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Application for Patent filed June 7, 1989, Serial No. 363,318; which is a continuation of application Serial No. 799,369, filed November 11, 1985, now abandoned; which is a continuation-in-part of application Serial No. 728,906, filed April 30, 1985, now abandoned. Plant-Colonizing Microorganisms Containing The Toxin Gene B. Thuringiensis As A Chromosomal Insertion.
This is an appeal from the examiner's final rejection of claims 39 through 41 and 43 through 51. Claims 52 through 56, 58, 60 through 62, 64, 66 through 68, 70, 72 through 74, 76, 78 and 79 remain in the application but have been indicated as allowable by the examiner.
39. A method of combatting plant insect pests which comprises applying to the plant environment or plant seed plant-colonizing bacteria having within its chromosome heterologous DNA encoding for the protein toxin of Bacillus thuringiensis which bacteria are capable of proliferating in the plant environment and which express an insecticidally effective amount of the protein toxin.
McKay et al. (McKay), Applied and Environmental Microbiology, "Stabilization of Lactose Metabolism in Streptococcus lactis C2," Vol. 36, August 1978, pages 360-367.
Kloepper et al. (Kloepper), Phytopathology, "Development of a Powder Formulation of Rhizobacteria for Inoculation of Potato Seed Pieces," Vol. 71, 1981, pages 590-592.
Held et al. (Held), Proceedings of the National Academy of Science, U.S.A., "Cloning and localization of the lepidopteran protoxin gene of Bacillus thuringiensis subsp. kurstaki," Vol. 79, October 1982, pages 6065- 6069.
Simon et al. (Simon), Bio/Technology, "A Broad Host Range Mobilization System For In Vivo Genetic Engineering Transposon Mutagenesis In Gram Negative Bacteria," Vol. 1, November 1983, pages 784-791.
Weller, Applied and Environmental Microbiology, "Distribution of a Take-All Suppressive Strain of Pseudomonas fluorescens on Seminal Roots of Winter Wheat," Vol. 48, No. 4, October 1984, pages 897-899.
Dean, Biotechnology and Genetic Engineering Reviews, "Biochemical Genetics of the Bacterial Insect-Control Agent Bacillus thuringiensis: Basic Principles and Prospects for Genetic Engineering," Vol. 2, October 1984, pages 341-363.
Goldberg et al. (Goldberg), Maximizing Gene Expression, "The Selective Degradation of Abnormal Proteins in Bacteria," Chapter 9, W. Reznikoff and L. Gold (eds.), Butterworth Press, Boston, 1985, pages 287-314.
*2 Kennell, Maximizing Gene Expression, "The Instability of Messenger RNA in Bacteria," Chapter 4, W. Reznikoff and L. Gold (eds.), Butterworth Press, Boston, 1985, pages 101-142.
Cullen et al. (Cullen), TIBTECH, "Biological control of leaf damage in plants," 1986, pages 115-119.
Lindow, Microbiology of the phyllosphere, "Strategies And Practice Of Biological Control Of Ice Nucleation-Active Bacteria On Plants," N.J. Fokkema and J. Van Den Heuvel (eds.), Cambridge University Press, Cambridge, 1986, pages 293-311.
Panopoulos, Microbiology of the Phyllosphere, "Tactics And Feasibility Of Genetic Engineering Of Biocontrol Agents," N.J. Fokkema and J. Van Den Heuvel (eds.), Cambridge University Press, Cambridge, 1986, pages 312-334.
Appellants' invention concerns a method of combatting plant insect pests utilizing plant colonizing bacteria which have been genetically modified to produce the protein toxin of Bacillus thuringiensis. The modification is accomplished by inserting DNA encoding for the protein toxin into the chromosome of the bacteria. The genetically modified bacteria are applied to the plant environment or the plant seed and express the insecticidally active protein toxin which is consumed by plant pests. This is said to control the growth and activity of the plant pests.
All of appellants' claims stand rejected under 35 U.S.C. § 112, first paragraph, as being broader than what is enabled by the specification's disclosure. The examiner is of the opinion that appellants' specification is "enabling only for claims limited in accordance with the as-filed specification" (Answer, page 4).
Appellants' claims also stand rejected under 35 U.S.C. § 103 over Dean in view of Held, Simon and McKay, and further in view of Weller or Kloepper, the latter two references being applied only with regard to claims 48 through 51.
We consider first the rejections under 35 U.S.C. § 103.
In proceedings before the Patent and Trademark Office, the examiner bears the burden of establishing a prima facie case of obviousness based upon the prior art. In re Piasecki, 745 F.2d 1468, 1471-72, 223 USPQ 785, 787-88 (Fed.Cir.1984). The examiner can satisfy this burden only by showing some objective teaching in the prior art or that knowledge generally available to one of ordinary skill in the art would lead that individual to combine the relevant teachings of the references. In re Fine, 837 F.2d 1071, 1074, 5 USPQ2d 1596, 1598 (Fed.Cir.1988). Indeed, the teachings of references can be combined only if there is some suggestion or incentive to do so. ACS Hospital Systems, Inc. v. Montefiore Hospital, 732 F.2d 1572, 1577, 221 USPQ 929, 933 (Fed.Cir.1984).
