T he US Supreme Court in KSR International Co v Teleflex Inc raised the bar forestablishing non-obviousness, arguably the most easily challenged patentabil-ity requirement in the United States. By rejecting the Federal Circuit’s require-

ment that the prior art contain an express teaching, suggestion or motivation (theTSM test) to combine the claimed elements of the invention, the Supreme Courtencouraged an analytical shift towards a framework focusing on the predictabilityof the art and reasonable expectation of success. This article explores how this shiftmay be used to the patentee’s advantage in the fields of biotechnology and pharma-ceuticals.

Origins of non-obviousnessDespite repeatedly revising the Patent Act after its enactment in 1790, Congress foralmost two centuries relied solely on the statutory requirements of novelty and util-ity. Thus, the question of how to further refine patentability was largely left to thecourts. Accordingly, the US Supreme Court in Hotchkiss v Greenwood (1851) cre-ated a new condition of patentability, requiring that the invention evidence “moreingenuity and skill ... than were possessed by an ordinary mechanic acquainted withthe business”.

Congress codified the Hotchkiss test in Section 103 of the Patent Act of 1952,labelling the requirement as one of non-obviousness. As the Court later noted in theseminal case Graham v John Deere Co (1966), Hotchkiss had established a practi-cal test requiring “a comparison between the subject matter of the patent, or patentapplication, and the background skill of the calling”. The Section 103 formulationsimilarly “place[d] emphasis on the pertinent art existing at the time the inventionwas made and ... [was] implicitly tied to advances in that art”. The Court then elab-orated on this basic non-obviousness framework:

Under § 103, the scope and content of the prior art are to be determined; differ-ences between the prior art and the claims at issue are to be ascertained, and thelevel of ordinary skill in the prior art resolved.... Such secondary considerationsas commercial success, long felt but unsolved needs, failure of others, etc, mightbe utilized to give light to the circumstances surrounding the origin of the subjectmatter sought to be patented.

As the Supreme Court more recently explained: “The non-obviousness requirementextends the field of unpatentable material beyond that which could readily bededuced from publicly available material by a person of ordinary skill in the perti-nent field of endeavor” (Bonito Boats, Inc v Thunder Craft Boats, Inc, 1989).

Obviousness pre-KSRFollowing the Graham decision, federal courts attempted to develop general guide-lines – not only to ease non-obviousness analysis, but also to help establish judicialconsistency.

First, use of hindsight is improper in determining whether a combination is obvi-ous (In re Fine, Fed Cir 1988). To guard against use of hindsight, the Federal Circuitinsisted that a claimed combination was obvious only where the prior art containeda teaching, suggestion or motivation to combine the individual elements (Al-SiteCorp v VSI Int’l, Inc, Fed Cir 1999). Such a teaching, suggestion, or motivation maybe found in the prior art references themselves, the nature of the problem, or theknowledge of those of ordinary skill in the art.

Second, the cited prior art need not assure the inventor that a particular combi-nation will meet with certain success. Rather, obviousness requires only a “reason-able expectation of success” (In re O’Farrell, Fed Cir 1988). But, at least until

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How biotech patentees can navigate KSREwa M Davison and Gary M Myles provide strategies for establishing non-obviousness in thebiotechnology and pharmaceutical arts in light of the Supreme Court’s rejection of a rigid TSM test

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In overcoming an obvious-ness challenge assertedduring patent prosecutionor litigation, the patenteeof a biotechnology or phar-maceutical invention must

stress the unpredictability of the art and/orthe absence of a reasonable expectation ofsuccess. Consequently, although inventions inthese unpredictable fields are more vulnerableto a finding of obviousness post-KSR, severalfactors lend themselves to a strong non-obvi-ousness argument. While practitioners can nolonger rely on the absence of an expressteaching, suggestion or motivation in theprior art to overcome an obviousness chal-lenge, the approaches outlined here provide aroadmap for navigating the post-KSR non-obviousness framework.

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recently, obviousness could not be established on the basis thatthe claimed combination was “obvious to try” – that is, thateither the inventor (1) varied all the numerous parameters orchoices presented by the prior art until a successful result wasreached, at least where the prior art provides “no indication ofwhich parameters were critical or no direction as to which ofmany possible choices is likely to be successful”; or (2)explored a promising new technology or approach with only“general guidance” from the prior art.

Third, particular types of evidence aid in the establishmentof non-obviousness. For example, the Supreme Court indicat-ed that unexpected or synergistic results constitute particular-ly compelling evidence of non-obviousness (United States vAdams, 1966; Anderson’s-Black Rock, Inc v PavementSalvage Co, 1969). The same tends to be true where the priorart “teaches away” from the claimed combination by identify-ing its disadvantages (United States v Adams, 1966).

