Ex Parte 6,777,231 et al

Patent Trial and Appeal Board

Jul 31, 2017

95001592 (P.T.A.B. Jul. 31, 2017)

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.
95/001,592 04/01/2011 6,777,231 606512800500 8338
23460 7590 07/31/2017
LEYDIG VOIT & MAYER, LTD
TWO PRUDENTIAL PLAZA, SUITE 4900
180 NORTH STETSON AVENUE
CHICAGO, IL 60601-6731
EXAMINER
PONNALURI, PADMASHRI
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
07/31/2017 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
____________

UNIVERSITY OF PITTSBURGH OF THE COMMOMWEALTH
SYSTEM OF HIGHER EDUCATION
(Patent Owner and Appellant)

v.

CELLERIX
(Requester and Cross-Appellant)
____________

Appeal 2016-008300
Reexamination Control 95/001,592
US Patent 6,777,231 B1
Technology Center 3900
____________

Before LORA M. GREEN, RICHARD M. LEBOVITZ, and
RAE LYNN P. GUEST, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION UNDER 37 CFR 41.77(f)
This is a final decision under 37 C.F.R. § 41.77(f). The above-
identified inter partes reexamination of United States Patent No. 6,777,231
B1 (“the ’231 patent”) was decided by the Patent Trial and Appeal Board
Decision on Nov. 27, 2013 (“Decision” or “Dec”). In the Decision, the
Examiner’s determination not to adopt the rejection under 35 U.S.C.
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§ 102(b) of claims 11, 22, 25, and 28 as anticipated by Hauner was reversed.
A reversal of an examiner’s determination not to adopt a rejection
constitutes a new ground of rejection. 37 C.F.R. § 41.77(b).
Patent Owner requested that prosecution be re-opened under 37
C.F.R. § 41.77(b)(1). Patent Owner proposed amendments to claims 1 and
3–5 and requested that claims 2 and 6 be canceled. Corrected Patent Owner
Response Requesting Reopening of Prosecution. Patent Owner also
amended claims 11–24, which were previously added during this
reexamination proceeding, in the form of “new” claims 11-24. A
declaration under 37 C.F.R. § 1.132 of Robert J. Harman, V.M.D. was
provided (“Harman Decl.”). Id. Claims 1–6 were not subject to the new
ground of rejection and the amendments made to them were not entered.
Order Granting-in-Part Patent Owner’s Request to Reopen Prosecution (Oct.
27, 2014). Prosecution is therefore closed as to claims 1–6.
Requester filed comments on the Board Decision under § 41.77(c)
(“Req. Comments after Dec.”) in which new rejections were proposed under
35 U.S.C. § 112, first paragraph (lack of written description and
enablement), 35 U.S.C. § 112, second paragraph, 35 U.S.C. § 101, 35 U.S.C.
§ 102(b) over Van,1 and 35 U.S.C. § 102(b) over Zilberfarb.2

1 Robin L.R. Van et al., Cytological and Enzymological Characterization of
Adult Human Adipocyte Precursors in Culture, 58 J. CLIN. INVEST. 699–704
(1976).
2 Vladimir Zilberfarb et al., Human Immortalized Brown Adipocytes Express
Functional β3-adrenoceptor Coupled to Lipolysis, 110 J. CELL SCIENCE 801–
807 (1997).
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Subsequently, the Examiner issued a determination under § 41.77(d)
(“Determination”). Patent Owner filed a response under § 41.77(e) to the
Examiner’s determination (“PO Comments after Determination”).
Requester also filed a response under § 41.77(e) to the Examiner’s
determination (“Req. Comments after Determination”).
Claim 11 is representative of the appealed claims and is reproduced
below:
11. An isolated adipose-derived stem cell that can differentiate
into two or more of the group consisting of a bone cell, a
cartilage cell, a nerve cell, or a muscle cell, wherein the isolated
adipose-derived stem cell is substantially free of other adipose
tissue cells and extracellular matrix material, and which can be
cultured for at least 15 passages without differentiating,
wherein the cell is cultured in DMEM and 5-15% serum for the
at least 15 passages without losing the capacity to differentiate.

ADOPTED REJECTIONS
The following rejections are adopted in this final decision under
37 C.F.R. § 41.77(f).
1. Claims 11–24 under 35 U.S.C. § 112 ¶ 2, as indefinite.
2. Claims 11–24 under 35 U.S.C. § 102(b) as anticipated by or,
alternatively, under 35 U.S.C. § 103(a) as obvious in view of Zilberfarb.
3. Claims 11–15, 17, 18, and 21–24 under 35 U.S.C. § 102(b) as
anticipated by Van.

