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position of the pedal. The pedals and sensors were individually known in the art.

The Court rejected the Federal Circuit’s formalistic approach, but indicated that it would be “important to identify a reason that would have prompted a person of ordinary skill in the relevant field to combine the ele-ments in the way the claimed new invention does7.” The TSM test itself remains essen-tially intact, because the Supreme Court still required the identification of some ratio-nale for the combination of the known ele-ments or prior art. Identification of a reason requires a detailed analysis of the facts, which in biotech is helpful as the inventions and techniques are varied.

Biotech combination inventionsBiotech inventions that are combinations of dissimilar elements or methods are diverse and can include, among other inventions, fusion proteins, therapeutic cord blood com-positions, nucleic acid probes and expression vectors. For biotech combination inventions such as these, the Federal Circuit has recently followed a traditional obviousness analysis, guided by KSR. Given the unique nature of biotech, the Court has been careful in evalu-ating unpredictability, the level of skill of the ordinary artisan and the maturity of the art.

In In re Sullivan, the invention was an anti-venom composition comprising antigen- binding fragments (Fab)8. The key obvious-ness analysis involved the combination of two pieces of prior art, one of which dis-closed the use of anti-venom composition comprising whole antibody molecules and a second that suggested that whole antibodies are equivalent to Fab and disclosed a method of producing Fab for enzyme immunoassay detection of venom. The Board of Patent Appeals and Interferences held the patent obvious owing to the prior art, which was

biotech inventions is expected to become more pronounced. The nature of invention is to look at what is around you and ponder what unseen and unexpected advantages can be gained from their combination. KSR spe-cifically dealt with a combination invention in the mechanical arts. The question becomes, To what extent does KSR limit combination inventions in the field of biotech?

Whether an invention is obvious was laid out by the Supreme Court’s Graham factors: the scope and content of the prior art, the level of ordinary skill in the art, the differ-ences between the claimed invention and the prior art, and objective evidence of nonobvi-ousness (e.g., commercial success, long-felt but unsolved needs and failure of others)5. In evaluating differences between the claimed invention and the prior art, the US Court of Appeals for the Federal Circuit has applied in certain cases the teaching, suggestion or motivation (TSM) test. It was devised by the Federal Circuit as a uniform method and involves asking whether there was a specific reason at the time of the invention found either in the prior art or the knowledge of a person of ordinary skill in the art (POSA) to make a change to the prior art or to com-bine prior art. If there was no such teaching, suggestion or motivation, then prima facie obviousness can be overcome. It was also developed to guard against hindsight bias that potentially occurs when evaluating prior art many years after the fact.

What did KSR say?In KSR, the Supreme Court directed the Federal Circuit to return to an “expansive and flexible approach” in evaluating when prior art can be combined together or modified to come up with the claimed invention6. KSR involved a vehicle pedal assembly includ-ing an electronic sensor for detection of the

The world of biotech inventions runs the gamut from recombinant therapeutic

fusion proteins to methods of treating reti-nal degenerative disease using gene therapy to genetically modified tobacco. To the lay-person, these would appear to be significant biotech inventions. However, the rulings from the United States Supreme Court’s KSR International Co. v. Teleflex1 and post-KSR cases seemingly subject biotech inventions to more stringent scrutiny than other inven-tions under a new obviousness analysis.

There are three types of obviousness-type analyses in this arena: (i) biotech inventions with structurally similar prior art composi-tions, (ii) biotech inventions without struc-turally similar prior art compositions and (iii) biotech combination inventions. An example of scenario (i) is the identification of a new protein that is a homolog of and based on a known protein. An example of scenario (ii) is the identification of a cDNA sequence when the protein sequence is known. An example of scenario (iii) is a fusion protein of compo-nents from two different proteins.

Given that biotech as an art is relatively immature, the first two types of inventions have been prominent. The negative impact on the issue of patenting DNA sequences has been discussed2 and the issue of structurally similar biotech inventions would appear to follow small-molecule cases decided since KSR3,4. But what does this really mean for biotech inventions? As the field continues to mature and scientists begin to reach saturation in understanding and characterizing genes and proteins, as well as development of standard techniques, the emergence of combination

Combine and conquer: handling biotech combination inventions in the wake of KSRHa Kung Wong & Dana Lau

To what extent will KSR limit combination inventions in biotech?

