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408 NATURE BIOTECHNOLOGY VOL 17 MAY 1999 http://biotech.nature.com
CORRESPONDENCE
Patent amplificationTo the Editor:As the inventor of the Kauffman/Ballivetpatent, I read with interest your recent com-mentary (Nature Biotechnol. 17, 2, 1999). Ibelieve I can contribute two important addi-tional pieces of information.
First, the commentary presents a briefchronicle of scientific literature pertinent tothe Kauffman/Ballivet patent. The date of fil-ing of the patent is critical in order to evalu-ate this literature in the context of prior art.The Kauffman/Ballivet patent series claimspriority from early 1985.
Second, the final sentence of the pieceexpresses the hope that the price of licensingthe Kauffman/Ballivet patent will not be toohigh. In fact, we intend to make the patentavailable on a nonexclusive basis to anyone
who needs it. To this end, it is interestingthat reference is made in your piece to theCohen and Boyer patent. We have developeda licensing program in consultation withNiels Reimber who devised the licensingprogram for the Cohen and Boyer patent.
I hope this information is useful.Stuart A. Kauffman, M.D.
Bios Group LPSanta Fe, NM [email protected]
To the editor:A recent commentary by Harvey Bialy(Nature Biotechnol. 17, 2, 1999) addressed apatent awarded to Stuart Kauffman andMarc Ballivet. Bialy is certainly correct thatthe patent is “every bit asfundamental…and every bit as important”as that of Stanley Cohen and Herbert Boyercovering recombinant DNA technology.However, I must correct the record withrespect to the nine scientific publicationsthat Bialy characterizes as “pertinent toKauffman’s staggeringly broad claims.”
The referenced publications do not con-stitute history against which the patentabilityof the issued claims is to be judged. TheKauffman–Ballivet patent application was, infact, filed in 1985, prior to all but one of thereferences cited in the commentary.Furthermore, Hutchinson et al., which hadindeed been previously published, describesonly the methods that had become conven-tional by 1985 for introducing singlesequence changes into DNA. It is in factKauffman’s pioneering technique of produc-ing stochastically generated arrays of poly-mers that distinguishes his invention from theconventional wisdom of the time and sup-ports the award of proprietary protection.
Bialy further expresses the “hope that theUS Patent Office has been rigorous” in itsevaluation of Kauffman’s application forpatent. As an attorney of record of the appli-cation, I can assure him and your readers thatit has. Numerous references, including scien-tific articles and published patent docu-ments, were considered by the US PatentOffice during the extensive examinationdetermining the patentability of the claimedinvention. None was found to anticipate orrender obvious the elegant invention ofKauffman and Ballivet.
I would also point out that the patent towhich the commentary is directed is but oneof five related patents that have thus farissued from the original application; eachclaims different aspects of the original inven-tion of Kauffman and Ballivet.
Cathryn CampellCampell and Flores LLP
4370 La Jolla Village Drive, Suite 700San Diego, CA 92122
Uncloaking RNasesTo the editor:We would like to comment on the recentpaper describing ribonucleases (RNases)engineered to be resistant to the intracellularRNase inhibitor (RI) (Suzuki et al., NatureBiotechnol. 17, 265, 1999) and the accompa-nying analysis “Smartbombs and cloakingdevices” because we feel that the authors ofthe respective pieces neglected to clearlyframe these results in the context of otherwork in this emerging field.
Several published studies suggest that therole of RI in RNase cytotoxicity is notstraightforward; there is not always a positivecorrelation between RI resistance of engi-neered RNases and cytotoxicity. In oneexample, two hybrid rhRNase-onconase pro-teins were equally cytotoxic to cells, eventhough one of the hybrids was 100,000 timesmore sensitive to inhibition by RI1.
These results suggest that factors otherthan RI sensitivity affect cytotoxicity. In thisregard onconase and RNase A were shown tocause cell death by affecting different points isthe cell cycle in NIH/3T3 fibroblasts2. Thus,intracellular targets of individual RNases haveto be considered as well as RI inhibition.
Misreferencing obscured other importantcontributions in this field. Deonarain andEpenetos3 designed, engineered, andexpressed an sFv-bovine seminal RNasefusion protein targeted to the placental anti-gen alkaline phosphatase, and not Zewe etal.4 Work on a small chimeric anti-transfer-rin receptor single-chain sFv fused to thehuman RNase angiogenin by Newton et al.5
was assigned to Deonarain and Epenetos,while Zewe et al. actually engineered thesame sFv with pancreatic rhRNase andrhEDN4.
All of these fusion proteins engineeredwith “uncloaked RNases” were potent cyto-toxins to their respective target cell lines. WasRI not present in those cell lines or was it in acompartment not accessible to the targetedRNases? To try to resolve these questions,future feats of imaginative engineeringshould be combined with studies of cellularbiology to correlate RNase cytotoxicity withdirect measurement of intracellular RI levels,RNase mechanism and intracellular routing.
Susanna M. RybakDianne L. Newton
National Cancer Institute-Frederick CancerResearch and Development Center,
Frederick, MD [email protected]
1. Boix, E. et al. J. Mol. Biol. 257, 992–1007 (1996).2. Smith. M. et al. Exp. Cell Res. 247, 220–232 (1999).3. Deonarain, M. et al. Br. J. Cancer 77, 537–546
(1998).4. Zewe, M. et al. Immunotechnology 3, 127–136
(1997).5. Newton, D. et al. Biochemistry 35, 545–553(1996).
Letters may be edited for space and clarity.They should be addressed to:CorrespondenceNature Biotechnology345 Park Avenue SouthNew York, NY 10010-1707, USAor sent by e-mail to [email protected] include your telephone and fax numbers.
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