The Supreme Court weighs inIn KSR International Co v Teleflex Inc, the Supreme Courtrejected the Federal Circuit’s “rigid” application of the TSM testas “inconsistent” with the “expansive and flexible approach”necessitated by the Graham obviousness framework. Althoughnoting that the TSM test embodied a “helpful insight” and thatno “necessary inconsistency” existed “between the idea under-lying the TSM test and the Graham analysis”, the Court con-cluded that an overly formulaic approach risked “[g]rantingpatent protection to advances that would occur in the ordinarycourse without real innovation”. Accordingly, although it is stillimportant to identify a reason motivating a claimed combina-tion, an obviousness analysis “need not seek out precise teach-ings directed to the specific subject matter of the challenged

claim, for a court can take account of the inferences and creativesteps that a person of ordinary skill in the art would enjoy”.

The Court focused much of its obviousness analysis on pre-dictability: “The combination of familiar elements according toknown methods is likely to be obvious when it does no morethan yield predictable results.” Thus, when determiningwhether a claimed invention that combines prior art elementsis obvious, “a court must ask whether the improvement is morethan the predictable use of prior art elements according to theirestablished functions”. Absence of predictability may be estab-lished by unexpected results, synergy, or teaching away; a com-bination is also unpredictable if “beyond [the] skill” of one ofordinary skill in the art. The Court further noted:

When there is a design need or market pressure to solve aproblem and there are a finite number of identified, pre-dictable solutions, a person of ordinary skill has good rea-son to pursue the known options within his or her technicalgrasp. If this leads to the anticipated success, it is likely theproduct not of innovation but of ordinary skill and commonsense. In that instance the fact that a combination was obvi-ous to try might show that it was obvious under § 103.The Court in KSR thus seems to have espoused the “obvi-ous to try” standard long rejected by the Federal Circuit.The new examination guidelines issued by the USPTO inlight of KSR similarly emphasize that an examiner mustfocus on predictability in analyzing an invention’s obvious-ness during patent prosecution (see box).

A long dry spell: obviousness post-KSRIn an unpublished decision issued a mere three days after KSR,the Federal Circuit affirmed a jury verdict of obviousness(Syngenta Seeds, Inc v Monsanto Co, Fed Cir 2007). The

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35 USC § 103(a) provides: “A patent may not be obtained though the invention is not identicallydisclosed or described as set forth in section 102 of this title, if the differences between the sub-ject matter sought to be patented and the prior art are such that the subject matter as a wholewould have been obvious at the time the invention was made to a person having ordinary skill inthe art to which said subject matter pertains.”

Statutory non-obviousness requirement

In light of the Supreme Court’s KSR decision, the USPTO issued new rationales for use by its exam-iners in rejecting an invention as obvious:

A) combining prior art elements according to known methods to yield predictable results; B) simple substitution of one known element for another to obtain predictable results; C) use of known technique to improve similar devices (methods, or products) in the same way; D) applying a known technique to a known device (method, or product) ready for improve-

ment to yield predictable results; E) “obvious to try” – choosing from a finite number of identified, predictable solutions, with a

reasonable expectation of success; F) known work in one field of endeavor may prompt variations of it for use in either the same

field or a different one based on design incentives or other market forces if the variationswould have been predictable to one of ordinary skill in the art;

G) some teaching, suggestion, or motivation in the prior art that would have led one of ordi-nary skill to modify the prior art reference or to combine prior art reference teachings toarrive at the claimed invention.

Source: 72 Fed Reg 57526, 57529 (October 10 2007) (emphasis added). Of particular note is howmany of these bases for an obvious rejection centre on the concept of predictability.

Post-KSR USPTO guidelines emphasize a predictability standard

patent at issue claimed transgenic corn expressing the insecti-cidal protein Bt. To increase expression, patentee Syngentamodified the Bt gene so that at least 60% of its nucleotidesconsisted of guanine and cytosine. This patent was renderedobvious, however, by a prior art reference teaching that Btgene expression could be improved in tobacco plants byincreasing guanine and cytosine content, and that this findingwas “equally applicable in other plant species”. Syngentafailed to establish teaching away, absence of a reasonableexpectation of success, or unexpected results.

