T
he US Supreme Court in KSR International Co v Teleflex Inc raised the bar for
establishing non-obviousness, arguably the...
recently, obviousness could not be established on the basis that
the claimed combination was “obvious to try” – that is, t...
patent at issue claimed transgenic corn expressing the insecti-
cidal protein Bt. To increase expression, patentee Syngent...
drug were obvious under KSR because of the “finite number
of identified, predictable solutions” to the market’s need for
a...
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Post-KSR Obviousness

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This article discusses changes in the patent law obviousness doctrine after KSR and provides strategy recommendations for protecting biotechnology inventions

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Post-KSR Obviousness

  1. 1. T he US Supreme Court in KSR International Co v Teleflex Inc raised the bar for establishing 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 (the TSM test) to combine the claimed elements of the invention, the Supreme Court encouraged an analytical shift towards a framework focusing on the predictability of the art and reasonable expectation of success. This article explores how this shift may be used to the patentee’s advantage in the fields of biotechnology and pharma- ceuticals. Origins of non-obviousness Despite repeatedly revising the Patent Act after its enactment in 1790, Congress for almost 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 the courts. Accordingly, the US Supreme Court in Hotchkiss v Greenwood (1851) cre- ated a new condition of patentability, requiring that the invention evidence “more ingenuity and skill ... than were possessed by an ordinary mechanic acquainted with the 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 the seminal 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 patent application, and the background skill of the calling”. The Section 103 formulation similarly “place[d] emphasis on the pertinent art existing at the time the invention was 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 the level of ordinary skill in the prior art resolved.... Such secondary considerations as commercial success, long felt but unsolved needs, failure of others, etc, might be utilized to give light to the circumstances surrounding the origin of the subject matter sought to be patented. As the Supreme Court more recently explained: “The non-obviousness requirement extends the field of unpatentable material beyond that which could readily be deduced 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-KSR Following the Graham decision, federal courts attempted to develop general guide- lines – not only to ease non-obviousness analysis, but also to help establish judicial consistency. 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 Circuit insisted that a claimed combination was obvious only where the prior art contained a teaching, suggestion or motivation to combine the individual elements (Al-Site Corp v VSI Int’l, Inc, Fed Cir 1999). Such a teaching, suggestion, or motivation may be found in the prior art references themselves, the nature of the problem, or the knowledge 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 US: BIOTECHNOLOGY PATENTS How biotech patentees can navigate KSR Ewa M Davison and Gary M Myles provide strategies for establishing non-obviousness in the biotechnology and pharmaceutical arts in light of the Supreme Court’s rejection of a rigid TSM test www.managingip.com July/August 2008 79 In overcoming an obvious- ness challenge asserted during patent prosecution or litigation, the patentee of a biotechnology or phar- maceutical invention must stress the unpredictability of the art and/or the absence of a reasonable expectation of success. Consequently, although inventions in these unpredictable fields are more vulnerable to a finding of obviousness post-KSR, several factors lend themselves to a strong non-obvi- ousness argument. While practitioners can no longer rely on the absence of an express teaching, suggestion or motivation in the prior art to overcome an obviousness chal- lenge, the approaches outlined here provide a roadmap for navigating the post-KSR non- obviousness framework. One-minute read
  2. 2. recently, obviousness could not be established on the basis that the claimed combination was “obvious to try” – that is, that either the inventor (1) varied all the numerous parameters or choices presented by the prior art until a successful result was reached, at least where the prior art provides “no indication of which parameters were critical or no direction as to which of many 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 establishment of non-obviousness. For example, the Supreme Court indicat- ed that unexpected or synergistic results constitute particular- ly compelling evidence of non-obviousness (United States v Adams, 1966; Anderson’s-Black Rock, Inc v Pavement Salvage Co, 1969). The same tends to be true where the prior art “teaches away” from the claimed combination by identify- ing its disadvantages (United States v Adams, 1966). The Supreme Court weighs in In KSR International Co v Teleflex Inc, the Supreme Court rejected the Federal Circuit’s “rigid” application of the TSM test as “inconsistent” with the “expansive and flexible approach” necessitated by the Graham obviousness framework. Although noting that the TSM test embodied a “helpful insight” and that no “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]ranting patent protection to advances that would occur in the ordinary course without real innovation”. Accordingly, although it is still important 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 creative steps 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 to known methods is likely to be obvious when it does no more than yield predictable results.” Thus, when determining whether a claimed invention that combines prior art elements is obvious, “a court must ask whether the improvement is more than the predictable use of prior art elements according to their established 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 of ordinary skill in the art. The Court further noted: When there is a design need or market pressure to solve a problem 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 technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. 