclosed compounds “were improvements over the prior art” and that compound 12 was “one of the more potent of the eighteen compounds,” and expert testimony “that one of ordinary skill in the art would have selected the eighteen compounds to pursue further investigation.” The Federal Circuit rejected the argument that the prior art must point to “a single lead compound,” as creating the type of “rigid test” that was rejected in KSR.
When reviewing this case, it is important to keep in mind its procedural posture: the Federal Circuit was reviewing a district court decision that denied the patentee’s motion for a preliminary injunction, on the ground that the patentee had not established a likelihood of success on the merits because the defendant had raised a substantial question of invalidity for obviousness. Neither decision was a decision on the merits.
In KSR, the Supreme Court resurrected the “obvious to try” rationale when it stated that “obvious to try” might amount to “obvious” under certain circumstances. As outlined in the 2007 Obviousness Examination Guidelines, “obvious to try” requires:
As noted in the Guidelines, this area of law is “developing quickly in the chemical arts,” with the courts emphasizing the requirements for “a finite number of identified predictable solutions” and “a reasonable expectation of success.”
In re Kubin, 561 F.3d 1351 (Fed. Cir. 2009)
Teaching point: A claimed polynucleotide would have been obvious over the known protein that it encodes where the skilled artisan would have had a reasonable expectation of success in deriving the claimed polynucleotide using standard biochemical techniques, and the skilled artisan would have had a reason to try to isolate the claimed polynucleotide. KSR applies to all technologies, rather than just the ‘‘predictable’’ arts.
This case overruled In re Deuel, but did not come as much of a surprise in view of the discussion of the “obvious to try” approach in KSR. Although the Kubin decision upheld a determination of obviousness, it cited In re O’Farrell for identifying specific situations where an “obvious to try” rationale does not support obviousness, and these points also are cited in the guidelines.
Any “obvious to try “ rejection should be scrutinized against these examples.
Takeda Chem. Indus. v. Alphapharm Pty., Ltd., 492 F.3d 1350 (Fed. Cir. 2007)
Teaching point: A claimed compound would not have been obvious where it was not obvious to try to obtain it from a broad range of compounds, any one of which could have been selected as the lead compound for further investigation, and the prior art taught away from using a particular lead compound, and there was no predictability or reasonable expectation of success in making the particular modifications necessary to transform the lead compound into the claimed compound.
The claims at issue were directed to pioglitazone, “a member of a class of drugs known as thiazolidinediones (TZDs).” Modification of prior art “compound b” by “homologation and ring-walking . . . would have produced pioglitazone.” However, the record revealed “no reason to select compound b as a lead compound,” and “[t]here were a large number of similar prior art TZD compounds,” with fifty-four being specifically identified in the cited prior art patent, and “‘hundreds of millions’” more generally disclosed. Additionally, “one reference had taught certain disadvantageous properties associated with compound b.” There also was evidence that the claimed compound exhibited an “unexpected lack of toxicity.”
The Federal Circuit walked through the “obvious to try” analysis and noted that “[r]ather than identify predictable solutions . . . the prior art disclosed a broad selection of compounds any one of which could have been selected as a lead compound for further investigation.” The court also noted that “the closest prior art compound . . . exhibited negative properties that would have directed one of ordinary skill in the art away from that compound.”
The Guidelines emphasize that this case demonstrates the importance of the factual findings that must underlie an “obvious to try rejection.” There must be a “finite number of identified, predictable solutions” to a “recognized problem” and a “reasonable expectation of success.”
This is one of the first post-KSR cases that I cited to overcome obviousness rejections. There is other useful language in this decision, such as emphasis on the requirement for a reason to modify the prior art.
Ortho-McNeil Pharmaceutical, Inc. v. Mylan Labs, Inc., 520 F.3d 1358 (Fed. Cir. 2008)
Teaching point: Where the claimed anti-convulsant drug had been discovered somewhat serendipitously in the course of research aimed at finding a new anti-diabetic drug, it would not have been obvious to try to obtain a claimed compound where the prior art did not present a finite and easily traversed number of potential starting compounds, and there was no apparent reason for selecting a particular starting compound from among a number of unpredictable alternatives.
The claims at issue were direct to topiramate, “which is used as an anticonvulsant.” Both the Federal Circuit and the Guidelines note the course of experimentation that led to its discovery:
In the course of working toward a new anti-diabetic drug, Ortho-McNeil’s scientist had unexpectedly discovered that a reaction intermediate had anticonvulsant properties.
In rejection the “obvious to try” challenge, the Federal Circuit emphasized that the invention did not arise from “a finite (and small in the context of the art) number of options easily traversed to show obviousness,” or arise from predictable undertakings.
The district court decision in this case was rendered before KSR and “endorsed a ‘rigorous application’ of the teaching, suggestion, or motivation (TSM) test,” but the Federal Circuit still found that “the record amply supports the district court’s finding of nonobviousness” under KSR.
Bayer Schering Pharma A.G. v. Barr Labs., Inc., 575 F.3d 1341 (Fed. Cir. 2009)
Teaching point: A claimed compound would have been obvious where it was obvious to try to obtain it from a finite and easily traversed number of options that was narrowed down from a larger set of possibilities by the prior art, and the outcome of obtaining the claimed compound was reasonably predictable.
The patent at issue was directed to a micronized oral dosage form of drospirenone. Oral drospirenone tablets suffered from known problems of poor water solubility and acid sensitivity. Although not stated clearly in the Guidelines, the district court had determined that micronizing drospirenone was known in the art, and that using a “normal” (non-enteric coated) pill would have been obvious to try.
As summarized in the Guidelines, the Federal Circuit viewed the state of the art as presenting two options: “either a ‘normal’ pill or an enteric coated-pill.” Thus, the number of options were limited. Moreover, predictability was supported by prior work with a structurally related compound.
Comparing this case to In re Omeprazole Patent Litigation, 536 F.3d 1361 (Fed. Cir. 2008) (discussed above), one key difference appears to be that the invention at issue in Omeprazole solved and unrecognized problem, while the invention at issue in Bayer addressed a known problem.
Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d 1075 (Fed. Cir. 2008)
Teaching point: A claimed isolated stereoisomer would not have been obvious where the claimed stereoisomer exhibits unexpectedly strong therapeutic advantages over the prior art racemic mixture without the correspondingly expected toxicity, and the resulting properties of the enantiomers separated from the racemic mixture were unpredictable.
The claimed compound was clopidogrel, which is the D-isomer of a racemate product that was known in the art. Here, unlike the Aventis case discussed above, “the extent to which each [isomer] contributed to the observed properties of the racemate was not known and was not predictable.”
The principle enunciated in the Guidelines is striking:
Office personnel should recognize that even when only a small number of possible choices exist, the obvious to try line of reasoning is not appropriate when, upon consideration of all of the evidence, the outcome would not have been reasonably predictable and the inventor would not have had a reasonable expectation of success.
Thus, even if there are only two possible options—the D isomer and the L isomer—if the properties of the claimed compound (therapeutic efficacy and lack of toxicity) are not predictable, then the compound may not have been “obvious to try.”
(The Guidelines distinguish this case from the Bayer decision discussed above, by noting that there was a reasonable expectation that both options in that case “would be therapeutically suitable.”)
The Guidelines provide a useful outline of important post-KSR obviousness decisions, but should be used as a starting point—not a substitute—for a fact-specific analysis of the obviousness of a given claim. If the Guidelines (or underlying cases) are cited in an obviousness rejection, it could be beneficial to read the case in its entirety to confirm its applicability and/or identify points of distinction, and to consider whether other decisions might support a different finding.