Ha Kung Wong and Dana Lau are at Fitzpatrick, Cella, Harper & Scinto, New York, New York, USA. e-mail: hwong@fchs.com

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shows that several scientists mentioned the idea of rebuilding destroyed blood cells. However, none achieved this long-sought goal, and the record shows the extreme skep-ticism concerning even the possibility of this achievement”16.

These three cases represent the Federal Circuit’s recent practice to closely follow KSR and Graham, while clearly being cognizant of the unique nature of biotech combina-tion inventions. They have taken to heart the Supreme Court’s directive to be flexible in the application of the TSM test, but have recognized that the test can and still should be used.

There are biotech-specific concerns that should be applied to the four Graham fac-tors. With regard to the first factor, scope and content of the prior art, we learn from Innogenetics that mere identification of a problem in prior art is not enough to pro-vide the motivation to invent17; one must have a specific reason to combine the prior art in addressing that problem. The Federal Circuit has chosen in some cases to charac-terize creativity as an attribute within the toolbox of the ordinary artisan (“A person of ordinary skill is also a person of ordinary creativity, not an automaton”18) and in other cases the level of skill as necessarily high, as in Pharmastem19. In Pharmastem, we deduce that the POSA is not only aware of other sci-entists’ attempts at hematopoietic reconsti-tution, she is sufficiently skilled to overcome the great unpredictability of methods used to successfully make the claimed composition.

As for the third factor, differences between the claimed invention and the prior art, unpre-dictability is crucial. Patent applicants should be vigilant in documenting and preserving proof of the unpredictability of their experi-ments. If methods are not routine and results derived from such methods are unpredictable and typically end in failure, it will be helpful in establishing the lack of reasonable expectation of success derived from products of various biotech methods. Also helpful is the documen-tation of teaching away in the prior art.

KSR also noted the importance of second-ary considerations and it would behoove applicants to note when other scientists have tried and failed, skepticism by other scien-tists of the ideas and methods employed by the applicant, recognition by other scientists of the value of the invention, and the value of actually bringing a product to market.

ConclusionsFrom a procurement point of view, obvious-ness must be overcome for a patent to be awarded. From a defensive viewpoint, it is one

success in creating the cord blood composition and method as the discoveries “merely used routine research to prove what was already believed to be the case”13. The Court also stressed that routine research does not give rise to patentable inventions.

The Federal Circuit imposed both a high level of skill for the ordinary artisan and an acute awareness of the prior art in Pharmastem to support its ruling. Although the Court recognized the scientists’ inno-vation, the opinion stated that they merely “proved conclusively what was strongly sus-pected before—that umbilical cord blood is capable of hematopoietic reconstitution” and that “the inventors merely used routine research methods to prove what was already believed to be the case. Scientific confirma-tion of what was already believed to be true

may be a valuable contribution, but it does not give rise to a patentable invention”13. By following KSR, the Court required that the “combination of elements ‘must do more than yield a predictable result’; combining elements that work together ‘in an unex-pected and fruitful manner’ would not have been obvious”14. In the dissent, Judge Pauline Newman criticized the majority for ignoring (i) the lack of prior art disclosure confirming actual existence of stem cells in cord blood, (ii) the lack of actual hematopoietic recon-stitution in the prior art, (iii) the unpredict-ability of cryopreservation techniques on stem cell viability, (iv) the unpredictability of efficacious and safe dose of composition for full adult hematopoietic reconstitution, as well as (v) various secondary considerations, including the difficulty of others attempting the same in the field, the expression of sur-prise of successful reconstitution by others in the field, and the ability to bring inven-tion to market in a biotech company15. In particular, she lamented the majority’s fun-damental misunderstanding of the scientific process stating that the “court’s approach reflects misperception of the scientific pro-cess as well as the patent purpose. Scientific methodology usually starts with a hypothesis based on what is already known; the record

vacated and remanded by the Federal Circuit. Although the Federal Circuit agreed that a prima facie case of obviousness was estab-lished, it also required that the Board review the rebuttal evidence provided by the appli-cant. Specifically, three declarations provided support for unexpected use, teaching away and long-felt need.

In addition to condemning the procedural misstep, the Federal Circuit recognized that the claimed composition was unique (“While a statement of intended use may not render a known composition patentable, the claimed composition was not known, and whether it would have been obvious depends upon consideration of the rebuttal evidence”9.)Moreover, the opinion also criticized the district court for focusing on the intended use of the composition, rather than on its unexpected property of neutralizing rattle-snake venom. (“The issue here is not whether a claim recites a new use, but whether the subject matter of the claim possesses an unexpected use”9.)This demonstrates the importance of secondary considerations of non-obviousness in detecting whether a bio-tech combination invention is obvious.