PROPOSED 35 U.S.C. § 112 ¶ 1, REJECTION
Claims 11 to 24 are directed to an “isolated adipose-derived stem cell”
which, inter alia, “can be cultured for at least 15 passages without
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differentiating, wherein the cell is cultured in DMEM and 5-15% serum for
the at least 15 passages without losing the capacity to differentiate.”
Requester contends that the new claims fail to meet the written
description and enablement requirements of 35 U.S.C. § 112, first paragraph
(Pre-AIA), because the ’231 patent fails to describe or enable the limitation
“without losing the capacity to differentiate.” Req. Comments after Dec. 5–
6.
To satisfy the written description requirement of 35 U.S.C. § 112, the
inventor must “convey with reasonable clarity to those skilled in the art that,
as of the filing date sought, he or she was in possession of the invention.”
Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563–64 (Fed. Cir. 1991)
(emphasis omitted). “One shows that one is ‘in possession’ of the invention
by describing the invention, with all its claimed limitations . . . .” Lockwood
v. Am. Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997) (emphasis
omitted). In describing the claimed invention, there is no requirement that
the wording be identical to that used in the specification as long as there is
sufficient disclosure to show one of skill in the art that the inventor
“invented what is claimed.” Union Oil Co. v. Atlantic Richfield Co., 208
F.3d 989, 997 (Fed. Cir. 2000). The written description “need not recite the
claimed invention in haec verba but [it] must do more than merely disclose
that which would render the claimed invention obvious.” ICU Med., Inc. v.
Alaris Med. Sys., Inc., 558 F.3d 1368, 1377 (Fed. Cir. 2009). Thus, as long
as a person “of ordinary skill in the art would have understood the inventor
to have been in possession of the claimed invention at the time of filing,
even if every nuance of the claims is not explicitly described in the
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specification, then the adequate written description requirement is met.” In
re Alton, 76 F.3d 1168, 1175 (Fed. Cir. 1996).
In this case, while the disputed phrase does not appear in the ’231
patent, the patent provides explicit support for it:
Desirably the cells can be cultured without differentiation using
standard cell culture media (e.g., DMEM, typically
supplemented with 5-15% (e.g., 10%) serum (e.g., fetal bovine
serum, horse serum, etc.). Preferably, the cells can be passaged
at least five times in such medium without differentiating, while
still retaining their developmental phenotype, and more
preferably, the cells can be passaged at least 10 times (e.g., at
least 15 times or even at least 20 times) without losing
developmental phenotype.
’231 patent, col. 4, ll. 9–18. This passage states that cells can be “passaged
. . . in such medium without differentiating,” and mentions in the same
paragraph a preference for “at least 15 times,” providing support for the
limitation that the claimed cells “can be cultured for at least 15 passages
without differentiating.” The same medium as claimed is also recited in the
passage reproduced above.
Claims 1, 2, and 3 as originally filed, also provide written descriptive
support. These claims are reproduced below:
1. A mammalian lipo-derived stem cell substantially free of
mature adipocytes.

2. The cell of claim 1, which can be cultured in DMEM + about
10% fetal bovine serum for at least 15 passages without
differentiating.

3. The cell of claim 2, which has two or more developmental
phenotypes selected from the group of developmental phenotypes
consisting of adipogenic, chondrogenic, cardiogenic, dermatogenic,
hematopoetic, hemangiogenic, myogenic, nephrogenic, neurogenic,
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neuralgiagenic, urogenitogenic, osteogenic, pericardiogenic,
peritoneogenic, pleurogenic, splanchogenic, and stromal
developmental phenotypes.

The ’231 patent discloses that “the isolated cells can be cultured to a
suitable point when their developmental phenotype can be assessed.” Id. at
col. 4, ll. 60–62. Thus, after the cells have been passaged for 15 times
without differentiating, they are assessed to determine whether the “capacity
to differentiate” (as claimed) has been retained by inducing them to
differentiate. Claim 3, reproduced above, provides written descriptive
support for cells which have retained the capacity to differentiate into two or
more cell phenotypes after 15 passages.
The ’231 patent discloses various conditions which are used to induce
differentiation (id. at col. 5, ll. 1–45; cols. 13–14, ll. 30–45), providing the
requisite enablement under § 112.
Accordingly, we conclude that the new claims meet the written
description and enablement requirements of § 112, first paragraph.
Requester contends that Patent Owner cannot challenge the written
description and enablement rejections of claims 22 and 28 because they were
not appealed. Req. Comments after Determination 2–3. This argument in
not persuasive. Claim 22 and 28 are new claims. The PTO examines new
claims for compliance with the statutory requirements of for patentability.
The Examiner determined the claims complied with 35 U.S.C. § 112 ¶ 1
(Determination 22), and as explained above, we agree with that
determination. Patent Owner is not precluded from explaining why the
Examiner’s determination is correct in view of Requester’s challenge.