*3 It is the examiner's position that Dean suggests a method of combatting plant insect pests which comprises applying to the plant environment bacteria which is capable of survival and colonization in nature sand harbors a gene encoding the toxin produced by Bacillus thuringiensis. It is further the examiner's position that the secondary references teach the advantages of and techniques for insertion of the B. thuringiensis toxin gene into the chromosome of the bacteria to stabilize expression of the gene.
We have carefully reviewed all of the references cited by the examiner in their entirety. We are unable to find a suggestion therein to do what appellants have done, namely incorporate the gene into the chromosome of a bacteria capable of proliferating in the plant environment and applying that bacteria to the environment or seed of the plant.
The Dean reference, though many pages long, is replete with advice regarding incorporation of the gene into plasmids of various bacteria, particularly, E. coli, but contains little information regarding how to use the transformed bacteria and clearly does not specifically suggest appellants' use. At page 357, Dean contains a short discussion of utility and suggests insertion of the gene into the plant itself to create a systemic and highly specific toxin. Dean also suggests increasing the amount of toxin per bacterial cell to lower the cost of conventional processes wherein the toxin itself is applied to the plant. Neither of these teachings is concerned with appellants' method of use. Dean also suggests the transfer of toxin genes "to other bacteria which have better survival in nature." Dean exemplifies this concept by noting that the mosquito-toxic bacteria B. thuringiensis var. israelensis survives only two days in nature and that other bacteria, such as "natural pond microflora," would make more suitable hosts.
This specific statement regarding combatting mosquitos using genetically engineered "natural pond microflora" is relied on by the examiner for the "suggestion" required by the aforementioned case law. However, the specific statement by Dean is not a suggestion to insert the gene into the chromosome of bacteria and apply that bacteria to the plant environment in order to protect the plant. At best, the Dean statement is but an invitation to scientists to explore a new technology that seems a promising field of experimentation. The Dean statement is of the type that gives only general guidance and is not at all specific as to the particular form of the claimed invention and how to achieve it. Such a suggestion may make an approach "obvious to try" but it does not make the invention obvious. See In re O'Farrell, 853 F.2d 894, 7 USPQ2d 1673, 1681 (Fed.Cir.1988).
The importance of a prior art suggestion's guidance as to the particular form of the invention may be dramatically illustrated by noting that the Dean comments regarding insertion of the gene into "other bacteria such as natural pond microflora" may well have been construed as referring to the entirely different approach of including the toxin gene in cyanobacteria, the bacteria that forms blue-green algae on pond surfaces. See In re Vaeck, 947 F.2d 488, 20 USPQ2d 1438 (Fed.Cir.1991), [FN1] which discusses such an invention.
*4 We recognize that given the teachings in appellants' specification regarding incorporation of the gene into the chromosome and utilizing the bacteria in the plant environment, one can theoretically explain the technological rationale for the claimed invention using selected teachings from the references. This approach, however, has been criticized by our reviewing court as hindsight reconstruction. See In re Fine, supra, 837 F.2d at 1075, 5 USPQ2d at 1600. See also In re Sernaker, 702 F.2d 989, 217 USPQ 1 (Fed.Cir.1983).
We consider next the rejection under 35 U.S.C. § 112. It is the examiner's position that appellants' disclosure is enabling only for claims limited in accordance with the "as-filed specification." The examiner is of the opinion that undue experimentation would be required to practice the invention particularly with regard to the development of host strains, transformation protocols and vectors for the insertion of toxin genes into the chromosomes of the vast number of heterogenous gram-positive and gram-negative bacteria encompassed by the claims. As explained by the examiner, difficulty would be encountered regarding identification and construction of host strains capable of expressing the gene without interfering with the ability of the strains to colonize the plant environment. The examiner notes that in the instant case there is not only unpredictability with regard to expression of any B. thuringiensis gene in the vast number of heterogenous bacteria encompassed by the claims but additional unpredictability in the use of any of the transformed bacteria in the claimed method of bio-control. In support of his position, the examiner has cited the literature articles by Lindow, Panopoulos and Cullen which discuss factors affecting the ability of bacteria to colonize plant tissue, and articles by Kennell and Goldberg which discuss the instability of mRNA in bacteria and the degradation of heterogenous proteins in bacteria.
Appellants, on the other hand, strongly urge the inapplicability of the literature articles to the facts of the instant case and provide declaration evidence by Dr. Douglas E. Berg. Dr. Berg is expert in the field of genetic engineering using the prokaryotic transposable element Tn5, the same transposon utilized by appellants. [FN2] Appellants also submitted the declaration of Dr. Pamela Marrone describing evaluations conducted utilizing leaf colonizing bacteria engineered to contain B. t. gene as described in the application. The declaration indicates that the bacteria Pseudomonas putida, a leaf colonizer, was engineered to express the gene coding for the B. t. toxin. The results of her work show that populations of the bacteria survived for as long as five weeks and that insect damage was less with the plants treated with the transgenic bacteria. The data also showed that the engineered microorganism not only survived but proliferated to a stable population when the inoculum concentration of the population was initially low.
