Laura Brown et al.

Patent Trials and Appeals Board

May 5, 2021

2020004486 (P.T.A.B. May. 5, 2021)

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.
11/315,969 12/22/2005 Laura Brown JNJ-0207C1US
(001705.0012
4989
93358 7590 05/05/2021
BakerHostetler/ Johnson & Johnson
Washington Square, Suite 1100
1050 Connecticut Avenue, NW
Washington, DC 20036-5304
EXAMINER
WILSON, MICHAEL C
ART UNIT PAPER NUMBER
1632
NOTIFICATION DATE DELIVERY MODE
05/05/2021 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):
eofficemonitor@bakerlaw.com
jnjuspatent@corus.jnj.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________________

Ex parte LAURA BROWN, SRIDEVI DHANARAJ, and
AGNIESZKA SEYDA1
____________________

Appeal 2020-004486
Application 11/315,969
Technology Center 1600
____________________

Before ERIC B. GRIMES, RICHARD M. LEBOVITZ, and
ROBERT A. POLLOCK, Administrative Patent Judges.

POLLOCK, Administrative Patent Judge.

DECISION ON APPEAL
This appeal under 35 U.S.C. § 134(a) involves claims to in vitro
methods of inducing chondrogenic differentiation in a homogeneous cell
population. Appellant seeks our review of the Examiner’s decision to reject
claims 2, 3, and 63–66 for obviousness-type double patenting, and as
obvious in view of the prior art. We have jurisdiction under 35 U.S.C.
§ 6(b).
We REVERSE.

