Ex Parte Schiller et alDownload PDFPatent Trials and Appeals BoardMar 26, 201914540563 - (D) (P.T.A.B. Mar. 26, 2019) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 14/540,563 11/13/2014 119489 7590 Vivex Biomedical Inc. David L. King 5131 NE County Road 340 High Spring, FL 32643 03/26/2019 FIRST NAMED INVENTOR Paul C. Schiller 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. DN0215 8717 EXAMINER FOX, ALLISON M ART UNIT PAPER NUMBER 1653 MAIL DATE DELIVERY MODE 03/26/2019 PAPER 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. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte PAUL C. SCHILLER and GIANLUCA D'IPPOLIT0 1 Appeal2018-005564 Application 14/540,563 Technology Center 1600 Before RICHARD M. LEBOVITZ, JAMES A. WORTH, and ROBERT A. POLLOCK, Administrative Patent Judges. LEBOVITZ, Administrative Patent Judge. DECISION ON APPEAL This appeal involves claims directed to a method of collecting non- expanded post-natal multilineage-inducible cells. The Examiner rejected the claims as obvious under 35 U.S.C. § 103 and under non-statutory obviousness-type double-patenting. Pursuant to 35 U.S.C. § 134, Appellants appeal the Examiner's determination that the claims are unpatentable. We have jurisdiction under 35 U.S.C. § 6(b). The Examiner's decision is affirmed. 1 The Appeal Brief ("Br." entered Jan. 22, 2018) lists the University of Miami and the Government of the United States of America as the real- parties-in-interest. Br. 3. Appeal2018-005564 Application 14/540,563 STATEMENT OF THE CASE The Examiner rejected claims 1, 2, 9, 15-19, 25-28, 48-56, and 61-69 as follows: 1. Claims 1, 2, 9, 15-19, 25-28, 48-50, 54--56, and 65-67 under 35 U.S.C. § 103 as obvious in view of Gang et al. (Blood, 2007, 109(4):1743-1751) ("Gang"), Dawidowska (in Molecular Aspects of Hematologic Malignancies, 2012, Chapter 19, 305-308), and Rojewski et al. (Transfusion Medicine and Hemotherapy, 2008, 35: 168-184) ("Rojewski"). Ans. 3. 2. Claims 1, 2, 9, 15-19, 25-28, 48-56, and 65-57 under 35 U.S.C. § 103 as obvious in view of Gang, Dawidowska, Rojewski, and further in view of Schiller et al. (U.S. Patent 7,807,458 B2, issued Oct. 5, 2015) ("Schiller '458"). Ans. 8-9. 3. Claims 1, 2, 9, 15-19, 25-28, 48-50, 54--56, and 61-69 under 35 U.S.C. § 103 as obvious in view of Gang, Dawidowska, Rojewski, and further in view of Quirici et al. (Experimental Hematology, 2002, 30:783-791) ("Quirici"). Ans. 9. 4. Claims 1, 2, 9, 15-19, 25-28, 48-56, and 61-69 under 35 U.S.C. § 103 as obvious in view of Schiller '458, Furcht et al. (US 2005/0181502 Al, published Aug. 18, 2005) ("Furcht"), and Dawidowska. Ans. 12. 5. Claims 1, 2, 9, 15-19, 25-28, 48-56, and 61-69 on the ground of non-statutory obviousness-type double patenting as being unpatentable over claims 1-17 of Schiller' 458. Ans. 18. Independent claim 1, which is illustrative of the appealed claims, is reproduced below: 2 Appeal2018-005564 Application 14/540,563 1. A method of collecting non-expanded post-natal multilineage-inducible cells comprising: obtaining bone marrow from a biological sample of an animal; isolating total nuclear cells (TNCs) from the bone marrow; incubating the TN Cs in the presence of an antibody, wherein the antibody is directed to a cell surface marker comprising SSEA-4; separating non-expanded post-natal multilineage- inducible cells that bind to the antibody from cells that do not bind to the antibody; and collecting the non-expanded post-natal multilineage- inducible cells at a yield of 1.5% or greater of the TN Cs before the number of cells obtained from bone marrow have increased in number due to cell division in vitro. OBVIOUSNESS BASED ON GANG The Examiner found that Gang teaches that cell surface marker SSEA-4 is present on human mesenchymal cells ("MSCs") in the bone marrow. Ans. 3. The Examiner found that Gang performed fluorescent activated cell separation (FACS) on the MSCs using a SSEA-4 antibody. Id. F ACS separates cells based on expression of a cell surface marker, which in this case is SSEA-4. Thus, the Examiner found that Gang accomplished the claimed steps of "incubating" cells "in the presence of an antibody, wherein the antibody is directed to a cell surface marker comprising SSEA-4" and "separating non-expanded post-natal multilineage-inducible cells that bind to the antibody from cells that do not bind to the antibody." Ans. 3--4. The Examiner found that the cells isolated from the bone marrow using the SSEA-4 would be the claimed "non-expanded post-natal multilineage- inducible cells" because they are isolated by F ACS prior to expansion in culture and were shown to be "multilineage" after expansion in culture. 