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PROPOSED 35 U.S.C. § 112 ¶ 2, REJECTION
“Substantially free”
Requester proposed a rejection under § 112 ¶ 2, of new claims 11–14,
23, and 24 as indefinite. Req. Comments after Dec. 4. Requester contends
that the Examiner found that the recited phrase “the isolated adipose-derived
stem cell is substantially free of other adipose tissue cells and extracellular
matrix material” is indefinite because one of ordinary skill in the art would
not understand the “metes and bounds” of “substantially free.” Id.
Requester stated that the Examiner found that Example 1 of the ’231 patent
did not provide sufficient guidance as to the meaning of the disputed phrase.
Id. Requester also contends that the Patent Owner did not appeal the
Examiner’s rejection and therefore cannot challenge it now. Id.
As indicated by the Requester, the Examiner had rejected the claims
as indefinite because of the recitation of the phrase “substantially free.”
RAN 10. This phrase did not appear in all the claims. Id. In the Notice of
Appeal dated July 5, 2012 (“NOA”), Patent Owner appealed “all rejections
(including related objections and other assertions) of all pending claims
(claims 1–28).” However, in the subsequently filed Appeal Brief, Patent
Owner did not address the § 112 ¶ 2, and consequently, it was not
specifically addressed in the Decision, either.
While Patent Owner did not address the § 112, second
paragraph, rejection in the Appeal Brief, the rejection was appealed. See
Patent Owner’s statement in the NOA reproduced above. Thus, we do not
agree with Requester that such rejection was not appealed. Nonetheless,
because the new claims cite the “substantially free” language, we have
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addressed the question of it is indefinite under § 112, second paragraph.
Patent Owner identifies numerous disclosures in the ’231 patent in which the
stem cells are separated from other cells types (stromal cells, erythrocytes)
and from debris. PO Comments after Determination 20–21. Such disclosure
describes separating cells from other materials, achieving “greater purity,”
and subjecting the cells to various steps of separation by centrifugation,
filtration, cell sorting, and immunologically based separation techniques. Id.
Based on this disclosure, one of ordinary skill in the art, to whom the claim
language is directed, would understand that the separation techniques
described in the ’231 patent are designed to remove contaminating cells and
debris from the adipose-derived stem cells, but such skilled worker would
recognize that the techniques have limits, and that some contaminating cells
and materials may remain because of these technical constraints. For this
reason, we conclude that the disputed phrase, “the isolated adipose-derived
stem cell is substantially free of other adipose tissue cells and extracellular
matrix material,” informs the skilled worker with reasonable certainty and
clarity of the scope of the claim, namely, that some detectable contamination
may persist because of the technical shortcomings of cell separation
techniques. Consequently, we will not adopt the Examiner’s determination
that the claims do not comply with 112 ¶ 2, (Determination 22) based on the
recitation of “substantially free.”
“without differentiating” and “without losing the capacity to differentiate”
Claim 11 is directed to a cell. Requester contends that the claims are
indefinite because it “mixes statutory classes of inventions within each
independent Claim,” namely product and process classes of invention. Req.
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Comments after Dec. 2. Specifically, Requester identifies the following
limitations as process limitations (numbering has been added in brackets):
“[1] which can be cultured for at least 15 passages without differentiating,
and [2] wherein the cell is cultured in DMEM and 5-15% serum for the at
least 15 passages without losing the capacity to differentiate.”
Requester states:
A product-by-process claim is proper as long as it is clear that
the product is being claimed in terms of the process by which it
was made. See MPEP 2173(p)(I). In this case, Patent Owner
used the present tense “is cultured” or “are cultured” rather than
the past tense “was cultured” or “were cultured”. With the
present tense verb, the Claims are unclear as to whether
infringement occurs upon creation of an adipose-derived stem
cell that can differentiate into two or more of the claimed groups
or whether infringement occurs when the adipose-derived stem
cell is cultured in DMEM and 5-15% serum for at least 15
passages. Because of this lack of clarity, the Examiner should
reject all of the Claims as indefinite.
Id.
We agree with Requester that the disputed limitation makes the claims
indefinite.
Limitation [1] recites that the cell “can be cultured” for 15 passages,
but does not require it to have been cultured for 15 passages. Limitation [2],
in contrast, recites that the cell “is cultured” and appears to require the cell to
have been cultured for 15 passages. The scope of the claim cannot be
discerned with reasonably certainty because it cannot be ascertained whether
the claimed cell is only capable of being passaged 15 times without
differentiation or whether the claim requires the cell to have been passaged
15 times. (“[I]f a claim is amenable to two or more plausible claim
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constructions, the USPTO is justified in requiring the applicant to more
precisely define the metes and bounds of the claimed invention by holding
the claim unpatentable under 35 U.S.C. § 112, second paragraph, as
indefinite. Ex parte Miyazaki, 89 USPQ2d 1207 (BPAI 2008) (Precedential).
Consequently, the ordinary skilled worker would be unable to determine
whether a cell infringed the claim.
As all claims 11–24 have this limitation, we conclude that claims 11–
24 do not comply with the definiteness requirement of 35 U.S.C. § 112 ¶ 2.