1 Appellant identifies, via an extensive chain of title, DePuy Synthes
Products, Inc. as the real party in interest. Appeal Br. 3. We use the word
Appellant to refer to “applicant” as defined in 37 C.F.R. § 1.42(a).
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Statement of the Case
Appellant describes the invention as “directed to in vitro methods of
inducing differentiation of an isolated homogeneous population of umbilical
cord tissue-derived cells (having defined characteristics) into a chondrogenic
phenotype.” App. Br. 4; see Spec. ¶ 10 (reciting extensive list of defined
characteristics).
On appeal are claims 2, 3, and 63–66, of which, only claim 2 is
independent:
2. An in vitro method of inducing differentiation of a
population of cells to a chondrogenic phenotype comprising:
i) obtaining an isolated homogeneous population of
umbilical cord tissue-derived cells,
wherein said isolated cell population is obtained from
human umbilical cord tissue substantially free of blood,
can undergo at least 40 doublings in culture, maintains a
normal karyotype upon passaging,
expresses each of CD10, CD13, CD44, CD73, CD90,
PDGFr-alpha, PD-L2, and HLA-A,B,C; and
does not express any of CD31, CD34, CD45, CD80, CD86,
CD117, CD141, CD178, B7-H2, HLA-G, or HLA-
DR,DP,DQ, exhibits increased expression of a gene
encoding interleukin 8 relative to expression of an
endogenous gene encoding interleukin 8 by a human cell
that is a fibroblast, a mesenchymal stem cell, or an iliac crest
bone marrow cell, and
exhibits increased expression of a gene encoding reticulon l
relative to expression of an endogenous gene encoding
reticulon 1 by a human cell that is a fibroblast, a
mesenchymal stem cell, or an iliac crest bone marrow cell;
ii) culturing said isolated cell population in chondrogenic
induction medium, wherein the induction medium comprises
modified essential medium comprising L-glutamine, sodium
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pyruvate, L-proline, L-ascorbic acid, insulin, transferrin, and
selenium; and
iii) exposing the isolated homogeneous population of cells in
culture to one or more chondrogenic differentiation-inducing
agents, wherein said exposing induces differentiation of said
isolated cell population to a chondrogenic phenotype.
See App. Br. 29 (claims appendix, paragraphing added).
Obviousness-Type Double Patenting
In the Final Action, the Examiner withdrew obviousness-type double
patenting rejections over claims of US Pat. Nos. 7,510,873, 8,318,483, and
8,815,587, as well as a number of provisional obviousness-type double
patenting rejections, in view of Appellant’s filing of terminal disclaimers.
Final Act. 24–25. Presently before us is a similar rejection of claims 2, 3,
and 63–66 on the grounds of nonstatutory double patenting over the claims
of US Pat. No. 9,579,351 (“the ’351 Patent”).
The doctrine of obviousness-type double patenting is intended to
“prevent the extension of the term of a patent . . . by prohibiting the issuance
of the claims in a second patent not patentably distinct from the claims of the
first patent.” In re Longi, 759 F.2d 887, 892 (Fed. Cir. 1985). “A later patent
claim is not patentably distinct from an earlier claim if the later claim is
obvious over, or anticipated by, the earlier claim.” Eli Lilly & Co. v. Barr
Labs., Inc., 251 F.3d 955, 968 (Fed. Cir. 2001). Accordingly, we focus first
on the patent claims.
As indicated above, the claims before us relate to a “method of
inducing differentiation of a population of cells to a chondrogenic
phenotype” using “an isolated homogeneous population of umbilical cord
tissue-derived cells.” The claims of the ’351 patent, in contrast, relate to “an
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isolated homogeneous cell population . . . obtained from human postpartum
placenta.” See e.g., ’351 Patent, 127:18–37 (claim 1).
In arguing that the two sets of claims are not patentably distinct, the
Examiner contends that “the cells obtained from the placenta in ’351 and
used [in] the method of claim 2 in the instant application are linked as
methods of using the same product” such that “the method of using the cells
in claim 2 of the instant application is an obvious process for using the cells
. . . disclosed in ’351.” Ans. 21. More specifically, the Examiner contends
that, although “[t]he cell culture claims of ’351 are obtained from human
postpartum placenta while the cells in the method of differentiating cells into
chondrogenic cells in the instant application are from umbilical cord. . . the
cells used in ’351 and in claim 2 are related as processes of using the same
product.” Ans. 18. In support, the Examiner points to Example 29 of the
’351 Patent’s specification (see col. 115:12–119:24) as teaching
“administering matrix and a homogenous population of undifferentiated
placenta- or umbilical cord-derived cells free of blood to create cartilage in
patients.” Id. The Examiner further finds that the instant Specification and