*5 We have carefully reviewed all of the references cited by the examiner, the Berg and Marrone declarations, the Berg article and, indeed, an article written by the examiner and referred to by Dr. Berg. We are of the opinion that any prima facie case of non-enablement established by the examiner has been overcome by the evidence submitted by appellants and, accordingly, we reverse the examiner's rejection.
We note specifically that Dr. Berg has supplied sound scientific reasoning in support of his position that the transposon strategy described in the application would have permitted many other plant colonizing bacteria to be transformed with B. thuringiensis gene. As noted by Dr. Berg, the inventors described the successful testing of four separate isolates of Pseudomonas fluorescens and two separate isolates of Agrobacterium radiobacter. Transposition was obtained by the inventors utilizing a suicide plasmid. This appears to be the same approach utilized by the examiner and others to obtain transposition in Pseudomonas syringae. As noted in Dr. Berg's review article, the transposable elements are ubiquitous and have a characteristic ability to insert into many sites in the genomes of many host organisms.
Dr. Berg notes that most bacteria containing the gene would be expected to kill or impair the growth of insects in a plant environment. This is not an irrational statement considering the teachings of the Dean reference which indicate that the gene has been inserted into plasmids and introduced into several types of bacteria while retaining its capability of producing an active protein. Moreover, there is no indication that the gene caused the bacteria to alter its colonization behavior.
We recognize that the inventors' success with root colonizing bacteria may not have been extrapolatable to bacteria colonizing the leaves of the plants. Accordingly, the examiner correctly challenged enablement from that viewpoint. In this case, however, appellants have submitted the Marrone declarations which show that the strain Pseudomonas putida, a naturally occurring non-genetically engineered leaf colonizing bacteria, was genetically engineered to contain the B. t. gene in the chromosome as claimed herein. That bacteria proliferated on the plants and expressed the protein toxin.
The examiner has not challenged the findings of Dr. Marrone other than to state that the tests were conducted in vitro under controlled environmental conditions in which the effects of the hostile plant environment (high temperature, osmotic stress, etc.) upon heterogenous gene expression were not determined.
We recognize that Dr. Marrone's testing may well have been "in vitro" as compared to the growth of plants in open fields. We note, however, that this is a carefully regulated field of experimentation wherein there is great fear that the cloned trait may be undesirably mobilized into other types of bacteria in the field (appellant's specification, page 5, lines 30-33). As we understand it, the growth chamber test conducted by Dr. Marrone is a test customarily used for screening of plant related developments of potential utility in horticultural applications. [FN3] See In re Jolles, 628 F.2d 1322, 206 USPQ 885 (CCPA 1980) regarding the use of "customarily used" screening tests for evaluation of utility of chemical compounds.
*6 The issue of whether or not undue experimentation is required must be decided on the facts of each case. Reported cases are of limited precedential value. See, e.g., In re Angstadt, 537 F.2d 498, 190 USPQ 214 (CCPA 1976); In re Metcalfe, 410 F.2d 1378, 161 USPQ 789 (CCPA 1969). It is well settled that patent applicants are not required to disclose every species encompassed by their claims, even in an unpredictable art. In re Vaeck, supra; In re Angstadt, supra 537 F.2d at 502-03, 190 USPQ at 218. In the case before us, appellants' specification literally describes the plant-colonizing microorganisms which may be engineered as belonging to eight different genera, bacteria from the genus Pseudomonas being preferred. Moreover, the claims limit the microorganisms to those capable of colonizing the "plant environment," i.e., the surface of the plant, e.g., leaf, stem, buds, stalk, flower parts or root surface and the "rhizosphere" or soil which surrounds and which is influenced by the roots of the plant. The bacteria of the claims is also described as bacteria "capable of proliferating in the plant environment and which express an insecticidally effective amount of the protein toxin." The claims are not as broad as asserted by the examiner.
Appellants' declarations and the literature accompanying the Berg declaration indicate the ubiquity of the Tn5 transposon and substantiate the capability of one skilled in the art to prepare the claimed bacteria without undue experimentation. On the facts of this case, appellants have rebutted the examiner's prima facie case of non-enablement.
The examiner's rejections of claims 39 through 41 and 43 through 51 under 35 U.S.C. § 103 and 35 U.S.C. § 112 are reversed.
FN1. The title of the Vaeck patent application reads as follows: "Hybrid Genes Incorporating a DNA Fragment Containing a Gene [B. t.] Coding for an Insecticidal Protein, Plasmids, Transformed Cyanobacteria Expressing Such Protein and Method for Use as a Biocontrol Agent." (Inserts and emphasis added).
FN2. A copy of Dr. Berg's review article, "The prokaryotic transposable element Tn5," which appeared in Bio/Technology, July 1983, is in the file.
FN3. See also Watrud et al. (Watrud), "Cloning of the Bacillus thuringiensis subsp. kurstaki Delta-Endotoxin Gene into Pseudomonas fluorescens: Molecular Biology and Ecology of an Engineered Microbial Pesticide," which appeared in Engineered Organisms in the Environment, a cross disciplinary symposium June 10-13, 1935.

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