Ex Parte Dassler et alDownload PDFPatent Trials and Appeals BoardJun 18, 201911859350 - (D) (P.T.A.B. Jun. 18, 2019) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 11/859,350 22045 7590 Brooks Kushman 1000 Town Center 22nd Floor Southfield, MI 48075 09/21/2007 06/20/2019 FIRST NAMED INVENTOR Tobias Dassler UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www .uspto.gov ATTORNEY DOCKET NO. CONFIRMATION NO. WAS0905PUS 4494 EXAMINER TREPTOW, NANCY ANN ART UNIT PAPER NUMBER 1636 NOTIFICATION DATE DELIVERY MODE 06/20/2019 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): docketing@brookskushman.com kdilucia@brookskushman.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte TOBIAS DASSLER, ANNELIESE REUTTER-MAIER, and GUENTER WICH Appeal2018-008485 1 Application 11/859,3502 Technology Center 1600 Before DONALD E. ADAMS, RICHARD M. LEBOVITZ, and JACQUELINE T. HARLOW, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL This Appeal under 35 U.S.C. § 134(a) involves claims 3-5, 10, 11, 16-20, 25, and 27-34. Final Act. 3 1. 4 Examiner entered rejections under 35 U.S.C. § 103(a). We have jurisdiction under 35 U.S.C. § 6(b). 1 This Appeal is related to Appeal 2013-005593 (Application 11/859,305) Decision on Appeal affirming the obviousness rejections of record entered March 3, 2016, Decision on Request for Rehearing, denying rehearing, entered May 19, 2016. 2 Appellants identify "Wacker Chemie AG" as the real party in interest. Appellants' January 3, 2018 Appeal Brief (App. Br.) 2. 3 Examiner's July 11, 2017 Final Office Action. 4 Appellants' pending claim 21 stands withdrawn from consideration. Final Act. 1. Appeal2018-008485 Application 11/859,350 We AFFIRM. STATEMENT OF THE CASE Appellants' disclosure "relates to a process for the fermentative production of heterologous proteins by using an Escherichia coli strain having a lipoprotein mutation." Spec. 5 ,r 2. Appellants' claims 25 and 34 are representative and reproduced below: 25. A method for producing a eukaryotic protein by utilizing an E. coli strain in a fermentation medium, the method compnsmg: a) fermenting an E. coli strain in a fermenter with a volume of more than 5 0 liters fermentation medium such that the E. coli strain secretes the eukaryotic protein into the fermentation medium, wherein the fermentation medium comprises Ca2+ ions in a concentration from 10 mg/I to 5000 mg/I, the E. coli strain having: 1) a mutation in a Lipoprotein (lpp) gene or in a promoter region of the lpp gene, the mutation in the lpp gene being a substitution, a deletion or an insertion of one or more nucleotides in the lpp gene or in the promoter region of the lpp gene, leading to: i) the lpp gene no longer being expressed or being expressed to only a reduced extent such that only a maximum of 80% of an amount of lpp protein is detectable in cells of the E.coli strain by comparison with cells of wild-type strain W31 10 (ATTC: 27325), or ii) an altered amino acid sequence of lpp protein which is associated with a reduction in functionality of lpp protein so that at least 10% of alkaline phosphatase activity normally present in periplasm is realized to the fermentation medium or an increase in resistance of the cells to globomcin 5 Dassler et al., US 2008/0076158 Al, published Mar. 27, 2008. 2 Appeal2018-008485 Application 11/859,350 by a factor of at least 2 compared with lpp wild-type strain W3110, or iii) replacement of an arginine residue at position 77 of SE ID No. 2 by a cysteine residue (lpp I mutants), or iv) replacement of a glycine residue at position 14 of SEQ ID No. 2 by an aspartic acid residue (lpp3 mutants); and 2) a gene coding for the eukaryotic protein which is functionally linked to a signal sequence coding for a signal peptide; and b) removing the eukaryotic protein from the fermentation medium, wherein the eukaryotic protein is an antibody fragment comprising more than 100 amino acids wherein the antibody fragment is produced in an extracellular yield of more than 1 g/1. Claims App'x6 2-3 (emphasis added). 34. A method for producing a eukaryotic protein by utilizing an E. coli strain in a fermentation medium, the method compnsmg: a) fermenting an E. coli strain in a fermenter with a volume of more than 5 liters fermentation medium such that the E. coli strain secretes the eukaryotic protein into the fermentation medium, wherein the fermentation medium comprises Ca2+ ions in a concentration from 10 mg/I to 5000 mg/I, the E. coli strain having: 1) a mutation in a Lipoprotein (lpp) gene or in a promoter region of the lpp gene, the mutation in the lpp gene being a substitution, a deletion or an insertion of one or more nucleotides in the lpp gene or in the promoter region of the lpp gene, leading to: i) the lpp gene no longer being expressed or being expressed to only a reduced extent such that only a maximum of 80% of an amount of lpp protein is detectable in cells of the 6 Appellants' March 15, 2018 Claims Appendix. 