The Federal Circuit provided a more instructive opinion inAventis Pharma Deutschland GMBH v Lupin, Ltd, whereby itreversed the district court’s summary judg-ment of infringement (Fed Cir 2007). TheFederal Circuit found obvious those claimsof a pharmaceutical patent relating to the5(S) stereoisomer of ramipril, an ACEinhibitor used for treating high blood pres-sure, in a form substantially free of otherisomers. The prior art contained a mixtureof the 5(S) and SSSSR stereoisomers of ramipril; nonetheless, thedistrict court, requiring “an explicit teaching to purify the 5(S)stereoisomer”, found the claims valid. Rejecting this reasoning as“precisely the sort of rigid application of the TSM test that wascriticized in KSR”, the Federal Circuit concluded:

if it is known that a desirable property of a mixture derivesin whole or in part from a particular one of its components,or if the prior art would provide a person of ordinary skillin the art with reason to believe that this is so, the purifiedcompound is prima facie obvious over the mixture evenwithout an explicit teaching that the ingredient should beconcentrated or purified.

Moreover, although the 5(S) stereoisomer was significantlymore potent than other ramipril stereoisomers, no unexpect-ed result occurred here as the 5(S) stereoisomer’s potency cor-related with its percentage in the prior art mixture.

In Pharmastem Therapeutics, Inc v Viacell, Inc, the FederalCircuit concluded that a reasonable jury could not have foundnon-obvious the challenged patents claiming cryopreservedumbilical cord blood and its use in transplants for hematopoi-etic reconstitution (Fed Cir 2007). The Federal Circuit notedthat prior art references suggested both cryopreserving cordblood and using cord blood to effect hematopoietic reconsti-tution, and that one of skill in the art would have had a rea-sonable expectation of success in combining these references.Moreover, the prior art “spelled out” each step required forthe cryopreservation and transplantation procedures. At most,therefore, the inventors proved conclusively that stem cells incryopreserved cord blood were capable of hematopoieticreconstitution. Although “[s]cientific confirmation of whatwas already believed to be true may be a valuable contribu-tion, ... it does not give rise to a patentable invention” – a find-ing to the contrary would contravene KSR by “[g]rantingpatent protection to advances that would occur in the ordinarycourse without real innovation”.

Needle in a haystack: non-obviousness post-KSRIn Takeda Chemical Industries, Ltd v Alphapharm Pty, Ltd,the Federal Circuit clarified that “in cases involving newchemical compounds, it remains necessary to identify somereason that would have led a chemist to modify a knowncompound in a particular manner” (Fed Cir 2007).Alphapharm argued that Takeda’s claims to the antidiabeticcompound pioglitazone were obvious because: (1) the priorart would have led a chemist to choose the related “com-pound b” as the lead for further modification; and (2) itwould have been obvious to try modifying compound bthrough homologation and ring-walking, thus creating piogli-tazone. Affirming the district court’s finding of non-obvious-ness, the Federal Circuit concluded that the obvious-to-trystandard was not satisfied because a chemist would have hadno reason to choose compound b for further study. Not onlydid “the prior art disclose a broad selection of compoundsany one of which could have been selected as a lead com-pound for further investigation”, but compound b led toweight and fat increases and thus “exhibited negative proper-ties that would have directed one of ordinary skill in the art

away from that compound”. Moreover, even if this were notthe case, non-obviousness could still be established based onthe unexpectedly decreased toxicity of pioglitazone as com-pared to compound b.

Most recently, in Ortho-McNeil Pharmaceutical, Inc vMylan Laboratories, Inc, the Federal Circuit found that thedistrict court did not err in finding non-obvious patentclaims to an anti-epilepsy drug (Fed Cir 2008). Topiramate,a reaction intermediate with anticonvulsive properties, wasdiscovered by an Ortho-McNeil scientist during his searchfor new diabetes treatments. Seeking to market a genericform of topiramate, Mylan argued that the claims to this

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The KSR decision mandated a shift away fromrigid application of the TSM test in assertionsof non-obviousness

drug were obvious under KSR because of the “finite numberof identified, predictable solutions” to the market’s need fora new antidiabetic drug – that is, that topiramate was obvi-ous to try. In reaching the contrary conclusion, however, theFederal Circuit noted the multiple steps at which a person ofordinary skill would have had to make one of multiple choic-es in order to produce topiramate and recognize its utility asan anticonvulsant; such steps included choice of enzymatictarget, choice of starting material, choice of synthesis route,and the decision to test a reaction intermediate for propertiesunrelated to the purpose of the drug development undertak-en. Consequently, the path to topiramate’s discovery did notconstitute “the easily traversed, small and finite number ofalternatives that KSR suggested might support an inferenceof obviousness”. This case thus demonstrates that “a flexibleTSM test remains the primary guarantor against a non-statu-tory hindsight analysis such as” that proposed by Mylan.