the ’351 Patent teach that “both placenta-derived and umbilical derived cells
have the same markers expressed . . . and are both capable of differentiating
into cartilage and chondrogenic phenotypes.” Id. at 29–30; see Final Action,
28 (“The cells are the same because they have the same marker pattern; the
location from which they are taken does not alter the structure of the cells.”).
Appellant responds that the “the Examiner errs by incorrectly
equating different cell populations” and, thus, has not established that the
cells claimed in the ’351 Patent are patentably indistinct from those used in
the method claims on appeal. App. Br. 6. According to Appellant, the two
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cell populations “are from different sources and have a different marker
profile.” Id. at 8; see id. at 9 (table illustrating different marker profiles for
the two cell populations). Considering the record before us, Appellant has
the better position.
We find particularly compelling Appellant’s comparison of cellular
markers based on Examples 7 and 12 of the instant application and
Examples 8 and 12 of the ’351 patent. In this respect, the record shows that
placenta-derived cells of the ’351 patent show increased expression of
oxidized low density lipoprotein and renin (Spec. Table 7-4; ’351 patent,
Table 8-3) as compared to other cell types, whereas umbilical cord-derived
cells have increased expression of interleukin 8 and reticulon 1 not seen with
those claimed in the ’351 patent (Spec. Table 7-4; ’351 patent, Table 8-4).
The record similarly shows that levels of various secretory factors differ
markedly between the two lines. See Spec. ¶ 365, Tab. 12–1, 12–2, 12–3
(head-to-head comparisons showing, e.g., non-detectable levels of FGF and
MIF1a in placenta-derived but not umbilical-derived cells, and non-
detectable levels of I309 antigen and MDC in umbilical-derived cells but not
in those derived from placenta). As summarized in the Specification:
The amount of HGF, FGF, and BDNF secreted from
umbilicus-derived cells were noticeably higher than fibroblasts
and placenta-derived cells (Tables 12-2 and 12-3). Similarly,
TIMP1, TPO, HBEGF, MCP-1, TARC, and IL-8 were higher in
umbilicus-derived cells than [fibroblasts and placenta-derived
cell] populations (Table 12-3).
Spec. ¶ 365.
In light of the above differences in expression, we are not persuaded
that the Examiner had sufficient evidence to conclude that the placenta-
derived cells claimed in the ’351 patent are “the same product” as the
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umbilicus-derived cells used in the method claims on appeal. See Ans. 18.
The Examiner has, therefore, not established that the appealed claims are
patentably indistinct from those of the ’351 patent. Accordingly, we reverse
the obviousness-type double patenting rejection.
Obviousness
The obviousness rejections rely on the following prior art references:
US Pat. No. 5,962,325, issued October 5, 1999 (“Naughton”);
Pittenger et al., “Human Mesenchymal Stem Cells: Progenitor
Cells for Cartilage, Bone, Fat and Stroma,” Lymphoid
Organogenesis, 3–11, F. Melchers (ed.), Springer-Verlag
Berlin Heidelberg 2000 (“Pittenger”);
Ciavarella et al, “Umbilical Cord Mesenchymal Stem Cells:
Role of Regulatory Genes in Their Differentiation to
Osteoblasts,” 18(8) Stem Cells and Development 1211–
1220 (2009) (“Ciavarella”);
US Pat. No. 6,291,240, issued Sept. 18, 2001 (“Mansbridge”);
US Pat. No. 5,308,763, issued May 3, 1994 (“Ronnett”).
Liddiard et al., “An Improved Method for the Preparation of
Human Fetal and Adult Hepatocytes,” 44 Arch. Toxicol
107–112 (1980) (“Liddiard”); and
The Examiner rejects claims 2, 3, 63, 64, and 66 under 35 U.S.C.
§ 103(a) as obvious in view of Naughton and Pittenger, as supported by
Ciavarella. Final Act. 2, 9. The Examiner also rejects claim 65 in view of
Naughton, Pittenger, and Ciavarella as applied to claims 2, 3, 63, 64, and 66,
and further in view of Mansbridge, Ronnett, and Liddiard. Id. at 13.
For the purposes of this appeal, we focus on the rejection of claim 2 as
obvious in view of Naughton and Pittenger, as supported by Ciavarella.
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Findings of Fact
FF1. Naughton “relates to growing stromal cells, such as
chondrocytes, progenitor-chondrocytes, fibroblasts and/or
fibroblast-like cells on a three-dimensional scaffold or framework
in vitro under conditions which enhance the formation of cartilage
in culture.” Naughton, 2:10–14. In particular, “stromal cells,
including, but not limited to, chondrocytes, chondrocyte-
progenitors, fibroblasts, fibroblast-like cells, umbilical cord cells or
bone marrow cells from umbilical cord blood are inoculated and
grown on a three-dimensional framework in the presence of TGF-
β.” Id. at Abstract; see also id. at 6:11–32, 11:35–41. “[T]he
stromal cells are stimulated to produce cartilage using exogenously
added growth factors, e.g., TGF-β with or without ascorbate, in
culture.” Id. at 6:41–43.