3 Appeal2018-008485 Application 11/859,350 E.coli strain by comparison with cells of wild-type strain W31 10 (ATTC: 27325), or ii) an altered amino acid sequence of lpp protein which is associated with a reduction in functionality of lpp protein so that at least 10% of alkaline phosphatase activity normally present in periplasm is realized to the fermentation medium or an increase in resistance of the cells to globomcin by a factor of at least 2 compared with lpp wild-type strain W3110, or iii) replacement of an arginine residue at position 77 of SE ID No. 2 by a cysteine residue (lppl mutants), or iv) replacement of a glycine residue at position 14 of SEQ ID No. 2 by an aspartic acid residue (lpp3 mutants); and 2) a gene coding for the eukaryotic protein which is functionally linked to a signal sequence coding for a signal peptide; and b) removing the eukaryotic protein from the fermentation medium, wherein the eukaryotic protein is an antibody fragment comprising more than 100 amino acids wherein the antibody fragment is produced in an extracellular yield of more than 1 g/1, wherein an initial concentration for an E. coli food source is 10-30 g/1 with feeding started when the E.coli food source concentration has fallen to less than 5 g/1 such that the E. coli food source concentration is kept below 5 g/1. Id. at 4--5. 4 Appeal2018-008485 Application 11/859,350 Grounds of rejection before this Panel for review: 7 Claims 5, 6, 16, 19, 20, 25, 30, and 32-34 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination ofinouye, 8 Better,9 Simmons, 1° Kasche, 11 Carter, 12 and Bernard. 13 Claims 10 and 11 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard and either or Kowalski 14 or Schmid. 15 Claim 4 stands rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard, and Giam. 16 7 Appellants' pending claims 27-29 stand free from rejection. 8 Inouye et al., US 4,643,969, issued Feb. 17, 1987. 9 Better et al., Potent anti-CD5 ricin A chain immunoconjugates from bacterially produced Fab' and F(ab ')2, 90 PROC. NATL. ACAD. SCI. USA 457--461 (1993). 10 Simmons et al., Expression of full-length immunoglobulins in Escherichia coli: rapid and efficient production of aglycosylated antibodies, 263 J. IMMUNOLOGICAL METHODS 133-147 (2002). 11 Kasche et al., Ca2+ Is a Cofactor Required for Membrane Transport and Maturation and Is a Yield-Determining Factor in High Cell Density Penicillin Amidase Production, 21 BIOTECHNOL. PROG. 432--438 (2005). 12 Carter, WO 93/06217, published Apr. 1, 1993. 13 Bernard et al., Fermentation and Growth of Escherichia coli for Optimal Protein Production in CURRENT PROTOCOLS IN PROTEIN SCIENCE, 5.3.1- 5.3.15 (1995). 14 Kowalski et al., US 5,521,084, issued May 28, 1996. 15 Schmid et al., US 5,204,254, issued Apr. 20, 1993. 16 Giam et al., Prolipoprotein modification and processing in Escherichia coli: A unique secondary structure in prolipoprotein signal sequence for the recognition by glyceryl transferase, 141 EUR. J. BIOCHEM. 331-337 (1984). 5 Appeal2018-008485 Application 11/859,350 Claim 3 stands rejected under 35 U.S.C. § I03(a) as unpatentable over the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard and Inouye II. 17 Claims 17 and 18 stand rejected under 35 U.S.C. § I03(a) as unpatentable over the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard and Suzuki. 18 Claim 31 stands rejected under 35 U.S.C. § I03(a) as unpatentable over the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard, and Adams. 19 ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? ANALYSIS We adopt Examiner's findings concerning the scope and content of the prior art. Ans. 20 3-13. The rejection over the combination of Inouye, Better, Simmons, Kasche, Carter, and Bernard: Based on the combination of Inouye, Better, Simmons, Kasche, Carter, and Bernard, Examiner concludes that, at the time Appellants' invention was made, it would have been prima facie obvious "to have used 17 Inouye et al., Amino Acid Replacement in a Mutant Lipoprotein of the Escherichia coli Outer Membrane, 132 J. BACTERIOLOGY 308-313 (1977). 18 Suzuki et al., Murein-Lipoprotein of Escherichia coli: A protein Involved in the Stabilization of Bacterial Cell Envelope, 167 MOLEC. GEN. 1-9 (1978). 19 Adams et al., US 6,624,295 Bl, issued Sept. 23, 2003. 20 Examiner's June 28, 2018 Answer. 