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 in light of KSR similarly emphasize that an examiner must focus on predictability in analyzing an invention’s obvious- ness during patent prosecution (see box). A long dry spell: obviousness post-KSR In 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 US: BIOTECHNOLOGY PATENTS www.managingip.com July/August 200880 35 USC § 103(a) provides: “A patent may not be obtained though the invention is not identically disclosed 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 whole would have been obvious at the time the invention was made to a person having ordinary skill in the 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 variations would 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 to arrive at the claimed invention. Source: 72 Fed Reg 57526, 57529 (October 10 2007) (emphasis added). Of particular note is how many of these bases for an obvious rejection centre on the concept of predictability. Post-KSR USPTO guidelines emphasize a predictability standard
  3. 3. patent at issue claimed transgenic corn expressing the insecti- cidal protein Bt. To increase expression, patentee Syngenta modified the Bt gene so that at least 60% of its nucleotides consisted of guanine and cytosine. This patent was rendered obvious, however, by a prior art reference teaching that Bt gene expression could be improved in tobacco plants by increasing guanine and cytosine content, and that this finding was “equally applicable in other plant species”. Syngenta failed to establish teaching away, absence of a reasonable expectation of success, or unexpected results. The Federal Circuit provided a more instructive opinion in Aventis Pharma Deutschland GMBH v Lupin, Ltd, whereby it reversed the district court’s summary judg- ment of infringement (Fed Cir 2007). The Federal Circuit found obvious those claims of a pharmaceutical patent relating to the 5(S) stereoisomer of ramipril, an ACE inhibitor used for treating high blood pres- sure, in a form substantially free of other isomers. The prior art contained a mixture of the 5(S) and SSSSR stereoisomers of ramipril; nonetheless, the district 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 was criticized in KSR”, the Federal Circuit concluded: if it is known that a desirable property of a mixture derives in whole or in part from a particular one of its components, or if the prior art would provide a person of ordinary skill in the art with reason to believe that this is so, the purified compound is prima facie obvious over the mixture even without an explicit teaching that the ingredient should be concentrated or purified. Moreover, although the 5(S) stereoisomer was significantly more 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 Federal Circuit concluded that a reasonable jury could not have found non-obvious the challenged patents claiming cryopreserved umbilical cord blood and its use in transplants for hematopoi- etic reconstitution (Fed Cir 2007). The Federal Circuit noted that prior art references suggested both cryopreserving cord blood 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 for the cryopreservation and transplantation procedures. At most, therefore, the inventors proved conclusively that stem cells in cryopreserved cord blood were capable of hematopoietic reconstitution. Although “[s]cientific confirmation of what was 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]ranting patent protection to advances that would occur in the ordinary course without real innovation”. Needle in a haystack: non-obviousness post-KSR In Takeda Chemical Industries, Ltd v Alphapharm Pty, Ltd, the Federal Circuit clarified 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” (Fed Cir 2007). Alphapharm argued that Takeda’s claims to the antidiabetic compound pioglitazone were obvious because: (1) the prior art would have led a chemist to choose the related “com- pound b” as the lead for further modification; and (2) it would have been obvious to try modifying compound b through 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-try standard was not satisfied because a chemist would have had no reason to choose compound b for further study. Not only did “the prior art disclose a broad selection of compounds any one of which could have been selected as a lead com- pound for further investigation”, but compound b led to weight 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 not the case, non-obviousness could still be established based on the unexpectedly decreased toxicity of pioglitazone as com- pared to compound b. Most recently, in Ortho-McNeil Pharmaceutical, Inc v Mylan Laboratories, Inc, the Federal Circuit found that the district court did not err in finding non-obvious patent claims to an anti-epilepsy drug (Fed Cir 2008). Topiramate, a reaction intermediate with anticonvulsive properties, was discovered by an Ortho-McNeil scientist during his search for new diabetes treatments. Seeking to market a generic form of topiramate, Mylan argued that the claims to this US: BIOTECHNOLOGY PATENTS www.managingip.com July/August 2008 81 The KSR decision mandated a shift away from rigid application of the TSM test in assertions of non-obviousness
