Ex Parte Ho et al

Patent Trial and Appeal BoardNov 26, 2012

09960244 (P.T.A.B. Nov. 26, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE 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 APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 09/960,244 09/21/2001 Tony W. Ho 2560.0020000/JAG/CMB 4326 26111 7590 11/26/2012 STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C. 1100 NEW YORK AVENUE, N.W. WASHINGTON, DC 20005 EXAMINER LANKFORD JR, LEON B ART UNIT PAPER NUMBER 1651 MAIL DATE DELIVERY MODE 11/26/2012 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 TONY W. HO, GENE C. KOPEN, WILLIAM F. RIGHTER, J. LYNN RUTKOWSKI, and JOSEPH WAGNER __________ Appeal 2011-002458 1 Application 09/960,244 Technology Center 1600 __________ Before TONI R. SCHEINER, LORA M. GREEN, and ULRIKE W. JENKS, Administrative Patent Judges. SCHEINER, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 from the final rejection of claims 14, 21, 25, 26, and 97, directed to an isolated population of human cells which co-expresses CD49c and CD90. The claims have been rejected as anticipated. We have jurisdiction under 35 U.S.C. § 6(b). 1 This appeal is related to Appeal No. 2011-009014 (in Application No. 10/251,685) and Appeal No. 2011-009671 (in Application No. 11/054,824). We have considered the three appeals together. Appeal 2011-002458 Application 09/960,244 2 STATEMENT OF THE CASE Claims 14, 21, 25, 26, and 97 are pending and on appeal. Claims 1-13, 15-20, 22-24, and 27-96 have been canceled (App. Br. 4). 2 The Specification discloses “a substantially homogeneous population of cells” with “the potential to differentiate or develop into neuronal, glial or other cells (e.g., cardiac muscle)” (Spec. 5: 21-26). Claim 14 is representative of the subject matter on appeal: 14. An isolated cell population derived from human bone marrow, wherein greater than about 91% of the cells of the cell population co-express CD49c and CD90, and wherein the cell population maintains a doubling rate of less than about 30 hours after 30 cell doublings. The Examiner relies on the following evidence: Haynesworth et al. US 5,733,542 Mar. 31, 1998 Mark F. Pittenger et al., Multilineage Potential of Adult Human Mesenchymal Stem Cells, 284 SCIENCE 143-147 (1999). Dale Woodbury et al., Adult Rat and Human Bone Marrow Stromal Cells Differentiate Into Neurons, 61 JOURNAL OF NEUROSCIENCE RESEARCH 364- 370 (2000). Tracey A. Lodie et al., Systematic Analysis of Reportedly Distinct Populations of Multipotent Bone Marrow-Derived Stem Cells Reveals a Lack of Distinction, 8 TISSUE ENGINEERING 739-751 (2002). Kuan-Der Lee et al., In Vitro Hepatic Differentiation of Human Mesenchymal Stem Cells, 40 HEPATOLOGY 1275-1284 (2004). Giselle Chamberlain et al., Concise Review: Mesenchymal Stem Cells: Their Phenotype, Differentiation Capacity, Immunological Features, and Potential for Homing, 25 STEM CELLS 2739-2749 (2007). 2 References to the Appeal Brief are to the Supplemental Appeal Brief dated January 25, 2010. Appeal 2011-002458 Application 09/960,244 3 In addition, Appellants rely, in relevant part, on the following evidence: Caplan et al. US 5,486,359 Jan. 23, 1996 Caplan et al. US 5,811,094 Sep. 22, 1998 Declaration of inventor Dr. Gene Kopen, submitted under the provisions of 37 C.F.R. § 1.132, dated May 17, 2007 (“1 st Kopen Decl.”). Declaration of inventor Dr. Gene Kopen, submitted under the provisions of 37 C.F.R. § 1.132, dated March 3, 2008 (“2 nd Kopen Decl.”). The Examiner rejected claims 14, 21, 25, 26, and 97 under 35 U.S.C. § 102(b) as anticipated by Haynesworth “in light of” Pittenger, Woodbury, and Lee (Ans. 5-10). We reverse. PRINCIPLES OF LAW “A claim is anticipated only if each and every element as set forth in the claim is found, either expressly or inherently described, in a single prior art reference.” Verdegaal Bros., Inc. v. Union Oil Co. of California, 814 F.2d 628, 631 (Fed. Cir. 1987). “[W]hen 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.” See also In re Spada, 911 F.2d 705, 708 (Fed. Cir. 1990). In other words, “the examiner must provide some evidence or scientific reasoning to establish the reasonableness of the examiner’s belief that the functional limitation is an inherent characteristic of the prior art” before the burden is shifted to the applicant to disprove