6 Appeal2018-008485 Application 11/859,350 at least 50 liters of fermentation media, containing the carbon source at levels recited as taught by Better ... and Bernard, in the method of Inouye in order to obtain large quantities of product", such as a F(ab')2 antibody fragment. See Ans. 7-8. Claim 25: Appellants contend that their claim 25 requires "the fermenter to be greater than 50 litres" and under the conditions set forth in Appellants' claim 25, "E. coli strains comprising an lpp mutation and a gene coding for heterologous protein which is linked in frame to a signal sequence coding for a signal peptide functional in E.coli unexpectedly grow in a short fermentation time on a production scale to normal cell densities." App. Br. 3 ( citing Spec. ,r,r 96-97); see also Reply Br. 1. Appellants further contend that their "Specification details that '[p ]reference is therefore given to fermenters with a volume of more than 5 1, particularly preferably fermenters with a volume of >50 1. "' App. Br. 4 ( emphasis omitted, alteration original) ( citing Spec. ,r 92); see also Reply Br. 1-2. Appellants also direct attention to Table 3 of their Specification, which "lists the yields of functional anti-lysozyme Fab fragment that could each be isolated from 20 ml portions of fermentation supernatant after fermentation for 72 h" in a non-disclosed fermentation volume. See App. Br. 4--5; see also Spec. ,r 151. According to Appellants, the foregoing contentions and Specification disclosures refute Examiner's assertion that Appellants' contentions are not persuasive because they are unsupported by evidence on this record. See App. Br. 5; cf Final Act. 13. We are not persuaded by Appellants' contentions. 7 Appeal2018-008485 Application 11/859,350 As Examiner explains, Appellants have the burden of establishing that their results are surprising or unexpected compared to those of the closest prior art. See Ans. 14; see also In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991). Notwithstanding Appellants' contentions to the contrary, this burden has not been met on this record. See Ans. 14. Specifically, Appellants have not compared their results to the closest prior art on this record. Regarding Appellants' contentions regarding Bernard, Examiner explains that "Bernard was cited to show that large (greater than 50 liter) volumes in fermentation of E. coli for the production of heterologous proteins, were known in the art" and the rejection of Appellants' claim 25 was over the combination of Inouye, Better, Simmons, Kasche, Carter, and Bernard. Ans. 14--15. Therefore, we are not persuaded by Appellants' contention that "the rejection cannot be sustained by reliance on Bernard and should be found improper" because, "Bernard makes no reference to the yield of any [fermentation] ... processes," which fails to address the merits of Bernard in combination with Inouye, Better, Simmons, Kasche, and Carter. See App. Br. 4--5; see also Reply Br. 2-3. One cannot show nonobviousness by attacking references individually when the rejection is based on a combination of references. In re Merck & Co., 800 F .2d 1091, 1097 (Fed. Cir. 1986). To the contrary, the relevant inquiry is whether the claimed subject matter would have been obvious to those of ordinary skill in the art in light of the combined teachings of those references. In re Keller, 642 F.2d 413,425 (CCPA 1981). 8 Appeal2018-008485 Application 11/859,350 Claim 34: We note that Appellants' contentions with respect to Appellants' claim 25 are not commensurate in scope with Appellant's claim 34, which (a) does not require a fermenter with a volume of more than 50 liters and (b) was not separately argued by Appellants. The rejection over the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard and either or Kowalski or Schmid: Based on the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard and either or Kowalski or Schmid, Examiner concludes that, at the time Appellants' invention was made, it would have been prima facie obvious to have utilized any of the disclosed and known signal sequences, in the expression of a heterologous protein in E. coli, since the cited references teach that any of these known signal sequences are useful for obtained large amounts of secreted protein that is linked downstream thereto. Based upon the teachings of the cited references, the high skill of one of ordinary skill in the art, and absent evidence to the contrary, there would have been a reasonable expectation of success to result in the claimed invention. Ans. 9. Having found no deficiency in the rejection of Appellants' claim 25 over the combination of Inouye, Better, Simmons, Kasche, Carter, and Bernard, we are not persuaded by Appellants' contention that Examiner's rejection of Appellants' claims 10 and 11 is improper for the reasons Appellants present for Appellants' claim 25. App. Br. 5. 9 Appeal2018-008485 Application 11/859,350 The rejection over the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard, and Giam: Based on the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard, and Giam, Examiner concludes that, at the time Appellants' invention was made, it would have been prima facie obvious to combine the teachings of Inouye, Better, Simmons, Kasche, Carter, Bernard and Giam to use the Lpp- mutant strain of Giam in the expression system for producing a heterologous protein. Because the strain of Giam produces a defective lipoprotein, one would have been motivated to do this because one of ordinary skill in the art would have recognized the mutant of Giam is equivalent to the strain of Inouye as being a "leaky" mutant. One would have had a reasonable expectation of success to use the Lpp- mutant strain of Giam in the expression system of