FF2. Naughton discloses that fibroblasts may be readily isolated
from mechanically and/or enzymatically disaggregated human
umbilical cord tissue using techniques known to those skilled in
the art. Id. at 12:4–47. For example, “[e]nzymatic dissociation can
be accomplished by mincing the tissue and treating the minced
tissue with any of a number of digestive enzymes either alone or in
combination. These include but are not limited to trypsin,
chymotrypsin, collagenase, elastase, and/or hyaluronidase, Dnase,
pronase, etc.” Id. at 12:12–16.
FF3. According to Naughton, chondrocytes, chondrocyte-
progenitors, fibroblasts or fibroblast-like cells may be isolated
from minced tissue incubated “in a freshly prepared solution of a
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dissociating enzyme such as trypsin. After such incubation, the
dissociated cells are suspended, pelleted by centrifugation and
plated onto culture dishes. All fibroblasts will attach before other
cells, therefore, appropriate stromal cells can be selectively
isolated and grown.” Id. at 12:48–59. Naughton discloses that other
types of “stromal cells may readily be derived from . . . umbilical
cord or placenta . . . using methods known in the art such as those
discussed above.” Id. at 13:7–10
FF4. Naughton discloses an Example in which chondrocyte
cultures were isolated from adult cow or rabbit cartilage by
collagenase digestion. Id. at 21:5–16.
FF5. Pittenger investigates culture conditions for the
differentiation of bone marrow derived human mesenchymal stem
cells (hMSCs) into adipogenic, osteogenic, and chondrogenic cell
lineages. See, generally, Pittenger, 5–7. Pittenger discloses, for
example, that culturing hMSCs in serum-free DMEM comprising
TGF-β3, ascorbic acid, sodium pyruvate, proline, and a
commercially available insulin-transferrin-selenium solution
induces chondrogenic differentiation as indicated by gross
phenotype and chondrogenic marker expression.
FF6. In support of inherency, the Examiner points to
Ciavarella as post-filing evidence that umbilical-derived
mesenchymal cells have at least a subset of the cell marker
characteristics recited in claims 2, 63, and 64. Ans. 9. Ciavarella
states that “[f]ibroblast-like cells from the Warthon’s Jelly [a
component of human umbilical cord] were cultured with dedicated
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media to obtain osteogenic-, adipogenic-, and chondrogenic-
differentiated cells.” Ciavarella, Abstract.
Analysis
According to the Examiner, “the starting material, disaggregation
techniques/enzymes, and culture methods used to obtain a cell population
from human umbilical cord described by Naughton must inherently result in
a ‘homogeneous population of umbilical cord tissue-derived’ cells as
required in . . . claim 2,” and its dependent claims. Ans. 6. The Examiner
relies on Pittenger as teaching a serum-free media that supports chondrocyte
differentiation. Id. at 8. Appellant argues, inter alia, that Naughton’s
isolation protocols “are insufficient to establish Naughton inherently
discloses the claimed cells.” Reply Br. 10.
As an initial matter, the record before us supports the Examiner’s
finding that
at the time the claimed invention was made, it was within the
routine skill level of the ordinary artisan to culture human stem
cells in chondrogenic medium comprising TGF-beta3 and L-
glutamine, sodium pyruvate, L-proline, L-ascorbic acid, insulin,
transferrin and selenium as required in lines 19-20 of claim 2,
as demonstrated by Pittenger, who used serum-free DMEM
comprising TGF-beta3, ascorbic acid, sodium pyruvate, proline,
and a commercially available insulin-transferrin-selenium
solution, for chondrogenic differentiation of human
mesenchymal stem cells (pg 6, para. 1).
Therefore, it would have been prima facie obvious to a
person of ordinary skill in the art to differentiate stromal cells
into chondrogenic cell types using TGFbeta3 and proline as
described by Naughton using the chondrogenic medium
comprising L-glutamine, sodium pyruvate, L-proline, L-
ascorbic acid, insulin, transferrin and selenium disclosed by
Pittenger. Those of ordinary skill in the art at the time the
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invention was made would have been motivated to use the
chondrogenic medium of Pittenger in the method of Naughton
because Pittenger showed the chondrogenic medium
successfully differentiated stromal cells into chondrogenic
phenotypes under serum-free conditions and for the obvious
advantage of reducing animal protein contamination. Those of
ordinary skill in the art at the time of filing would have had a
reasonable expectation of using the chondrogenic medium
comprising insulin, transferrin and selenium of Pittenger
instead of the medium described by Naughton because
Pittenger showed the chondrogenic medium successfully
differentiated stromal cells into chondrogenic phenotypes under
serum-free conditions.
Ans. 8.
This does not end our analysis because, as Appellant points out, claim