REJECTIONS BASED ON HAUNER, ZILBERFARB, AND VAN
Claim interpretation
The Examiner interpreted the claimed “adipose-derived stem cell” to
be a product-by-process claim in which the cell is claimed by the process
through which it was produced, namely, “cultured in DMEM and 5-15%
serum for the at least 15 passages without losing the capacity to
differentiate.” Determination 6–7. As discussed above, the scope of the
claim is unclear. However, even if the claim is construed to mean that cell
“can” be cultured for 15 passages without differentiating, but doesn’t require
it to have been passaged 15 times, this interpretation does not exclude the
cell from having been subjected to 15 passages without losing the capacity
to differentiate. Thus, the application of the Examiner’s interpretation of the
claim to the cited prior art would be the same under either claim construction
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for the purpose of determining whether the claims are unpatentable in view
of the cited Hauner,3 Zilberfarb, and Van publications

Discussion
The Examiner found that each of Hauner, Zilberfarb, and Van
anticipates the claimed subject matter. Each of the publications describes a
precursor or pre-adipocyte cell, derived from adipose tissue, which
differentiated into a mature adipose cell. While the publications do not
describe that the precursor cell “can differentiate into two or more of the
group consisting of a bone cell, a cartilage cell, a nerve cell, or a muscle
cell,” the Examiner found that the precursor cell was inherently capable of
differentiating into the recited cell types. Determination 8, 15, 19.
The Examiner’s determination is based several lines of evidence: 1) the
cells are derived from adipose tissue; 2) post-filing evidence that cells
isolated the same way as in the patent possessed the recited differentiation
capability; and 3) evidence that the differences in the isolation protocols
would not have led to a different population of cells (id. at 14, 19).
As additional evidence, the Examiner cited the teaching in Zilberfarb
of passaging the pre-adipocytes for several months without losing their
morphological characteristics (Zilberfarb 803) and in Van of carrying the
cells through 20 passages without evidence of a change in morphology (Van
701). Determination 17, 19.

3 Hans Hauner et al., Promoting Effect of Glucocorticoids on the
Differentiation of Human Adipocyte Precursor Cells Cultured in a
Chemically Defined Medium, 84 J. CLIN. INVEST. 1663–1670 (1989).
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Patent Owner contends that the Examiner improperly put the
affirmative burden on Patent Owner of “establishing, apparently through
experimental evidence, the absence of the substantive requirement of
anticipation by inherency” that cells described in the cited publications did
not possess the claimed properties (e.g., “wherein the cell is cultured in
DMEM and 5-15% serum for the at least 15 passages without losing the
capacity to differentiate”). PO Comments after Determination 6, 8, 12.
Patent Owner contends, “Only when there is reason to believe that a claim
element is necessarily present in the prior art – which is not the case here –
might it then be appropriate to place a burden of proof on a patentee.” Id. at
8.
First, we shall begin with the legal principles. As held in In re Best,
562 F.2d 1252 (CCPA 1977):
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 (citation and footnote 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).
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In this case, the Examiner provided adequate evidence of a sound
basis to believe that the precursor adipocytes isolated in Hauner, Zilberfarb,
and Van are “adipose-derived stem cell that can differentiate into two or
more of the group consisting of a bone cell, a cartilage cell, a nerve cell, or a
muscle cell.”
First, as summarized in Table 1 below, the isolation protocols for all
three publications involved similar steps of collagenase digestion and lysis
of erythrocytes.
’231 Patent Hauner (1989) Zilberfarb 
(1997)
Van (1976)
Source of tissue Adult 
lipoaspirates
Subcutaneous 
abdominal 
deposits
Vascular 
stromal cells 
from infant 
brown 
adipose
Omental
adipose
tissue
Isolation method Fibrous 
material and 
blood vessels 
dissected and 
discarded

Collagenase 
digestion
Collagenase 
digestion
Collagenase 
digestion
Collagenase
digestion
Filter through 
250µM nylon 
mesh
Filter through 
190µM nylon 
mesh
Filter
through
200-250µM
nylon mesh
Repeat 
collagenase 
digestion and 
filter
Repeat 
collagenase 
digestion and 
filter

RBC lysis in buffer  RBC lysis in 
buffer 
RBC lysis in 
buffer

Culture in 
DMEM+fetal 
bovine serum 
(about 10%) 
(14:2‐5)
Culture floating 
adipocytes in 
DME/HAM's F‐
12; 10% FCS 
(fetal calf 
serum), 
antibiotic.  
Culture cells in 
DME/HAM’s 
F‐12 10% CS 
(calf serum), 
antibiotic
Culture
until in
Alpha
medium,
20% FCS
until
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Fibroblast‐like 
and devoid of 
lipid droplets
spherical
shape lost
Differentiation Adipose‐derived 
stem cell 
differentiates into 
bone cell,  
cartilage cell, 
nerve cell, or 
muscle cell.
Human 
adipocyte 
precursor cells 
differentiated 
into adipose 
cells
SV‐40 
immortalized 
pre‐
adipocytes 
differentiated 
into mature 
adipocytes
Adipocyte
precursors
differentiate
d into
mature fat
cells
Passage 2/3 F‐12 medium 
+
20% fetal bovine 
serum and 1/3 
standard medium 
that was first 
conditioned by 
the cells isolated 
in Example 1, 
“cloning 
medium”)4
DME/HAM's F‐
12, 10% FCS, 
antibiotic
DME/HAM's 
F‐12; 10% CS
Alpha
medium,
20% FCS
“After 
maintainance 
in serum‐free 
medium of 
confluent cells 
previously 
cultured in the 
presence of 
serum, a nearly 
complete loss 
of 
differentiation 
capacity was 
observed 
“The 
immortalized 
brown 
preadipocytes 
(PAZ6 
preadipocytes
) were 
passaged in 
culture for 
several 
months 
without losing 
their 
morphological 
characteristics
, or their 
molecular 
“carried
these
through 20
passages
without any
evidence of
alterations
in
replicative
rate or
morphology
" (p. 701)