Inouye, Better, Simmons, Kasche, Carter and Bernard for producing the protein because of the results of Inouye, Better and Giam. Ans. 10. Having found no deficiency in the rejection of Appellants' claim 25 over the combination of Inouye, Better, Simmons, Kasche, Carter, and Bernard, we are not persuaded by Appellants' contention that Examiner's rejection of Appellants' claim 4 is improper for the reasons Appellants present for Appellants' claim 25. App. Br. 5---6. The rejection over the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard and Inouye II: Based on the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard and Inouye II, Examiner concludes that, at the time Appellants' invention was made, it would have been prima facie obvious to combine the teachings of Inouye, Better, and Inouye [II] to use the Lpp- mutant strain of Inouye (J. Bact. 1977) in the 10 Appeal2018-008485 Application 11/859,350 expression system of Inouye, Better, Simmons, Kasche, Carter and Bernard, for producing a heterologous protein. Because the strain of Inouye [II] produces a defective lipoprotein, one would have been motivated to do this because one of ordinary skill in the art would have recognized the mutant of Inouye [II] is equivalent to the strain of Inouye as being a "leaky" mutant. One would have had a reasonable expectation of success to use the Lpp- mutant strain of Inouye [II] in the expression system of the primary references for producing the protein because of the results of Inouye, Better and Inouye [II]. Ans. 11. Having found no deficiency in the rejection of Appellants' claim 25 over the combination of Inouye, Better, Simmons, Kasche, Carter, and Bernard, we are not persuaded by Appellants' contention that Examiner's rejection of Appellants' claim 3 is improper for the reasons Appellants present for Appellants' claim 25. App. Br. 6. The rejection over the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard and Suzuki: Based on the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard and Suzuki, Examiner concludes that, at the time Appellants' invention was made, it would have been prima facie obvious "to have used LB medium with Mg++ ion concentration adjusted to contain over 48 mg/L or greater, [because] Suzuki ... teach[ es] the advantage of doing so." Ans. 12. Having found no deficiency in the rejection of Appellants' claim 25 over the combination of Inouye, Better, Simmons, Kasche, Carter, and Bernard, we are not persuaded by Appellants' contention that Examiner's rejection of Appellants' claims 17 and 18 is improper for the reasons Appellants present for Appellants' claim 25. App. Br. 6. 11 Appeal2018-008485 Application 11/859,350 The rejection over the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard, and Adams: Based on the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard, and Adams, Examiner concludes that, at the time Appellants' invention was made, it would have been prima facie obvious "to have utilized the well[-]known carbon source, glucose, in the method of expression disclosed by the references, since both glycerol and glucose were equivalent carbon sources used for E.coli growth in fermentation methods, as disclosed by Adams and Bernard." Ans. 13. Having found no deficiency in the rejection of Appellants' claim 25 over the combination of Inouye, Better, Simmons, Kasche, Carter, and Bernard, we are not persuaded by Appellants' contention that Examiner's rejection of Appellants' claim 31 is improper for the reasons Appellants present for Appellants' claim 25. App. Br. 6. CONCLUSION The preponderance of evidence relied upon by Examiner supports a conclusion of obviousness. The rejection of claims 25 and 34 under 35 U.S.C. § 103(a) as unpatentable over the combination of Inouye, Better, Simmons, Kasche, Carter, and Bernard is affirmed. Claims 5, 6, 16, 19, 20, 25, 30, 32, and 33 are not separately argued and fall with claim 25. The rejection of claim 10 under 35 U.S.C. § 103(a) as unpatentable over the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard and either or Kowalski or Schmid is affirmed. Claim 11 is not separately argued and fall with claim 10. 12 Appeal2018-008485 Application 11/859,350 The rejection of claim 4 under 35 U.S.C. § 103(a) as unpatentable over the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard, and Giam is affirmed. The rejection of claim 3 under 35 U.S.C. § 103(a) as unpatentable over the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard and Inouye II is affirmed. The rejection of claim 17 under 35 U.S.C. § 103(a) as unpatentable over the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard and Suzuki is affirmed. Claim 18 is not separately argued and fall with claim 17. The rejection of claim 31 under 35 U.S.C. § 103(a) as unpatentable over the combination of Inouye, Better, Simmons, Kasche, Carter, Bernard, and Adams is affirmed. TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 3 7 C.F .R. § 1.13 6( a). AFFIRMED 13 Copy with citationCopy as parenthetical citation