the inherency. Ex parte Skinner, 2 USPQ2d 1788, 1789 (BPAI 1986). Moreover, “[i]nherency . . . may not be established by probabilities or possibilities. The mere fact that a certain thing may result from a given Appeal 2011-002458 Application 09/960,244 4 set of circumstances is not sufficient.” Continental Can Co. v. Monsanto Co., 948 F.2d 1264, 1269 (Fed. Cir. 1991). ISSUE The issue raised by this rejection is whether the Examiner has provided evidence or scientific reasoning sufficient to support a finding that Haynesworth discloses an isolated cell population identical to the claimed cell population. FINDINGS OF FACT 1. Examples 1 and 2 of the present Specification describe two different methods of isolating a cell population that meets the limitations of independent claim 14. Briefly, in Example 1, bone marrow cells were aspirated from the iliac crest of human subjects, the red cell component was lysed, and the resultant mononuclear cell suspension was pelleted and re- suspended twice. The mononuclear suspension was seeded in tissue culture flasks at a density of 50,000 cells/cm 2 and incubated at 37°C in an atmosphere consisting of 5% carbon dioxide, 5% oxygen, and 90% nitrogen for 5 days, at which point non-adherent cells were aspirated from the flasks and the remaining adherent cells (colony forming units (CFUs)) were expanded for an additional 3-5 days (Spec. 25: 9 - 26: 2). According to the Specification, “[m]ore than 94% of the adherent population was CD90 and CD49c positive” (id. at 27: 7-8). In Example 2, a bone marrow aspirate from iliac crest was diluted and overlaid onto an equal volume of Histopaque® 1.119 and centrifuged. The resulting mononuclear cell fraction was pelleted and resuspended twice. As in Example 1, the cell suspension was seeded in tissue culture flasks at a density of 50,000 cells/cm 2 and incubated at 37°C in an atmosphere Appeal 2011-002458 Application 09/960,244 5 consisting of 5% carbon dioxide, 5% oxygen, and 90% nitrogen for 5 days, at which point non-adherent cells and spent were aspirated from the flasks and the remaining adherent cells were expanded for an additional 3-5 days (Spec. 27: 9-26). In Example 2, “[m]ore than 91% of the adherent population was CD90 and CD49c positive” (id. at 28: 5). 2. Haynesworth discloses a population of mesenchymal stem cells, “normally present at very low frequencies in bone marrow and other mesenchymal tissues” (Haynesworth, col. 1, ll. 25-26). The initial fractionation of the bone marrow is described as follows: Aspirate marrow (5-10 ml) was transferred to sterile 50 ml plastic centrifuge tubes to which 20 ml complete medium was added. The tubes were spun . . . to pellet the cells. The supernatant and fat layer were removed and the cell pellets were resuspended . . . [and] loaded onto 70% Percoll . . . gradients with a 10 ml pipette and spun . . . . In order to harvest the cells, the tube is marked just below the high concentrated band of platelets, about 25% to 35% of the way down the tube. (Pooled density=1.03g/ml.) Using a 10 ml pipette, the medium is aspirated off from the top down to the marked line . . . the collected fraction is transferred to a 50 ml conical plastic tube. 30 ml of complete medium then is added to the tube and centrifuged for 5 minutes at 1,500 rpm. The supernatant then is removed and discarded. (Id. at col. 3, l. 58 - col. 4, l. 8.) According to Haynesworth, this is essentially the same method disclosed in “co-pending U.S. patent application Ser. No. 193,262” (Haynesworth, col. 1, ll. 25-31), which issued as U.S. Patent 5,486,359 to Arnold. I. Caplan and Stephen E. Haynesworth. The initial fractionation of bone marrow in Caplan '359, in relevant part, is as follows: The gradients were separated into three fractions with a pipet: top 25% of the gradient (low density cells-platelet fraction), Appeal 2011-002458 Application 09/960,244 6 pooled density=1.03 g/ml; middle 50% of the gradient (high density cells-mononucleated cells), pooled density=1.10 g/ml; and bottom 25% of the gradient (red blood cells), pooled density=1.14 g/ml. In preliminary experiments each of these three pools were plated separately in complete medium . . . . Adherent cells were observed to be localized to the low density cells. To produce adherent cells cultures for all subsequent experiments, only the low density cells were plated. (Caplan '359, col. 17, ll. 8-24.) Caplan '094, a continuation-in-part of Caplan '359, discloses the same MSC isolation method as Caplan '359. 