4 Claim 11 recites DMEM and 5–15% serum, but Example 3 in the ‘231
patent, which cultured cells for 15 passages, used a “cloning medium”
having the components listed in the table. ’231 patent, col. 15–16.
Undifferentiated cells were also cultured in DMEM and about 10% serum,
but the number of passages was not disclosed. Id. at col. 14, ll. 3–5
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(Table II).”5 (p. 
1666)
markers” (p. 
803)

While Patent Owner has argued that collagenase digestion (e.g.,
repeated twice in Hauner) and the step of removing fibrous material in
Hauner differ from the claimed method, we simply have not been provided
objective and scientific evidence that such routine steps, particularly a
second collagenase digestion step, would have changed the population of
cells harvested from fat tissue using substantially the same isolation
protocol. All four procedures utilized collagenase to dissociate cells.
Indeed, Patent Owner has not pointed to a step in the isolation procedure
disclosed in the patent that would explain why the cells isolated from its
procedure differ from those in the cited three publications.
To further support this argument, Requester provided a declaration by
Mario Delgado, Ph.D. (“Delgado 2 Decl.,” executed Sept. 20, 2011) in
which he demonstrated that adipose derived stem cells could be isolated
under different collagenase, filtration, centrifugation, and plating densities
(Delgado 2 Decl. ¶ 17), providing evidence that the isolation protocols did
not substantially change the success in isolating an adipose-derived stem cell
as claimed.
All three publications describe isolation of a precursor cell from fat
tissue that is capable of differentiating into a mature adipose fat cell (see
“Source of tissue” in table summary above). This potential to differentiate
into fat cells is also possessed by the isolated stem cells described in the

5 Cells were cultured in a serum-free medium to induce differentiation.
Hauner 1664.
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’231 patent. ’231 patent, col. 15, ll. 59–65. Based on the fact that adipose-
derived precursor cells of each of Hauner, Zilberfarb, and Van were able to
differentiate into mature adipose cells, the Examiner had reasonable basis to
believe that these isolated precursor cells were also capable of differentiating
into the other lineages recited in the claim. In other words, because the prior
art precursor cells behaved the same way as the cells of the ’231 patent, it is
reasonable that the prior art cells would also be able to differentiate into the
other cell types recited in the claims. Patent Owner has not provided
adequate evidence to the contrary.

“cultured in DMEM and 5-15% serum for the at least 15 passages without
losing the capacity to differentiate”
The claims were interpreted by the Examiner to require that the
adipose-derived stem cells were “cultured in DMEM and 5-15% serum for
the at least 15 passages without losing the capacity to differentiate.” We
address this limitation for each of the cited publications.
Hauner
Patent Owner contends that Hauner does not anticipate the claims
because it expressly teaches that the isolated cells lose their capacity to
differentiate after a second passage. PO Comments after Determination 4–8.
Patent Owner identified Findings of Fact 8 and 9 in the Decision to support
their argument. These findings are reproduced below:
FF8. Hauner found that longer exposure to serum lead to
a loss in differentiation capacity (id. at p. 1666, col. 2).
FF9. Table II shows that, as incubation time increased in
a serum-containing medium of DME and 10% serum, the
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capacity of the cells to produce the adipocyte marker GPDH
upon exposure to differentiation medium decreased (id. at p.
1667). GPDH expression decreased from 658 (4 hours in serum)
to 55 (180 hours in serum) after a first subculture and, after
second subculture” GPDH was not detected (“ND”) in cells (id.)
GPDH expression is associated with differentiation into adult adipose
cells. Hauner Abstract. The Examiner also relied upon the Winter6 and the
Zuk publications,7 and the Vivotecnia Lab Report,8 to establish that
Hauner’s cells inherently possessed the differentiation potential of the
claimed stem cells. Determination 9, 10. However, the Examiner did not
address the experiment in Hauner in which mature adipocyte cells were not
detected after a second passage. Requester did not explain how the explicit
disclosure in Hauner that its cells did not differentiate after two passages
meets the contrasting limitation of claim 11 that the cells must be “cultured
in DMEM and 5-15% serum for the at least 15 passages without losing the
capacity to differentiate.” Specifically, Hauner only shows the cells cultured
2 passages, and after the second passage the capacity to differentiate into
adipocytes was lost.
The report by Vivotecnia in which cells said to be isolated by
Hauner’s protocol does not change this determination. Vivotecnia only
looked at the morphology of cells and cell markers:

6 Anja Winter et al., Cartilage-Like Gene Expression in Differentiated
Human Stem Cell Spheroids, 48 ARTHRITIS & RHEUMATISM 418–429 (2003).
7 Patricia A. Zuk et al., Multilineage Cells from Human Adipose Tissue:
Implications for Cell-Based Therapies, 7 TISSUE ENG. 211–228 (2001);
Patricia A. Zuk et al., Human Adipose Tissue is a Source of Multipotent
Stem Cells, 13 MOL. BIOL. CELL 4279–4295 (2002).
8 Vivotecnia, Isolation, Propagation and Characterization of Human
Mesenchymal Stem Cells, Final Report N-01191 (Mar. 23, 2011).
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Cells were subcultured fifteen times and the period between
passages varied between 5 and 8 days. The morphology and
appearance of the cultures has been constant throughout the
study.
The presence or absence of certain cell surface markers was
analysed at the first and fifteenth passages. The results of theses
[sic] analyses show that following cell isolation a low percentage
of cells expressed CD45 (6.47%) and most of the cells were
positive for CD4ge (99.64%) and CD29 (94.05%), this
combination of markers indicate that most of the cells were
indeed human mesenchymal stem cells. At the fifteenth passage
a similar pattern was found, 0.14% of the cells were positive for
CD45, 99.68% were positive for CD49e and 85.60% were
positive for CD29.
Vivotecnia § 3 (“Summary”).
Vivotecnia did not perform experiments to determine whether such
cells were capable of differentiating into adipocyte cells and one of the other
cell types recited in the claims. The ’231 patent, in Example 3 (col. 15, l.
36), showed that not all cells isolated by its protocol retained the ability to
differentiate into all terminal cell types recited in claim 1. As discussed in
more detail below with respect to the cells of Zilberfarb, there is sufficient
evidence of record regarding heterogeneity within the isolated cell
populations to explain the differences between the claimed stem cells, the
precursor cells of Hauner, and those isolated in the Vivotecnia report.
In sum, because Hauner expressly taught that adipocyte potential was
lost after two passages, there is insufficient evidence to show that such cells
were structurally identical to cells that had been passed 15 times yet retained
the capacity for differentiation required by claim 11.
For the foregoing reasons, a preponderance of the evidence does not
support the Examiner’s determination that claim 11 and claims 12–24, each
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of which requires the cells to be capable of differentiation after 15 passages,
are anticipated by Hauner. Consequently, the rejection is not adopted. In
addition, there is insufficient evidence, or reasoning provided by the
Examiner, that it would have been obvious at the time of the invention to
isolate cells with the recited property. The obviousness rejection of the
claims in view of Hauner is also not adopted.

