Board of Patent Appeals and Interferences
Patent and Trademark Office (P.T.O.)
*1 EX PARTE ARJUN SINGH
Appeal No. 90-1174
June 22, 1990
Application for Patent filed June 20, 1983, Serial No. 06/506,098, which is a continuation-in-Part of Serial No. 06/488,323 filed April 25, 1983. Use Of Alpha Factor Sequences In Yeast Expression Systems.
Janet E. Hasak et al. for appellant
Supervisory Patent Examiner--Thomas G. Wiseman
Before Goldstein, Winters and W. Smith
This is an appeal from the final rejection of claims 2, 5, 8, 9 and 11. Claim 18, which was only objected to at the time of the final rejection, was newly rejected by the examiner in the Examiner's Answer. Thus, the claims before us for consideration are claims 2, 5, 8, 9, 11 and 18, all the claims remaining in the application.
Claims 2 and 8 are illustrative of the subject matter on appeal and read as follows:
2. A process for obtaining a mature protein heterologous to yeast as a product of yeast expression, which process comprises:
(a) transforming a yeast organism with an expression vehicle comprising the DNA sequence encoding a lys arg C-terminal pre-pro peptide of yeast alpha factor operably connected in translation reading frame without intervening Glu (or Asp)-Ala dipeptide repeats to a DNA sequence encoding a mature protein heterologous to the yeast organism;
(b) culturing the transformed organism; and
8. A yeast expression vehicle comprising the DNA sequence encoding a lys arg C-terminal pre-pro peptide of yeast alpha factor gene operably connected in translation reading frame without intervening Glu (or Asp)-Ala dipeptide repeats to a DNA sequence encoding a mature protein heterologous to the yeast organism.
Claims 2, 5, 8, 9, 11 and 18 stand rejected under 35 USC § 112, first paragraph, as being nonenabled. We affirm.
The claims on appeal are directed to a yeast expression vehicle which comprises the DNA sequence encoding a lys arg C-terminal pre-pro peptide of yeast ??Illegible Text?? <<alpha>>-factor gene connected in translation reading frame without intervening Glu (or Asp)-Ala dipeptide repeats to a DNA sequence encoding a mature protein which is heterologous to the yeast organism.
The first question of enablement raised by the examiner revolves around the requirement of the claimed expression vehicle that the DNA sequence encoding for the mature heterologous protein is connected in translation reading frame with a lys arg C-terminal pre-pro peptide of yeast ??Illegible Text?? <<alpha>>>>>>- factor gene without intervening Glu (or Asp)-Ala dipeptide repeats. Since appellant sets forth that ??Illegible Text?? <<alpha>>-factor genes contain plural repeat units for ??Illegible Text?? <<alpha>>-factor, each of which begins with lys arg and ends with the ??Illegible Text?? <<alpha>>-factor sequence with the lys arg being separated from the ??Illegible Text?? <<alpha>>>>>>-factor sequence by several Glu (or Asp)-Ala dipeptides repeats (specification, page 15, lines 10-30), the examiner questions the enablement of directly connecting the heterologous gene to any one or combination of the ?? Illegible Text?? <<alpha>>-factor units beyond the specific connection used in the present working examples. The working examples of the present specification are based upon an expression vehicle in which the nucleotides coding for the first lys arg pair are directly linked with the gene for the heterologous protein to be secreted where the remaining ??Illegible Text?? <<alpha>>-factor units, including the nucleotides coding for lys arg and the related spacer sequences, have been deleted.
*2 The examiner observes, without contradiction by appellant, that the claims on appeal are open to the heterologous gene being inserted after any one or more of the nucleotides coding for the lys arg pair. The examiner is of the opinion that it is unpredictable that constructs in which the heterologous gene is inserted in positions other than that demonstrated by the working examples of the present specification would, in fact, result in secretion of a mature protein as required by the claims on appeal.
The second portion of the examiner's position is based upon the fact that appellant has set forth only one working example in the present specification where a mature protein is secreted. The examiner questions whether claims such as those on appeal, which are not limited to the secretion of any specific protein, are enabled by the present disclosure which demonstrates the successful secretion of a single mature protein.