3 Appeal2018-005564 Application 14/540,563 Ans. 4. With respect to the claimed "yield of 1.5% or greater," the Examiner identified Gang's disclosure of yields of 2--4% SSEA-4+ cells from the bone marrow as meeting the limitation. Ans. 4--5. The Examiner stated that Gang differs from the claim in not disclosing the step of "isolating total nuclear cells (TN Cs) from the bone marrow." Ans. 5. However, the Examiner found that it was routine at the time of the invention to perform such a step as established by Dawidowska. Id. The Examiner found it obvious to do so to reduce the "overall volume of cellular material is reduced (by removing non-MNCs (e.g. red blood cells, adipocytes)) and thus would permit for use of reduced quantities of antibody and staining reagents, thereby saving money." Id. Appellants argue that "Gang failed to establish that their non- expanded SSEA-4+ cells have multilineage differentiation potential." Br. 13. Appellants identify the disclosure in Gang of cells passaged in culture and then differentiated (Gang, Fig. 6). Id. Based on this disclosure, Appellants state that, in all the examples, "Gang's SSEA-4+ cells were never shown to have multilineage differentiation potential without having previously been expanded" in culture. Br. 14. Appellants that that "[t]here is no evidence of record that one of ordinary skill would have reasonably expected that Gang's SSEA-4+ cells have multilineage differentiation potential after their isolation and before their expansion." Id. This argument does not persuasively demonstrate error in the Examiner's rejection. As found by the Examiner, Gang isolated SSEA-4+ 4 Appeal2018-005564 Application 14/540,563 cells in the same way as claimed, namely, using a SSEA-4 antibody. 2 The cells "obtained from SSEA-4+ -sorted cells" by Gang were "prove[d] conclusively" to be mesenchymal stem cells by their ability, after single-cell cloning by F ACS and 2 or more passages, to differentiate into bone, cartilage, and fat cells. Gang 17 48 ("Clonal analysis"). Gang thus persuasively demonstrated that a single cell, separated using the SSEA-4 antibody, is a "multilineage-inducible" cells as required by claim 1. Appellants did not identify a limitation in claim 1 that would require the "non-expanded post-natal multilineage-inducible cells" obtained after the F ACS sorting to have been induced to differentiate into adult lineages in the non-expanded state. Nonetheless, to the extent the claim would be interpreted this way, as found by the Examiner, Gang's cell were isolated from the same source, and by the same technique which is claimed, and therefore would be reasonably expected to possess the same characteristics. Ans. 19. Appellants argue that it is "well-known in the art that in vitro treatment of cells by reprogramming them can change their phenotype. For example, changing the expression of a limited number of genes in somatic cells can tum them into induced pluripotent stem (iPS) cell." Br. 14--15. Appellants, however, did not explain, why the same cell population isolated in the claims and in Gang, from the same source, would behave differently. Consequently, we find this argument unavailing. As held in In re Best, 562 F.2d 1252 (CCP A 1977): 2 "The SSEA-4 mouse monoclonal antibody recognizes the SSEA-4 antigen expressed on human and mouse cells." Gang 17 44 (in section titled "Flow cytometry and sorting of MS Cs."). 5 Appeal2018-005564 Application 14/540,563 Where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. Whether the rejection is based on "inherency" under 35 U.S.C. § 102, on "prima facie obviousness" under 35 U.S.C. § 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO' s inability to manufacture products or to obtain and compare prior art products. Id. at 1255 (footnote omitted) (citation omitted). Thus, once "the PTO shows sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 708 (Fed. Cir. 1990). Appellants have not demonstrated that the cells described in Gang would not inherently possess the same characteristics as the claimed cells. Appellants argue that the Examiner did not "did not provide a reason for one of ordinary skill in the art to include such an isolation step [ as described in Dawidowska] when trying to improve a method for collecting non-expanded multilineage-inducible cells." Br. 15. We do not agree. As stated above in the summary of the Examiner's rejection, the Examiner explained it would have been obvious to obtain the TNC fraction to reduce the volume and reagents necessary to accomplish the cell separation. Non-Final Act. 11. Appellants did not identify a defect