13433681 (P.T.A.B. Aug. 28, 2018)

Ex Parte Ding et al

Patent Trial and Appeal BoardAug 28, 2018

13433681 (P.T.A.B. Aug. 28, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE FIRST NAMED INVENTOR 13/433,681 03/29/2012 Dah-Ching Ding 100807 7590 09/06/2018 Mintz Levin/Special Group One Financial Center Boston, MA 02111 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. 48293-099001US 4089 EXAMINER CORDAS, EMILY ANN ART UNIT PAPER NUMBER 1651 NOTIFICATION DATE DELIVERY MODE 09/06/2018 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): IPDocketingBOS@mintz.com IPFileroombos@mintz.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Exparte DAR-CHING DING and TANG-YUAN CHU Appeal2016-008140 Application 13/433 ,681 Technology Center 1600 Before DEMETRA J. MILLS, ERIC B. GRIMES, and JEFFREY N. FREDMAN, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal 1,2 under 35 U.S.C. Â§ 134 involving claims to a method for non-tumorigenic expansion of human embryonic stem cells. The Examiner rejected the claims as anticipated and as obvious. We have jurisdiction under 35 U.S.C. Â§ 6(b). We affirm. 1 Appellants identify the Real Party in Interest as Buddhist Tzu Chi General Hospital (see App. Br. 1 ). 2 We have considered and herein refer to the Specification of Mar. 29, 2012 ("Spec."); Final Office Action of Oct. 8, 2014 ("Final Act."); Appeal Brief of July 8, 2015 ("App. Br."); Examiner's Answer of Oct. 29, 2015 ("Ans."); and Reply Brief of Dec. 29, 2015 ("Reply Br."). An oral hearing was also held on Aug. 21, 2018. Appeal 2016-008140 Application 13/433,681 Statement of the Case Background "Human embryonic stem (hES) cells are pluripotent, and they have great ability to differentiate into almost all cell types of the adult. These cells therefore hold great promise for regenerative medicine" (Spec. 1 :9-11 ). "Pluripotent embryonic stem cells are traditionally cultured on a layer of feeder cells such as mouse embryonic fibroblasts (MEFs) to keep them in an undifferentiated state" but "these mouse feeder support cells are often associated with contamination to the hES cell cultures ... thus rendering the hES cells that have been cultured on mouse feeder cells unsuitable for use clinically" (Spec. 1:14--19). The Specification teaches "a need exists for an alternative strategy for culturing hES cells by using another source of feeder cells that does not cause contamination and form teratomas" (Spec. 2: 1-2). The Claims Claims 1, 2, 4--7, 10-12, 14, and 15 are on appeal. 3 Independent claim 1 is representative and reads as follows: 1. A method for non-tumorigenic expansion of human embryonic stem (hES) cells, comprising co-culturing the human embryonic stem cells with human umbilical cord-derived mesenchymal stem cells (HU CMS Cs), wherein the human umbilical cord-derived mesenchymal stem cells have osteogenic or adipogenic differentiability. 3 Claims 3, 8, 9, and 13 were cancelled (see App. Br. 9-10) and claims 16-20 were withdrawn from prosecution in a restriction requirement made final in the Non-Final Action mailed Mar. 26, 2013. 2 Appeal 2016-008140 Application 13/433,681 The Issues The Examiner rejected claims 1, 2, 4, 5, 10-12, 14, and 15 under 35 U.S.C. Â§ I02(b) as anticipated by or, in the alternative, under 35 U.S.C. Â§ I03(a) as obvious over Weiss4 (Final Act. 4--5). The Examiner rejected claims 1, 2, 4--7, 10-12, 14, and 15 under 35 U.S.C. Â§ I03(a) as obvious over Weiss and Lu5 (Final Act. 6-8). Because these two rejections tum on the same Weiss reference and the same issues, we will consider them together. The Examiner finds "Weiss teaches a method of expanding a population of stem cells, which can be ES cells, using umbilical cord matrix cells (includes mesenchymal stem cells) derived from Wharton's Jelly as feeder cells in a co-culture with stem cells (pluripotent progenitor cells)" (Final Act. 4). The Examiner finds "Lu reports a method of co-culturing pluripotent stem cells with HUCMSCs" (Final Act. 8). The Examiner finds Lu evidences "that HUCMSCs have osteogenic or adipogenic differentiation potential" (Final Act. 8). The Examiner finds the Weiss methods "for generating hES cells and the cells resulting therefrom are either identical or sufficiently similar to the claimed method and cells that whatever differences exist are not patentably significant. Therefore, the burden of establishing novelty or unobviousness by objective evidence is shifted to applicants" (Final Act. 5). 