3. Haynesworth‟s mesenchymal stem cell population is the same as the cell population disclosed in Caplan '359, and the same as the population disclosed in Caplan '094 (compare Haynesworth, col. 3, l. 58 - col. 4, l. 8; Caplan '359, col. 8, ll. 8-24; and Caplan '094, col. 19, ll. 45-62). 4. Dr. Gene Kopen contends that Haynesworth‟s MSCs “are localized within a population of „low density cells‟ corresponding to the platelet fraction of bone marrow-derived cells. In contrast, the cell populations of the present invention are isolated from a high density mononuclear fraction” (2 nd Kopen Decl. 4). Dr. Kopen asserts that “Histopaque 1.119® alone, as described in the present specification could not be used to fractionate the low density „MSCs‟ of Haynesworth because, following gradient centrifugation, Haynesworth‟s „MSCs‟ would be found in an unfractionated plasma layer of cells on top of the high-density Histopaque 1.119® media” (id. at 5). 5. In addition, Caplan '094 discloses that the MSCs (i.e., the MSCs disclosed in Haynesworth) are CD44 negative (Caplan '094, Table 5). Appeal 2011-002458 Application 09/960,244 7 6. According to Dr. Kopen, however, “the cell populations of the present invention are CD44 positive” (2 nd Kopen Decl. 4). 7. The present Specification teaches that the cell population of the invention “has the potential to differentiate into a preselected phenotype[] (e.g., a chondrocyte, an astrocyte, an oligodendrocyte, a neuron, osteocyte, osteoblast, osteoclast, a cardiomyocyte, a pancreatic islet cell, a skeletal muscle, a smooth muscle, a hepatocyte and a retinal ganglial cell)” (Spec. 13: 28 - 14: 3). 8. Pittenger teaches that human MSCs display a stable phenotype in vitro and can be induced to differentiate into adipocytic, chondrocytic, or osteocytic lineages (Pittenger, Abstract; Figure 2). 9. Woodbury teaches “that rodent and human cultured MSCs can be induced to differentiate exclusively into neurons” (Woodbury 364, col. 2). 10. Lee teaches that “human MSCs from different sources are able to differentiate into functional hepatocyte-like cells” (Lee, Abstract). 11. Chamberlain teaches that “[p]henotypically, MSCs express a number of markers, none of which, unfortunately, are specific to MSCs” (Chamberlain 2740, col. 1). Chamberlain also teaches that MSCs “can express CD105 (SH2), CD73 (SH3/4), CD44, CD90 (Thy-1), CD71, and Stro-1” (id.), and cautions that “differences in cell surface expression of many markers may be influenced by factors secreted by accessory cells in the initial passages, and the in vitro expression of some markers by MSCs does not always correlate with their expression patterns in vivo” (id.). Appeal 2011-002458 Application 09/960,244 8 12. Lodie discloses that: Cell surface marker analysis [of adult human bone marrow- derived stem cells] revealed that more than 95% of the cells were positive for CD105/endoglin, a putative mesenchymal stem cell marker, and negative for CD34, CD31, and CD133, markers of hematopoietic, endothelial, and neural stem cells, respectively, regardless of cell isolation and propagation method. CD44 expression was variable, apparently dependent on serum concentration. (Lodie, Abstract.) ANTICIPATION The Examiner finds that Haynesworth discloses a population of isolated human mesenchymal stem cells (MSCs). According to the Examiner, “marrow is taken from the iliac crest as is done in Appellants‟ examples” and “[a] „low oxygen‟ culture is used (95% air/5% CO2) to culture the marrow cells and obtain an adherent cell population (CFUs) which is a population of MSCs” (Ans. 5). The Examiner acknowledges that “Haynesworth is silent on the presence or absence of CD49c and CD90 or on the specific doubling rate of the cell population” (id.), but finds that “the claimed cells are isolated from the same source and in the same manner as the cells of Haynesworth,” and therefore, “must necessarily be the same” (id.). In addition, the Examiner cites Pittenger, Woodbury, and Lee as evidence that Haynesworth‟s MSCs, like the claimed cells, can differentiate into bone, cartilage, adipose cells, neurons, and hepatocytes (id. at 