in this reasoning. Appellants contend that "[t]he inventors of the present invention have found a 3500-fold increase in yield over their previously disclosed method. This improved result would not have been obvious Gang in view of Dawidowska." Br. 15. This argument is not convincing because Appellants did not provide objective evidence of this result. An argument made by 6 Appeal2018-005564 Application 14/540,563 counsel in a brief does not substitute for evidence lacking in the record. Estee Lauder, Inc. v. L 'Orea!, S.A., 129 F.3d 588, 595 (Fed. Cir. 1997). Furthermore, the proper comparison is with the closest cited prior art in the rejection, which in this case is Gang, not the inventor's "previously disclosed method," which has not even been identified. To establish unexpected results, the claimed subject matter must be compared with the closest prior art. In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) ("[W]hen unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art."). Appellants also dispute that that the limitation of "collecting the non- expanded post-natal multilineage-inducible cells at a yield of 1.5% or greater of the TN Cs before the number of cells obtained from bone marrow have increased in number due to cell division in vitro" is met by Gang. Br. 15- 16. Appellants acknowledge that "Gang reported 2-4% of total bone marrow is SSEA-4+," but they argue Gang "did not teach all of them were mesenchymal stem cells (MSCs)." Br. 16. But Appellants provide no evidence for this assertion and their argument, standing alone, does not demonstrate error in the Examiner's rejection. As discussed above, Gang performed single-cell cloning using F ACS separation of bone marrow cells using the SSEA-4 marker and "prove[d] conclusively that cultures obtained from SSEA-4+-sorted cells contained true mesenchymal stem cells." Gang 1748 ("Clonal analysis"). In view of this disclosure, one of ordinary skill in the art would have had reason to believe that the SSEA-4+ cells identified as being 2-4% of total bone marrow are mesenchymal cells which are "multilineage-inducible" as required by the claim. 7 Appeal2018-005564 Application 14/540,563 Appellants also argue that there is no evidence that the disclosed process would provide sufficient cells for direct therapeutic use. Br. 17, 18. Appellants do not identify a deficiency in the rejection, but simply make this statement. As explained by the Examiner, the purpose of Gang is to provide cells for clinical application. Gang, Abstract. Gang isolates cell populations with mesenchymal cells which differentiate into different lineages. Id. Appellants have not explained why such isolated cell populations would not be sufficient for a therapeutic application. The Examiner cited additional publications to meet additional limitations in the dependent claims. Appellants argued that these publications do not make up for the deficiencies in Gang and Dawidowska. Br. 16, 17, 18. For the foregoing reasons, the obviousness rejection of claim 1 is affirmed. Claims 2, 9, 15-19, 25-28, 48-50, 54--56, and 65----67 were not argued separately and fall with claim 1. Rejections 2 and 3, also based on Gang and Dawidowska, are affirmed for the same reasons. 37 C.F.R. § 4I.37(c)(l)(iv). OBVIOUSNESS BASED ON SCHILLER '458 The Examiner found the Schiller '458 describes multilineage- inducible cells ("MIAMI") which can be isolated using the SSEA-4 marker, the same marker described in the claim. Ans. 12. The Examiner also found that the Schiller '458 teaches that the cells can be isolated from bone marrow, the same source recited in the claims. Id. The Examiner stated that Schiller' 458 does not disclose the step of "isolating total nuclear cells (TNCs) from the bone marrow," but found it obvious to do so because 8 Appeal2018-005564 Application 14/540,563 Schiller '458 teaches partial purification of cells after collection and that isolation of TN Cs was routine at the time of the invention as established by Dawidowska. Ans. 11-12. The Examiner determined it would have been obvious to one ordinary skill in the art to combine the teachings of Dawidowska with Schiller '458' s method to reduce the volume of material and the needed reagents to accomplish separation and "to save money by using less reagents." Id. at 13. Appellants argue that Schiller '458 has in vitro culture and expansion steps are that are not recited in claim 1. Br. 1 7. Appellants state that "there is no evidence of a reasonable expectation that multilineage-inducible cells can be isolated without in vitro expansion." Id. As discussed above for the rejections based on Gang, the claimed