2 and its dependent claims are directed to a “homogeneous population of
umbilical cord tissue-derived cells” having defined characteristics. See, e.g.,
Reply Br. 10 (“Naughton does not disclose or suggest that these cells are a
homogenous cell population having the same markers as claimed.”). In the
context of the instant specification and the relevant claim language, we
construe “homogeneous population” to mean that each cell in the referenced
population has the pattern of expression recited in claim 2.
According to the Examiner, Appellant has failed to establish that
“Naughton . . . cannot result in cells having the [claimed] characteristics.”
Ans. 26. However, this is not the appropriate standard for inherency, which
requires that “the allegedly inherent characteristic necessarily flows from the
teachings of the applied prior art.” Ex parte Levy, 17 USPQ2d 1461, 1464
(BPAI 1990). Thus, “[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.” In re Robertson, 169 F.3d 743, 745 (Fed.
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Cir. 1999) (citations and internal quotation marks omitted). For at least the
reasons set forth below, we are not persuaded that one of ordinary skill in the
art reading Naughton would have necessarily arrived at the homogeneous
cell population set forth in claim 2.
As noted by Appellant, Table 1-1 of the Specification discloses that
the claimed population of chondrogenic precursor cells cannot be isolated
from umbilical tissue using collagenase or hyaluronidase alone, whereas
combinations of collagenase and hyaluronidase, with or without the further
addition of dispase or thermolysin, were effective. Reply Br. 12; Spec. ¶¶
224–225, Table 1-1. Naughton, by contrast, suggests the isolation of
fibroblasts from umbilical cord tissue using any number of mechanical
and/or enzymatic techniques known to those skilled in the art. FF2; see
Reply Br. 10–11. As reasonably interpreted by Appellant, Naughton further
suggests that these same “general protocols may also be used to isolate
chondrocytes, chondrocyte-like cells, or fibroblast like cells, including
fibroblast-like cells from umbilical cord tissue.” Reply Br. 11 (citing
Naughton 12:4–65). Nowhere, however, does this teaching suggest the
enzyme combinations set forth in the Specification, or provide guidance for
other specific enzymes, enzyme combinations, or mechanical dissociation
methods that would necessarily provide the homogeneous cell population set
forth in claim 2.
With respect to the isolation of chondrocyte-lineage cells in particular,
Naughton suggests incubating “minced [umbilical] tissue . . . in a freshly
prepared solution of a dissociating enzyme such as trypsin,” and selectively
isolating non-fibroblast stromal cells based on the rapidity at which
fibroblasts adhere to culture plates. FF3. The Examiner, however, fails to
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provide persuasive evidence that this would provide a homogeneous
population of cells having the claimed characteristics. To the contrary,
because this teaching merely seeks to eliminate fibroblasts from a mixed
stromal population, the Examiner did not establish the likelihood that the
remaining stromal cells consist of a homogeneous population as required by
claim 2. See id. In this respect, we note Appellant’s citation to Yasumoto,
which showed that trypsin digestion of umbilical tissue also releases
myofibroblasts, which can be expanded and differentiated in appropriate
media. App. Br. 13 (citing Yasumoto et al., US 6,916,655 B2 at 7:25–8:41).
Naughton further exemplifies the isolation of chondrocytes by treating
adult animal cartilage with collagenase. FF4. Again, the Examiner does not
persuade us that this provides sufficient guidance for the isolation of the
claimed homogeneous population, with all of its attendant markers, from
umbilical tissue—particularly where the Specification teaches that treating
umbilical tissue with collagenase alone is insufficient for this purpose. See
Spec. Table 1-1. The Examiner does not explain sufficiently how the post-
filing disclosure of Ciavarella establishes inherency. See FF6 (noting subset
of claimed markers in cells derived from Wharthon’s Jelly).
Accordingly, we reverse the rejection of claims 2, 3, 63, 64, and 66 as
obvious in view of Naughton and Pittenger, as supported by Ciavarella.
Because the Examiner relies on the same evidence of inherency in rejecting
dependent claim 65 in view of Naughton, Pittenger, Ciavarella, Mansbridge,
Ronnett, and Liddiard, we reverse the rejection of claim 65 for the same
reasons.
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CONCLUSION
Claims
Rejected
35 U.S.C § Reference(s)/Basis Affirmed Reversed
2, 3, 63–66 Obviousness-Type
Double Patenting
2, 3, 63–66
2, 3, 63,
64, 66
103(a) Naughton,
Pittenger,
Ciavarella.
2, 3, 63,
64, 66
65 103(a) Naughton,
Pittenger,
Ciavarella,
Mansbridge,
Ronnett, Liddiard,
65
Overall
Outcome
2, 3, 63–66

REVERSED

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