Zilberfarb
A rejection of claims 11–24 as anticipated by Zilberfarb is also
proposed by Requester and adopted by the Examiner. Determination 15.
Zilberfarb describes adipose derived cell, immortalized with SV40
virus. Zilberfarb 801. Zilberfarb teaches:
The immortalized brown preadipocytes (PAZ6 preadipocytes)
were passaged in culture for several months without losing their
morphological characteristics, or their molecular markers. . . .
These immortalized brown preadipocytes (Fig. 2a) could be
converted to adipocytes at any time by treatment with insulin and
dexamethasone, following which they accumulated multilocular
fat (Fig. 2b).
Id. at 803 (emphasis added).
Zilberfarb also teaches:
The establishment of human immortalized preadipocytes with
cognate markers represents a first step towards obtaining clonal
cell lines which should make possible precise pharmacological
analyses of β3-AR function, including ligand binding, adenylyl
cyclase activation and lipolysis. This should yield information
directly applicable to the development of therapeutically useful
drugs. These cells are also suitable for studies on the various
stages of adipocyte differentiation, i.e. the appearance of new
markers and the possible disappearance of others, and should
allow analysis of the influence of various conditions (insulin,
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glucocorticoids, T3, β3-AR agonists and NPY) on adipocyte
differentiation.
Id. at 806.
While Zilberfarb does not expressly disclose culturing the cells for 15
passages, it does teach the immortalized preadipocytes were “passaged in
culture for several months” without losing the ability to differentiate into fat
cells. Id. at 803 (see above). Zilberfarb also mentions that the cells are
“suitable for studies on the various stages of adipocyte differentiation.” Id.
at 806 (see above). There is no indication from Zilberfarb that the cells
would lose the ability to differentiate upon additional passages in culture.
Instead, it is apparent that the reason Zilberfarb immortalized the pre-
adipocytes cells was to derive cell lines (id.) capable of being repeatedly
passaged in culture to study β3-AR function and adipocyte differentiation
without requiring isolation of primary cells from fat tissue each time. Based
on Zilberfarb’s teachings of an immortalized pre-adipocyte cell line and its
passage in culture over several months, the Examiner had a sound basis for
concluding that it could be passaged at least 15 times without losing the
capacity to differentiate.
Patent Owner argues that the Examiner’s determination was based on
the finding that Zilberfarb utilized Hauner’s isolation protocol and, thus,
would have isolated the same precursor cells as Hauner. PO Comments after
Determination 9. “As such is the logic underlying the rejection based on
Zilberfarb, the Patent Owner states that, because Hauner is non-anticipatory
at least as to the limitation, ‘cultured in DMEM and 5-15% serum for the at
least 15 passages without losing the capacity to differentiate,’ neither is
Zilberfarb.” Id.
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This argument does not persuade us that the Examiner erred because
Zilberfarb, as discussed above, showed that its cells could be passaged in
cultured for several months without losing adipocyte differentiation
potential. The Examiner explicitly made this finding in reaching the
determination that Zilberfarb anticipated the claimed adipose derived stem
cells. Determination 17. Once the Examiner established that Zilberfarb’s
immortalized cells could be passaged for extended times without losing the
ability to differentiate into fat cells and provided a reasonable basis to
believe that such precursor cells were stem cells, the burden shifted to Patent
Owner to show that the passaged cells were not stem cells. Best, 562 F.2d at
1255. Indeed, we have not been presented with evidence, or scientific
reasoning, that a precursor cell line derived from adipose tissue and capable
of differentiating into mature adipose cells, is not a stem cell able to
differentiate into other cell types, including at least two of the cell types
recited in claim 11.
To the extent that Zilberfarb’s cells were not passaged 15 times,
Patent Owner has not demonstrated that cells passaged after 15 times are any
different from those passaged fewer times. Determination 17. Process steps
are only relevant when they confer a structure or characteristic on the
product which distinguishes it from products made by other processes. See
In re Garnero, 412 F.2d 276, 279 (CCPA 1969). In addition to this, because
Zilberfarb describes an established cell line, continued cell passage of it
would have been obvious to one of ordinary skill in the art to maintain the
line in culture for further study. Thus, even if Zilberfarb is not anticipatory
to the claimed subject matter, it renders it obvious.
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Van
A rejection of claims 11–15, 17, 18, and 21–24 as anticipated by Van
is also proposed by Requester and adopted by the Examiner. Determination
19.
Van, as indicated in Table 1, discloses that the adipocyte precursor
cells were “carried . . . through 20 passages without any evidence of
alterations in replicative rate or morphology.” Van 701. The cells were
isolated by Van from fat tissue and had the morphology of precursor cells
until exposed to differentiation conditions, which caused them to
differentiate into mature adipocyte cells. Id. at 609 (Abstract). The isolation
method of using collagenase digestion is the same step as in the process
described in the ’231 patent. See supra, table on pages 14–15. The cells
possess the same properties as well, namely, precursor status until exposed
to differentiation conditions and then differentiation into adult cell
adipocytes. Van 701. In view of this similarity in isolation steps, tissue
source, and differentiation potential, the Examiner reasonably required
Patent Owner to show that such cell was not an adipose derived stem cell as
claimed.
Patent Owner did not provide evidence to the contrary, but simply
states that Van did not show culture in the DMEM medium and 5-15%
serum for the at least 15 passages. PO Comments after Determination 11.
As indicated in the table above, Van used alpha media supplemented with
20% fetal calf serum to culture cells. Van 700 (“Methods”). While the
medium may have differed, as indicated above, Patent Owner has not shown
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criticality of the precise process step (i.e., the precise cell culture medium)
such that the claimed medium results in a patentably distinct cell. Rather,
the cells were isolated under similar conditions from fat tissue, shared the
ability to differentiate into adipocytes, and could be maintained in culture for
at least 15 passages, shifting the burden to Patent Owner to show that such
cells were not the stem cells of claim 11, and that the medium utilized by
Van changed the developmental potential of the cell population. In view of
such similarities, the Examiner properly shifted the burden to Patent Owner
to show that the cells could not be “cultured in DMEM and 5-15% serum for
the at least 15 passages without losing the capacity to differentiate.” Best,
562 F.2d at 1255. With respect to this issue, the ’213 patent, discloses
culturing stem cells in both DMEM and in another medium comprising
DMEM and F12 medium (see fn. 4 above and ’231 patent, col. 15, ll. 40–
58), consistent with the medium not being critical.
As with Zilberfarb, we have not been presented with evidence, or
scientific reasoning, to explain why a precursor cell line derived from
adipose tissue and capable of differentiating into mature adipose cells, is not
a stem cell able to differentiate into other cell types, including at least two of
those recited in claim 11. Accordingly, the rejection of claims 11–15, 17,
18, and 21–24 as anticipated by Van is adopted.