method of using an SSEA-4 antibody to isolated cells from the bone marrow is the same method as disclosed in Schiller '458 3 and thus would have reasonably been expected to result in the isolation of the same cells. Appellants have the burden in such circumstances to prove that the claimed cells are different, but did not provide objective evidence to establish a difference. Best, 562 F.2d at 1255. Appellants argue that the cells isolated "by Appellant's invention and Schiller's previous process are also different." Br. 19. Appellants state that 3 "In other embodiments, MIAMI cells are isolated from a biological sample based on the physical properties of the MIAMI cells. For example, several techniques are known in the art by which MIAMI cells may be isolated based on the unique set of markers expressed by MIAMI cells, including, for example, fluorescence-activated cell sorting (F ACS), immobilized marker- specific antibodies (such as, antibody-coupled beads), or magnetic-activated cell sorting (MACS)." Schiller '458, col. 17, 11. 41--49. 9 Appeal2018-005564 Application 14/540,563 "[ s ]urprisingly, the claimed process can isolate about 3,500 times more multilineage-inducible cells than the inventors' previous process (i1 [131] of the specification as filed and corresponding ,r [0130] of the US 2015/0132266 publication)." Br. 19. Paragraph 131 from the Specification is reproduced below: In one embodiment, the isolation of ne-MIAMI cells was performed on fresh human BM. After Ficoll gradient separation total nuclear cells (MNCs) were incubated for 30 minutes at 4 degrees C in the presence of anti-SSEA-4 antibody phycoerythrin conjugated (SSEA-4-PE). At the end of the incubation time anti-PE microbeads (Miltenyi Biotech) were added to cells. FACS analysis demonstrated that 3.5% of TNCs are SSEA-4+ cells, as shown in figure lB, which is about 3,500 times more cells than the number of marrow stromal cells (MSCs) isolated from BM using the empirical isolation procedure used in the inventor's prior patented invention. We do not find Appellants' argument persuasive. First, there are steps described in paragraph 131 which do not appear in the claim, such as the incubation time and temperature, specific antibody, and the use anti-PE microbeads. To the extent the results are "surprising," it has not been established that the "surprising" results would be obtained for the full scope of the claim, for example, using different incubation times, temperatures, antibody, and no beads. Unexpected results must be commensurate with the full scope of the claim. In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005). Second, Appellants did not identify the "empirical isolation procedure used in the inventor's prior patented invention." Thus, it is not evident to what the comparison is being made. Indeed, no comparative data has been provided to determine whether such evidence is sufficient to establish surprising results for the full scope of the claim. 10 Appeal2018-005564 Application 14/540,563 OBVIOUSNESS-TYPE DOUBLE PATENTING The Examiner rejected the claims under obviousness-type4 double- patenting as obvious in view of claims of 1-17 of Schiller' 458. Ans. 18. The Examiner stated "[a]lthough the claims at issue are not identical, they are not patentably distinct from each other because the patented claims are to the cells which are produced via the method of the instant claims." Id. We reverse the rejection. An obviousness-type double-patenting rejection requires the determination of whether the claimed method would have been obvious based the claims of the patent. In this case, the patented claims are directed to a composition comprising multilineage-inducible cells "which (i) express at least CD29, CD 81, CD90, CD122, and CD164; and (ii) do not express CD13." The Examiner did not explain how the claimed method of collecting multilineage-inducible cells using an SSEA-4 antibody would have been obvious based on a composition of cells claimed in Schiller '458. Because the Examiner did not establish that the claimed method would have been obvious to one of ordinary skill in the art based on the claimed composition of Schiller' 458, the rejection is reversed. 4 The Examiner did not state the double-patenting was of the "obviousness- type." While the rejection is characterized as being non-statutory, it is based on 35 U.S.C. § 103 that the same inventions cannot be patented nor obvious variations thereof. 11 Appeal2018-005564 Application 14/540,563 TIME PERIOD No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a)(l)(iv). AFFIRMED 12 Copy with citationCopy as parenthetical citation