  4. 4. drug were obvious under KSR because of the “finite number of identified, predictable solutions” to the market’s need for a new antidiabetic drug – that is, that topiramate was obvi- ous to try. In reaching the contrary conclusion, however, the Federal Circuit noted the multiple steps at which a person of ordinary skill would have had to make one of multiple choic- es in order to produce topiramate and recognize its utility as an anticonvulsant; such steps included choice of enzymatic target, choice of starting material, choice of synthesis route, and the decision to test a reaction intermediate for properties unrelated to the purpose of the drug development undertak- en. Consequently, the path to topiramate’s discovery did not constitute “the easily traversed, small and finite number of alternatives that KSR suggested might support an inference of obviousness”. This case thus demonstrates that “a flexible TSM test remains the primary guarantor against a non-statu- tory hindsight analysis such as” that proposed by Mylan. New strategies The 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 art may 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 of obviousness or in overcoming an obviousness assertion during litigation. Instead, a non-obviousness argument must now focus on the predictability of the relevant art and on whether the person of ordinary skill in the art would, at the time of invention, have had a reasonable expec- tation of success in achieving the claimed invention. In the predictable arts, substantial challenges exist to demonstrating the non-obviousness of inventions based on combinations of known elements. In the areas of biotechnology and pharmaceuti- cals, however, unpredictability of the art may be used to the patentee’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 effective to argue the non-obviousness of a biotechnology or pharma- ceutical invention by demonstrating its unpredictability through surprising results. A well-drafted patent application documents the unexpect- ed results observed for a claimed invention – typically through working examples that include data demonstrating the sur- prising activity. While presenting and supporting unexpected results 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 in rebutting an obviousness rejection, and avoids the risks asso- ciated with scrutiny of a declaration during litigation. The included examples (see box) address commonly encountered circumstances in which an obviousness rejection or challenge may be raised to a biotechnology or pharmaceu- tical invention. US: BIOTECHNOLOGY PATENTS www.managingip.com July/August 200882 Ewa M Davison Gary M Myles © Ewa M Davison and Gary M Myles 2008. The authors are associates at Darby & Darby PC in Seattle Combination The 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 within the 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 by showing that the activity of the combination is either: (1) entirely new, or (2) a synergistic, as opposed to additive, property. Alternatively, the combination may be non-obvious where the prior art teaches away from the combination of compounds A and B, for example by teaching an undesirable property associated with one or both of the individual compounds. Finally, where the prior art discloses A and B among a large number of compounds but provides no guidance as to which should be combined for further investigation, the combination may not have been obvious – particularly where combin- ing compounds A and B proved uniquely chal- lenging or difficult. Structural similarity Where a claimed compound is rejected as obvious over a structurally similar prior art compound, the rejection can be most easily overcome by demonstrating that the claimed compound possesses an unexpected potency or 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 obviousness rejection may be overcome by emphasizing the unpredictability of the art and arguing that a skilled artisan would not have had a reasonable expectation of success in generat- ing the claimed compound from the numerous possibilities presented. Such an argument is likely to be particularly effective where the applicant encountered unexpected challenges during the synthesis or purification of the claimed compound. Similarly effective in rebutting a non-obviousness assertion based on structural similarity is a demonstration that the prior art, rather than merely provid- ing little or no guidance, actually “teaches away” from the invention by encouraging a different path of investigation. Purification A claim to a compound rejected as obvious over a prior art mixture containing the claimed compound may be nonetheless non-obvious where it was not previously known either: (1) that the claimed compound was present in the prior art mixture, or (2) that the compound was the active ingredient in the mixture. Alternatively, as for combinations and struc- turally similar compounds, the non-obviousness of a purified compound may be established by showing its unexpected potency or unexpected properties 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 from the prior art mixture presented unexpected challenges or required the development of a new protocol or technique. Strategies for overcoming common obviousness rejections In the areas of biotechnology and pharmaceuticals unpredictability of the art may be used to the patentee’s advantage

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