4 Weiss et al., US 2003/0161818 Al, published Aug. 28, 2003. 5 Lu et al., Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials, 91 Haematologica 1017-26 (2006). 3 Appeal 2016-008140 Application 13/433,681 The issue with respect to both of the rejections is: Does the evidence of record support the Examiner's conclusion that Weiss, as evidenced by Lu, teaches coculture of human embryonic stem cells with HUCMSCs? Findings of Fact 1. Weiss teaches "a method for isolating, purifying and culturally expanding human or other placental animals umbilical matrix (UCMS) cells derived from umbilical cord tissue" (Weiss ,r 24). 2. Weiss teaches that the "isolated and purified human or other placental animal's stem cells [are] derived from Umbilical Cord Matrix Stem (UCMS) cells. Such matrix cells typically include extravascular cells, mucous-connective tissue (e.g., Wharton's Jelly) but typically do not include cord blood cells or related cells" (Weiss ,r 24). 3. Weiss teaches the term 'Umbilical Cord Matrix Cell' as used herein refers to either: 1) A pluripotent, or lineage-uncommitted progenitor cell, typically referred to in the art as a 'stem cell' derived from the umbilical cord matrix ... or 2) A lineage-committed progeny cell produced from the mitotic division of a stem cell of the invention that can eventually differentiate into hematopoietic, mesenchymal or neuroectodermal cells. (Weiss ,r,r 54--56). 4. Weiss teaches "obtaining stem cells from umbilical cord matrix sometimes called mesenchyme or Wharton's Jelly" (Weiss ,r 25). 5. Weiss teaches a stem cell isolation method that "involves fractionating the source of cells (Wharton's Jelly) into two fractions, one of which is enriched with a stem cell and thereafter exposing the stem cells to conditions suitable for cell proliferation. The cell enriched isolate thus created comprises totipotent immortal stem cells" (Weiss ,r 7 5). 4 Appeal 2016-008140 Application 13/433,681 6. Weiss teaches "using the stem cells of the invention in a non- mitotic form [ that have] a feeder cell in combination with other stem cells capable of growth, transformation and use in treating human disease" (Weiss if 31 ). 7. Weiss teaches "the term 'feeder cell' or 'feeder cell culture', as used herein, refers to cells that provide a co-stimulating function in conjunction with typically the other stem cell cultures, not necessarily the cells of this invention" (Weiss ,r 45). 8. Weiss teaches One important application of the stem cells of the invention is the creation of feeder cell culture materials. The stem cells of the application can be used in the form of the feeder cell that remains alive, can produce growth factor and other materials for maintaining culture materials but do not divide[] or grow. The feeder cells are prevented from beginning or conducting a mitotic process by using irradiation, chemical treatment or other technique that can prevent such process. After performing such processes the feeder cells are alive and can function but will not divide or grow. (Weiss ,r 123). 9. Weiss teaches in "using feeder cells to culture the stem cells of the invention, the feeder cells provide growth factors to the growing totipotent, pluripotent or multi potent stem cells" (Weiss ,r 123 ). 10. Weiss teaches: "Feeder cell layers would be prepared from the Wharton's jelly obtained stem cells of the invention" (Weiss ,r 124). 