In Innogenetics NV v. Abbott Labs., the invention was a method of detecting HCV (hepatitis C virus) subtypes by probing 5′UTR and involved a combination of a gen-eral method of detecting HCV and specific subtype detection10. The invention was held not to be obvious owing to the failure of the district court to provide a specific obvious-ness analysis. The Federal Circuit provided some guidance on motivation to combine prior art, indicating that simple knowledge of a problem was insufficient motivation. (“The district court was nevertheless cor-rect that knowledge of a problem and moti-vation to solve it are entirely different from motivation to combine particular references to reach the particular claimed method”11.)This clearly indicates that TSM is important for biotech combination inventions.

In Pharmastem Therapeutics, Inc. v. Viacell, Inc., the invention was a combination of cord blood and cryopreservative sufficient to effect hematopoietic reconstitution of a human adult12. The composition was used in the first successful human cord blood transplantation. The claimed combination was deemed to be obvious because (i) vari-ous elements were found in the prior art, that is, bone marrow transplants resulting in hematopoietic reconstitution, cord blood containing progenitor cells and a high con-centration of progenitor cells, suggesting migration from fetal organ to bone marrow and (ii) there was a reasonable expectation of

The Federal Circuit has taken to heart the supreme Court’s directive to be flexible in the application of the TsM test, but has recognized that the test can and still should be used.

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3. Pfizer v. Apotex, 480 F.3d 1348 (Fed. Cir. 2007).4. Eisai Co. v. Dr. Reddy’s Labs. Ltd. 533 F.3d 1353

(Fed. Cir. 2008).5. Graham v. John Deere Co. of Kansas City, 383 Us 1

(1966).6. KSR v. Teleflex, 127 s. Ct. at 1739–1743.7. KSR v. Teleflex, 127 s. Ct. at 1741.8. In re Sullivan, 498 F.3d 1345 (Fed. Cir. 2007).9. In re Sullivan, 498 F.3d at 1353.10. Innogenetics NV v. Abbott Labs., 512 F.3d 1363 (Fed.

Cir. 2008).11. Innogenetics NV v. Abbott Labs., 512 F.3d at 1373.12. Pharmastem Therapeutics v. Viacell, 491 F.3d 1342

(Fed. Cir. 2007).13. Pharmastem Therapeutics v. Viacell, 491 F.3d at

1363.14. Pharmastem Therapeutics v. Viacell, 491 F.3d at

1360.15. Pharmastem Therapeutics v. Viacell, 491 F.3d at

1374–1378.16. Pharmastem Therapeutics v. Viacell, 491 F.3d at

1378.17. Innogenetics v. Abbott Labs., 512 F.3d at 1373.18. KSR v. Teleflex, 127 s. Ct. at 1742.19. Pharmastem Therapeutics v. Viacell, 491 F.3d at

1363.

inventions will have a greater role and also require patent protection to ensure continued development of the industry. For the sake of continued progress in the field, the hope is that combination biotech inventions will not be subjected to special scrutiny, but merely the normal vigor of traditional obviousness under Graham as guided by KSR.

ACKNOWLEDGMENTSH.K.W. thanks his parents, Sie Ting and Prapasri, his sister, Meelynn, and his wife, Joanne Kong, for their unconditional love and support. He dedicates this piece to his grandmother Tangon Thanesuan, his grandaunt Dorothy Hwang, and his mother-in-law, Esther Soo Kong, who continue to inspire him to think creatively and believe in what is right. You will never be forgotten.

1. KSR International Co. v. Teleflex, Inc., 127 s. Ct. 1727 (2007).

2. Yamanaka, M. Nat. Biotechnol. 26, 1085–1086 (2008).

of the basic attacks used to challenge patent validity during litigation. The obviousness analysis is critically fact-dependent whether it occurs at the procurement or litigation stage. Biotech, as an art, is still evolving and continues to be complex in comparison to more mature fields. In the short term, the key factors to ensuring greater patent protection are the reliance on unpredictability of results and demonstrating a lower level of skill for the POSA. These two factors in combination with support for secondary considerations (commercial success, long-felt needs, failure of others, praise by other scientists, teach-ing away by others), will allow a variety of biotech inventions to receive their entitled patent protection. In the long term, how-ever, as the various fields of biotech emerge from the growing pains of their teen years into adult maturity, combination biotech

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