Ex Parte Ho et al

Patent Trial and Appeal Board

Nov 26, 2012

10251685 (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.
10/251,685 09/20/2002 Tony W. Ho 2560.0060000/JAG/CMB 3598
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, JOSEPH WAGNER, W. JOSEPH HERRING,
and VANESSA RAGAGLIA
__________

Appeal 2011-009014
1

Application 10/251,685
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 1-11, 57-60, and 63, directed to an isolated population of cells which
co-expresses CD49c, CD90, and a cardiac-related transcription factor. The
claims have been rejected on the grounds of anticipation and double
patenting. We have jurisdiction under 35 U.S.C. § 6(b).

1
This appeal is related to Appeal No. 2011-002458 (in Application No.
09/960,244) and Appeal No. 2011-009671 (in Application No. 11/054,824).
We have considered the three appeals together.
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STATEMENT OF THE CASE
Claims 1-11, 57-60, and 63 are pending and on appeal. Claims 12-49
are also pending, but have been withdrawn from consideration; claims 50-
56, 61, and 62 have been canceled (App. Br. 4).
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. 9: 10-15).
Claim 1 is representative of the subject matter on appeal:
1. An isolated cell population induced to express at least one
cardiac-related transcription factor, wherein the cell population is derived
from bone marrow, wherein greater than about 91% of the cells of the cell
population co-express CD49c and CD90, and wherein the cell population is
capable of maintaining 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).
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Catherine M. Kolf et al., Biology of adult mesenchymal stem cells:
regulation of niche, self-renewal and differentiation, available at
http://arthritis-research.com/content/9/1/204 (2007).
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 1-11, 57-60, and 63 under 35 U.S.C.
§ 102(b) as anticipated by Haynesworth “in light of” Pittenger, Woodbury,
and Lee (Ans. 5-10).
In addition, the Examiner provisionally rejected claims 1-11, 57-60,
and 63 on the ground of non-statutory obviousness-type double patenting as
unpatentable over claims 25, 19-21, 24, 25, and 97 of co-pending, earlier-
filed Application No. 09/960,244.
We reverse the anticipation rejection, and affirm the double patenting
rejection.
ANTICIPATION
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,
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4
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
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. 37: 24 - 38: 18). According to
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the Specification, “[m]ore than 94% of the adherent population was CD90
and CD49c positive” (id. at 39: 24-25).
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
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. 40: 1-18). In Example 2, “[m]ore than 91% of the adherent
population was CD90 and CD49c positive” (id. at 40: 25-26).
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.
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(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),
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
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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).
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 “ha[s] the potential to differentiate into a preselected phenotype
(e.g., chondrocytes, astrocytes, oligodendrocytes, neurons, bone, osteoclasts,
osteoblasts, cardiomyocytes, pancreatic islet cells, skeletal muscle, smooth
muscle, hepatocytes and retinal ganglial cell)” (Spec. 14: 6 - 14: 9).
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. 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
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method. CD44 expression was variable, apparently dependent
on serum concentration.
(Lodie, Abstract).
12. Kolf discloses surface antigens commonly identified during
isolation of MSCs:

(Kolf, Table 1.)
13. 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
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the initial passages, and the in vitro expression of some markers by MSCs
does not always correlate with their expression patterns in vivo” (id.).
Discussion
The Examiner finds that Haynesworth discloses “a population of
mesenchymal stem cells (MSCs) isolated from human adult bone marrow”
(Ans. 5). The Examiner acknowledges that “the prior art does not clearly
disclose all of Appellants‟ claimed limitations” (id. at 6), in particular,
Haynesworth “does not teach cells which have been induced to express at
least one cardiac related transcription factor” (id. at 11). However, the
Examiner finds that “it would appear that the cells claimed are a population
of MSCs as disclosed by Haynesworth” (id. at 6), because “subsequent
examination of MSCs demonstrated that [Haynesworth‟s] cells were as
pluripotent as alleged by Appellants” (id. at 5). 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, respectively (id.).
Appellants contend that the Examiner has not established a prima
facie case of inherent anticipation (App. Br. 20), at least in part because
Haynesworth‟s MSCs and the claimed cells are not obtained from same sub-
population of bone marrow cells (id. at 23); the populations express different
cell surface markers (id.); and they have markedly different doubling times
(id. at 22).
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 (id. at 23-24),
“[h]ence, cell populations isolated from these different density gradient
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fractions represent different starting populations of cells even before any
subsequent seeding, plating, or culturing procedures are implemented” (id. at
24). 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. 12).
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., Lodie, Kolf, and Chamberlain] that
not all cell surface markers are conserved, i.e. are always present or absent
from a particular cell type” (Ans. 11); because “Appellants‟ comparisons of
doubling rates disclosed in the prior art with their optimized doubling culture
conditions are not directly comparable” (id. at 13); and because “a living cell
per se which has been induced to a transient phenotypic change by culturing
the cell differently than in the prior art does not change the cell” (id. at 11).
Contrary to the Examiner‟s findings, the evidence of record supports
Appellants‟ contention that Haynesworth‟s MSCs and the claimed cell
populations “represent different starting populations of cells even before any
subsequent seeding, plating, or culturing procedures are implemented” (App.
Br. 24). That is, 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
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11
Haynesworth (FF2)) could not have been present in the fraction from which
the claimed cell population was derived (FF4), and the Examiner has not
provided any evidence or rationale to the contrary. Thus, the record
reasonably supports Appellants‟ assertion that the cell populations isolated
from these different density gradient fractions are not the same.
Ultimately, the evidence supporting the Examiner‟s finding that the “it
would appear that the cells claimed are a population of MSCs as disclosed
by Haynesworth” (Ans. 6) 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 “not all
cell surface markers . . . are always present or absent from a particular cell
type” (Ans. 11; FFs 11-13).
Inasmuch as the claimed cell population and Haynesworth‟s MSCs
were not isolated from the same source in the same manner, 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.
Conclusion - Anticipation
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
1-11, 57-60, and 63 as anticipated by Haynesworth.
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DOUBLE PATENTING
The Examiner provisionally rejected claims 1-11, 57-60, and 63 on
the ground of non-statutory obviousness-type double patenting as
unpatentable over claims 25, 19-21, 24, 25, and 97 of co-pending
Application No. 09/960,244).
Appellants have not addressed this rejection on the merits (see App.
Br. 42). Accordingly, the provisional rejection of the claims on the grounds
of obviousness-type double patenting is summarily affirmed.
SUMMARY
The rejection of claims 1-11, 57-60, and 63 as anticipated by
Haynesworth is reversed.
The provisional rejection of claims 1-11, 57-60, and 63 under the
doctrine of non-statutory obviousness-type double patenting is affirmed.
TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED

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