11. Weiss teaches "the use of human stem cells derived from UCMS Jelly provides a final cell culture in which the feeder cells do not prevent the use of the cultured stem cells from application in human use" (Weiss ,r 125). 5 Appeal 2016-008140 Application 13/433,681 12. Lu teaches "[ m ]esenchymal stem cells (MSC) are of great therapeutic potential due to their capacity of self-renewal and multilineage differentiation. They support hematopoiesis and enhance the engraftment of hematopoietic stem cells after co-transplantation" (Lu 101 7, col. 1 ). 13. Lu teaches "recent data show[ s] that sections of UC [ umbilical cord], such as Wharton's jelly ... and perivascular tissue, contain MSC" (Lu 1018, col. 1). 14. Table 2, panel B of Lu is reproduced below: B S!Â·'(f~re ..i. C. ,., ; rna1Aers CD13 CD14 CD29 CD31 CD34 C038 CD44 C045 C[1'3 V ~ ! CD90 CD105 CD106 CD166 'HLA 1F"lC ~ r\""MD .. , Hrn-DR 1 ~t--i. lO/ \ Uc, t /a/ n=10 ++++ ++++ ++++ ++++ ++++ ++++ + +++ +++ BM(%) n=6 ++++ ++++ ++++ ++++ ++++ +++ +++ ++++ pi\ l(J/lJe NS NS NS NS NS NS t4S NS NS NS 0.001 NS 0.004 "Table 2B shows that UC-derived cells shared most of their immunophenotype with BM[bone marrow ]-derived cells, including positivity for CD13, CD29, CD44, CD105 (SH2), CD106, CD73 (SH3), CD166 (stromal markers) and HLA-ABC, but negativity for CD14, CD34, 6 Appeal 2016-008140 Application 13/433,681 CD38, CD45 (hematopoietic markers), CD31 (endothelial cell marker) and HLA-DR" (Lu 1022, col. 2 to 1023, col. 1). 15. Lu teaches "Differentiation of MSC was assessed"; that "[ o ]steogenic differentiation was detected by the calcification of the matrix (von Kossa) (Figure 2 A-D). All ten UC (100%) and five out of six BM (83%) samples formed mineralized matrix"; and that "[a]dipogenic differentiation was identified by oil red O staining (Figure 2 E-H). Ten out of ten UC ( 100%) and six out of six BM ( 100%) samples contained cells with an adipogenic phenotype" (Lu 1023, col. 2 to 1024, col. 1). Principles of Law Anticipation under 35 U.S.C. Â§ 102 requires that "each and every element as set forth in the claim is found, either expressly or inherently described, in a single prior art reference." In re Robertson, 169 F.3d 743, 745 (Fed. Cir. 1999). The Examiner has the initial burden of establishing a prima facie case obviousness under 35 U.S.C. Â§ 103. In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992). Use of the transition "comprising" in the language of a claim "creates a presumption ... that the claim does not exclude additional, unrecited elements". See Crystal Semiconductor Corp. v. TriTech Microelectronics Int'!, Inc., 246 F.3d 1336, 1348 (Fed. Cir. 2001). Analysis We adopt the Examiner's findings of fact and reasoning regarding the scope and content of the prior art (Final Act. 4--8; FF 1-13) and agree that the claims are anticipated and obvious over Weiss as evidenced by Lu. 7 Appeal 2016-008140 Application 13/433,681 We begin with claim interpretation. Claim 1 recites "co-culturing the human embryonic stem cells with human umbilical cord-derived mesenchymal stem cells" that have "osteogenic or adipogenic differentiability." The Examiner finds "the broadest reasonable interpretation of the instant claims only requires the co-culturing ofhES cells with HUCMSCs and does not exclude the presence of additional cell types in the culturing method" (Ans. 10). Appellants do not identify, and we do not find, a teaching in the Specification defining or limiting the "co-culturing" step of claim 1 to cells that were purified, isolated, or otherwise separated to form monocultures composed solely of either human embryonic stem cells or of human umbilical cord-derived mesenchymal stem cells. Therefore, the Examiner's interpretation of claim 1 as encompassing "co-culturing" steps that utilize cell mixtures with the required cells as well as additional cell types is reasonable in light of the Specification and supported by the open, comprising transition clause recited in claim 1. See Georgia-Pacific