6). Appellants contend that “the Examiner has not established a prima facie case of inherent anticipation” (App. Br. 15), at least in part because Haynesworth‟s MSCs and the claimed cells are not isolated in the same manner and therefore are not obtained from same sub-population of bone Appeal 2011-002458 Application 09/960,244 9 marrow cells (id. at 21); the populations express different cell surface markers (id.); and they have markedly different doubling times (id. at 20). In particular, Appellants contend that Haynesworth‟s MSCs were isolated from a low density gradient fraction, while the claimed cells were isolated from among a high-density mononuclear cell fraction, “[h]ence, cell populations isolated from these different density gradient fractions represent different starting populations of cells even before any subsequent seeding, plating, or culturing procedures are implemented” (id. at 22). The Examiner does not dispute that Haynesworth‟s cells and the claimed cells were isolated from different density fractions, but argues that “it is unclear how that cells can be established as different based on the density gradient fraction from which they are isolated” (Ans. 11). In addition, Appellants have provided evidence which establishes that Haynesworth‟s MSCs and the claimed cell populations differ in cell surface markers (2 nd Kopen Decl. 3-4) and population doubling times (id. at 8-11). Again, the Examiner does not dispute this evidence, but finds that it fails to distinguish the prior art cells from the claimed cells because “it is apparent from the literature on the subject [e.g., Chamberlain and Lodie] that not all cell surface markers . . . are always present or absent from a particular cell type” (Ans. 10), thus “it is unclear that the presence of one or even a few differences in cell surface markers is indicative of a new cell type” (id.), and because “Appellants‟ comparisons of doubling rates disclosed in the prior art with their optimized doubling culture conditions are not directly comparable” (id. at 11). Contrary to the Examiner‟s findings, the evidence of record supports Appellants‟ contention that Haynesworth‟s MSCs and the claimed cell Appeal 2011-002458 Application 09/960,244 10 populations were not, in fact, isolated “in the same manner.” Specifically, Haynesworth‟s MSCs were isolated from a low density fraction, while the claimed cell population was isolated from a relatively high density fraction (contrast FFs 1 and 2). According to Dr. Kopen, the cells in Haynesworth‟s low density fraction (the only fraction expanded by Haynesworth (FF2)) could not have been present in the fraction from which the claimed cell population was derived (FF4). Thus, the record reasonably supports Appellants‟ assertion that the “cell populations isolated from these different density gradient fractions represent different starting populations of cells even before any subsequent seeding, plating, or culturing procedures are implemented” (App. Br. 22). Ultimately, the evidence supporting the Examiner‟s finding that the two cell populations “must necessarily be the same” (Ans. 5) boils down to the fact that both populations are isolated from iliac crest marrow (which is made up of many cell types (FF2)); the fact that both isolated populations are capable of differentiating into some of the same general cell types (FFs 7-10); and the fact that, in general, “not all cell surface markers . . . are always present or absent from a particular cell type” (Ans. 10; FFs 11, 12). Inasmuch as the claimed cell population and Haynesworth‟s MSCs were not isolated “from the same source and in the same manner” (Ans. 5), the mere fact that both populations are multipotent (and might possibly express the same cell surface markers under certain cell culture conditions) is not sufficient to establish that the two cell populations are identical, or to shift the burden to Appellants to prove that they are not. Appeal 2011-002458 Application 09/960,244 11 CONCLUSION The Examiner has not provided evidence or scientific reasoning sufficient to support a finding that Haynesworth discloses an isolated cell population identical to the claimed cell population. On this record, we are constrained to reverse the rejection of claims 14, 21, 25, 26, and 97 as anticipated by Haynesworth. REVERSED cdc