An enabling disclosure under 35 USC § 112, first paragraph, is one which allows those skilled in the art to make and use the claimed invention without undue experimentation. In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed.Cir.1988). The initial burden of establishing a prima facie case of nonenablement rests on the examiner. In re Marzocchi, 58 CCPA 1069, 439 F.2d 220, 169 USPQ 367 (1971). It has been recognized that the unpredictability of a particular art area may alone provide a reasonable doubt as to the accuracy of a broad statement made in support of the enablement of a claim. In re Marzocchi, supra. See also In re Fisher, 57 CCPA 1099, 427 F.2d 833, 166 USPQ 18 (1970).
Appellant admits on page 2, lines 13-17 of the present specification that at the time of the present invention, conventional wisdom was that each protein has evolved with a signal sequence which is well suited for translocation of that particular protein through a cell membrane. Appellant also sets forth on page 4, lines 25-27 of the present specification that the precise mechanism involved in the overall secretory processes of yeast was not fully understood. It is also acknowledged at page 16, lines 15-17 of the specification that the actual processing steps for yeast precursor proteins seem to be unpredictably different from those of mammalian precursors proteins.
Keeping in mind that (1) the claims on appeal call for yeast expression vehicles which encode a mature protein heterologous to the yeast organism and obtaining secreted mature protein, (2) the lack of understanding at the time the invention was made of the complete set of secretory processes in yeast, (3) the knowledge that the processing steps for yeast precursor proteins is unpredictably different from those of mammalian precursor proteins, and (4) the single successful demonstration of producing and secreting a mature heterologous protein as set forth at page 25, line 26-page 27, line 14 of the present specification, we agree with the examiner's conclusion that one of ordinary skill in the art would not be able to make and use the claimed invention throughout its scope. In re Marzocchi, supra.
*3 Appellant's arguments on pages 5-7 of the Appeal Brief are directed toward a description issue under 35 USC § 112, first paragraph, not the enablement requirement of this section of the statute. The examiner has not rejected the claims on appeal as lacking description in the original disclosure of this application. Rather, the examiner has questioned whether one skilled in the art is enabled to practice the claimed invention throughout its scope.
Appellant argues in the paragraph bridging pages 6-7 of the Appeal Brief that the heart of this invention is the deletion of a spacer peptide avoids extraneous N-terminal amino acids on the heterologous protein and it is irrelevant which and how many spacer domains are deleted or whether other ?? Illegible Text?? <<alpha>>-factor domains are present in the precursor. Appellant reasons that in some cases one skilled in the art may find it desirable to include a-factor domains if one wishes to express ??Illegible Text?? <<alpha>>-factor concurrent with the exogenous protein. These arguments, however, do not address the issue raised by the examiner's rejection, i.e., is one skilled in the art enabled to practice the claimed invention throughout its scope? One may very well desire to do what appellant sets forth in these arguments but appellant has not established that one skilled in the art would in fact be enabled to do so.
Appellant argues on page 10 of the Appeal Brief that the examiner must set forth reasons for doubting the truth or accuracy of any statement in the presumptively accurate supporting disclosure, citing In re Marzocchi, supra. However, as set forth above, Marzocchi recognizes that the unpredictability of an art area may alone be enough to create a reasonable doubt as to the accuracy of statements in the specification. Appellant has set forth in the original disclosure of this application ample reasons to doubt the predictability of achieving secretion of a mature heterologous protein throughout the scope of the claims on appeal.
Appellant argues that the results set forth in Table I of the specification are indicative of secretion of "mature" proteins according to the present invention. We disagree. Appellant sets forth in the paragraph bridging pages 19-20 of the specification that the N-terminal amino acid sequence of the interferon secreted from the procedure described in that sequence of examples contains seven extra amino acids, three from the modified gene for the interferon and four from the presequence of ??Illegible Text?? <<alpha>>-factor. The work which is described immediately following this passage of the specification, which includes the results set forth in Table I, indicates that the other secreted proteins were obtained in a manner similar to that used for the interferon. This would indicate that these proteins also contain extra amino acids at the N-terminus. As set forth at page 7, lines 19-26 of the specification, proteins containing such extraneous units would not be considered "mature" as this term is used in the present invention.
*4 For the reasons set forth above and those in the Examiner's Answer, the examiner's rejection is affirmed.
No time period for taking any subsequent action in connection with this appeal may be extended under 37 CFR 1.136(a). See the final rule notice, 54 F.R. 29548 (July 13, 1989), 1105 O.G. 5 (August 1, 1989).
BOARD OF PATENT APPEALS AND INTERFERENCES
Sherman D. Winters
William F. Smith