Corp. v. US. Gypsum Co., 195 F.3d 1322, 1327 (Fed. Cir. 1999) (The transitional term "comprising" is "inclusive or open-ended and does not exclude additional, unrecited elements or method steps.") Appellants contend "the umbilical cord matrix stem cells of Weiss comprise many different types of stem cells, which are significantly distinct from the human umbilical cord-derived mesenchymal stem cells recited in the amended independent claim 1 of the present application" (App. Br. 4). Appellants contend the "matrix stem cells of Weiss display different gene expression profiles relative to the human umbilical cord-derived mesenchymal stem cells of the present invention" (id.). Appellants conclude 8 Appeal 2016-008140 Application 13/433,681 "[ s ]ince the gene markers present in the umbilical cord matrix stem cells of Weiss are not the same as the HUCMSCs recited in the amended independent claim 1 of the present application, it is clear that they are not equivalent to the HUCMSCs of the present invention" (App. Br. 5; cf Reply Br. 2). We find this argument unpersuasive because Weiss teaches stem cells that are pluripotent cells (FF 3) obtained from the Wharton's jelly within the umbilical cord (FF 5). Weiss' cells are therefore derived from an identical source as that disclosed in Appellants' Specification, which teaches "the umbilical cord-derived stem cells are human umbilical cord-derived mesenchymal stem cells (HUCMSCs), and are derived from Wharton's jelly of a human umbilical cord" (Spec. 2: 17-19). While Weiss' stem cell composition may comprise cell types other than those recited in claim 1, compositions that include additional cell types fall within the reasonable scope of claim 1 based on our claim interpretation of the open transitional term "comprising" as discussed above. Therefore, even if some cells within Weiss display different gene expression profiles that those disclosed in the Specification, the use of the identical stem cell source of Wharton's jelly reasonably supports the Examiner's position that Weiss' composition comprises stem cells identical to those recited in claim 1. Moreover, Lu evidences that cells derived from umbilical cord fragments comprise markers positive for one or more of CD13, CD29, CD44, CD73, CD90, and CD166 as required by dependent claim 6 and markers negative for one or more of CD 34, CD45, and HLA-DR as required by dependent claim 7 (FF 14). Therefore, the evidence of record supports 9 Appeal 2016-008140 Application 13/433,681 the Examiner's position that the Wharton's jelly umbilical cord cells of Weiss would necessarily share the gene expression profiles required by dependent claims 6 and 7, and consequently independent claim 1, and therefore fall within the scope of human umbilical cord-derived mesenchymal stem cells required by claim 1. Appellants contend "Weiss completely fails to teach or suggest co- culturing human embryonic stem cells with HUCMSCs" (App. Br. 5; cf Reply Br. 2). Appellants contend "Weiss fails to teach or suggest HUCMSCs, let alone that HUCMSCs can be used as feeder cells for co- culturing human embryonic stem cells" (id.). We find this argument unpersuasive because Weiss teaches obtaining umbilical cord stem cells (FF 3-5) and co-culturing the stem cells with feeder cells (FF 6-8) where the "[ fJeeder cell layers would be prepared from the Wharton's jelly obtained stem cells of the invention" (FF 10) where the Wharton's jelly necessarily comprises human umbilical cord-derived mesenchymal stem cells as evidenced by both Lu (FF 13) and dependent claim 4, which recites that "human umbilical cord-derived mesenchymal stem cells (HUCMSCs) are derived from Wharton's jelly of a human umbilical cord." Therefore, consistent with the broadest reasonable interpretation discussed above, while Weiss' feeder cell layers may comprise cell types other than human umbilical cord-derived mesenchymal stem cells, the evidence of record supports the Examiner's finding that Weiss' feeder cell layers necessarily also comprise human umbilical cord-derived mesenchymal stem cells found in Wharton's jelly (see, e.g., Ans. 10-11 ). 