New strategiesThe KSR decision mandated a shift away from rigid applica-tion of the TSM test in assertions of non-obviousness. Thus,while an express teaching, suggestion, or motivation in the artmay strongly support the obviousness of a claim, a practition-er can no longer rely on their absence to establish non-obvi-ousness – either in rebutting an examiner’s prima facie case ofobviousness or in overcoming an obviousness assertion duringlitigation. Instead, a non-obviousness argument must nowfocus on the predictability of the relevant art and on whetherthe person of ordinary skill in the art would, at the time of

invention, have had a reasonable expec-tation of success in achieving the claimedinvention.

In the predictable arts, substantialchallenges exist to demonstrating thenon-obviousness of inventions based oncombinations of known elements. In theareas of biotechnology and pharmaceuti-

cals, however, unpredictability of the art may be used to thepatentee’s advantage. This is particularly true where an ordi-narily skilled artisan would not have had a reasonable expecta-tion of success in achieving the invention through mere combi-nation of elements known in the art. Thus, it is most effectiveto argue the non-obviousness of a biotechnology or pharma-ceutical invention by demonstrating its unpredictabilitythrough surprising results.

A well-drafted patent application documents the unexpect-ed results observed for a claimed invention – typically throughworking examples that include data demonstrating the sur-prising activity. While presenting and supporting unexpectedresults through declarations may be effective in some circum-stances, it is preferred practice to thoroughly document unex-pected results within the patent specification itself. This per-mits the practitioner to cite support from the specification inrebutting an obviousness rejection, and avoids the risks asso-ciated with scrutiny of a declaration during litigation.

The included examples (see box) address commonlyencountered circumstances in which an obviousness rejectionor challenge may be raised to a biotechnology or pharmaceu-tical invention.

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Ewa M Davison Gary M Myles

© Ewa M Davison and Gary M Myles 2008. The authors are associatesat Darby & Darby PC in Seattle

CombinationThe non-obviousness of a composition compris-ing a combination of compound A and com-pound B, challenged as obvious over com-pounds A and B individually disclosed withinthe prior art, may be overcome by demonstrat-ing that the composition possesses an unex-pected activity not attributable to either com-pound A or B alone. This is usually achieved byshowing that the activity of the combination iseither: (1) entirely new, or (2) a synergistic, asopposed to additive, property. Alternatively, thecombination may be non-obvious where theprior art teaches away from the combination ofcompounds A and B, for example by teaching anundesirable property associated with one orboth of the individual compounds. Finally,where the prior art discloses A and B among alarge number of compounds but provides noguidance as to which should be combined forfurther investigation, the combination may nothave been obvious – particularly where combin-ing compounds A and B proved uniquely chal-lenging or difficult.

Structural similarityWhere a claimed compound is rejected asobvious over a structurally similar prior artcompound, the rejection can be most easilyovercome by demonstrating that the claimedcompound possesses an unexpected potencyor activity as compared to the prior art com-pound. Alternatively, where the prior art dis-closes a large number of compounds but pro-vides no guidance as to which should be cho-sen for further modification (or what modifi-cations might be desirable), an obviousnessrejection may be overcome by emphasizingthe unpredictability of the art and arguingthat a skilled artisan would not have had areasonable expectation of success in generat-ing the claimed compound from the numerouspossibilities presented. Such an argument islikely to be particularly effective where theapplicant encountered unexpected challengesduring the synthesis or purification of theclaimed compound. Similarly effective inrebutting a non-obviousness assertion basedon structural similarity is a demonstration

that the prior art, rather than merely provid-ing little or no guidance, actually “teachesaway” from the invention by encouraging adifferent path of investigation.

PurificationA claim to a compound rejected as obviousover a prior art mixture containing the claimedcompound may be nonetheless non-obviouswhere it was not previously known either: (1)that the claimed compound was present in theprior art mixture, or (2) that the compound wasthe active ingredient in the mixture.Alternatively, as for combinations and struc-turally similar compounds, the non-obviousnessof a purified compound may be established byshowing its unexpected potency or unexpectedproperties as compared to the prior art. Finally,an obviousness rejection or challenge to a puri-fied compound may be overcome by demon-strating that the compound’s purification fromthe prior art mixture presented unexpectedchallenges or required the development of anew protocol or technique.

Strategies for overcoming common obviousness rejections

In the areas of biotechnology and pharmaceuticalsunpredictability of the art may be used to thepatentee’s advantage