10 Appeal 2016-008140 Application 13/433,681 Appellants contend the human embryonic stem cells co-cultured with HUCMSCs used as feeder cells are non-tumorigenic, and do not result in teratoma formation in a xenograft model. Therefore, the absence of teratoma growth brought about by the claimed method of the present application means that the human embryonic stem cells co-cultured with HUCMSCs are free from forming teratomas in a xenograft model. Accordingly, the effect achieved by the presently claimed method is completely different from the Examiner's assumption that the umbilical cord matrix stem cells of Weiss are non-tumorigenic. (App. Br. 6; cf Reply Br. 3). We find this argument unpersuasive because Weiss teaches co- culturing human umbilical cord stem cells with a composition comprising human umbilical cord-derived mesenchymal stem cells as required by claim 1, and no evidence has been adduced by Appellants that the ordinary artisan would have expected this composition to be tumorigenic. In addition, the Examiner finds "the claim result of non-tumorigenic expansion of the hES cells must be inherent to the method as taught by the references and a necessary effect of practicing the method" (Ans. 11 ). Appellants provide no evidence rebutting the Examiner's finding, and as noted in Best, "[ w ]here, 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." In re Best, 562 F.2d 1252, 1255 (CCPA 1977). Appellants contend: Although Lu discloses that human umbilical cord mesenchymal stem cells have adipogenic and osteogenic differentiation potentials, it also fails to teach or suggest a step of co-culturing 11 Appeal 2016-008140 Application 13/433,681 the human embryonic stem cells with HUCMSCs as recited in independent claim 1 of the present application, let alone to obtain the unexpected results that co-culturing the human embryonic stem cells with HUCMSCs would be able to produce human embryonic stem cell growth without any associated teratoma growth. (App. Br. 7). We find this argument unpersuasive because the Examiner relies upon Weiss to teach the co-culturing of human embryonic stem cells with a feeder cell population that includes human umbilical cord-derived mesenchymal stem cells from Wharton's jelly (FF 1-11). The Examiner cites Lu to establish that the umbilical cord cells of Weiss have the same cell surface markers as required by the claims (FF 14) and have the capacity to undergo osteogenic and adipogenic differentiation (FF 15). With regard to the unexpected results argument, Appellants provide no evidence that the results of stem cell growth without teratoma growth would have been unexpected or surprising, whether by way of reference to the Specification, the prior art, or declaratory evidence. "It is well settled that unexpected results must be established by factual evidence. Mere argument or conclusory statements ... [do] not suffice." In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995). At best, there is attorney argument, but "[a]ttomey's argument in a brief cannot take the place of evidence." In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974). Conclusion of Law The preponderance of the evidence of record supports the Examiner's conclusion that Weiss, as evidenced by Lu, teaches coculture of human embryonic stem cells with HUCMSCs. 12 Appeal 2016-008140 Application 13/433,681 SUMMARY In summary, we affirm the rejection of claim 1 under 35 U.S.C. Â§ 102(b) as anticipated by or, in the alternative, underÂ§ 103(a) as obvious over Weiss. Claims 2, 4, 5, 10-12, 14, and 15 fall with claim 1. We affirm the rejection of claim 1 under 35 U.S.C. Â§ 103(a) as obvious over Weiss and Lu. Claims 2, 4--7, 10-12, 14, and 15 fall with claim 1. No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. Â§ 1.136(a). AFFIRMED 13