Clonal cell lines
Patent Owner focused on the fact that Hauner showed that no
detectable fat cells were observed after two passages to distinguish Hauner
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and Zilberfarb from the claimed stem cells. PO Comments after
Determination 9. Patent Owner stated:
As it has been alleged that the cells of Zilberfarb were obtained
in accordance with the method of Hauner, and as it has been
demonstrated – and indeed as the Board has found (DOA, FF8 &
FF9) – by Hauner that cells obtained in accordance with
Hauner’s methods lost the capacity to differentiate after merely
two passages in serum-containing medium (let alone DMEM and
5-15% serum for at least 15 passages), if it is accepted that
Zilberfarb followed Hauner’s protocol, then it must be accepted
as well that Zilberfarb did not obtain cells, or populations of
cells, as presently claimed, because Hauner demonstrated that
such protocol did not obtain such cells and populations.
Id.
We therefore consider how a cells obtained from fat cells by a
collagenase digestion method, substantially the same as the one carried out
by the ’231 patent (see Table 1), could lead to a different population of cells.
Dr. Harman stated in his declaration:
One of skill in the art would recognize that the most concentrated
area of stem cells is in the perivascular region, therein the name
stromal vascular fraction. By removing the vessels by “careful
dissection” Hauner necessarily has changed the population of
cells in his resulting mixture from that used by the ’231 patent.
Harman Decl. ¶ 6. However, despite Dr. Harman’s testimony, Hauner
characterizes its starting cell population as “stromal-vascular cells” and
showed that precursor cells could be isolated from the population which,
when cultured in a serum-free differentiation medium, terminally
differentiated into mature adipocyte cells (Hauner, Abstract), behaving just
as the stem cells described in the ’231 patent did. Thus, even if the starting
population was “changed” as proposed by Dr. Harman, this does not mean
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that Hauner eliminated the stem cells. To the contrary, Dr. Harman’s
testimony indicates only that the concentration of stem cells may be
different.
Nonetheless, Hauner’s cells were reported to lose the ability to
differentiate into adipocytes after two passages in contrast to the cells
described in Zilberfarb and Van. In other words, precursor cells were
obtained, but not all were capable of being passaged 15 times. The ’231
patent expressly teaches that the cloning method utilized in Example 3
obtained stem cells of different potentials:
The cells were cultured for more than 15 passages in
cloning medium and monitored for differentiation as indicated in
Example 1. The undifferentiated state of each clone remained
true after successive rounds of differentiation.
Populations of the clones then were established and
exposed to adipogenic, chondrogenic, myogenic, and osteogenic
medium as discussed in Example 1. It was observed that at least
one of the clones was able to differentiate into bone, fat,
cartilage, and muscle when exposed to the respective media, and
most of the clones were able to differentiate into at least three
types of tissues. The capacity of the cells to develop into muscle
and cartilage further demonstrates the pluripotentiality of these
lipo-derived stem cells.
’231 patent, col. 15, ll. 55–67 (Example 3) (emphasis added).
Zilberfarb mentions establishing clonal cell lines, as well. Zilberfarb
806. Dr. Delgado found that Zilberfarb’s method “acted as a type of clonal
selection.” Delgado 2 Decl. ¶ 46. Thus, in view of the evidence, we are not
persuaded that even if the cells isolated from Hauner lost ability after a few
passages to differentiate into adipocyte cells, such result casts doubt on the
capability of the cells isolated by Zilberfarb and Van, each of which were
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expressly described to retain differentiation potential after extended culture
or passages into at least two cell types as recited in claim 11. There is
adequate evidence that the isolation techniques result in cell heterogeneity
such that the end resulting population, after passages, may be representative
of only one type of cell present in the original population

Winter, Zuk
The Examiner relied upon the post-filing Winter and Zuk
publications, and the Vivotecnia report as further evidence supporting
finding the cited publications anticipatory to the claimed subject matter. The
post-filing evidence was cited by the Examiner to demonstrate that cells
isolated by the same procedures described in Hauner, Zilberfarb, and Van
were stem cells possessing the potential to differentiate into the cell types
recited in claim 11 and others.
Patent Owner provides arguments to undermine the Examiner’s
argument and relies on the declaration of Dr. Harman in support thereof.
Specifically, Dr. Harman testified that neither Winter nor Vivotecnia
followed Hauner’s isolation protocol. Dr. Harman testified that Winter did
not dissect away blood vessels, used a single collagenase digestion rather
than double digestion, used a different media, and used different growth
periods. Harman Decl. ¶¶ 6–11. For this reason, Dr. Harman concluded
Winter did not isolate the same cells as Hauner. Id. Dr. Harman made
similar statements about the Vivotecnia report. Id. ¶ 12
Dr. Harman’s conclusion is speculative because he did not identify
objective evidence or scientific reasoning as to why the steps in the isolation
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protocol would change the cell population isolated by it. Nonetheless,
Hauner was found not be to be anticipatory or to render the claimed cells
obvious because there was inadequate evidence that Hauner taught or
suggested a cell structurally the same as a cell that has been passed at least
15 times.
With regard to Zilberfarb and Van, for the reasons discussed above,
we find there is adequate evidence to conclude that the cells isolated in these
publications are anticipatory (or obvious) to the claimed stem cells. We do
not find that the evidence in the Winter or the Zuk publications change this
conclusion.

PROPOSED REJECTION UNDER 35 U.S.C. § 101
Requester proposes a rejection under § 101 because the claims
allegedly mix statutory classes of invention. Req. Comments after Dec. 3.
We do not agree. As found by the Examiner, the claims are “product-by-
process” claims because they claim the cell by the process by which it is
made. It is well settled that a product-by-process claim is a permissible
product claim. See In re Thorpe, 777 F.2d 695, 697 (Fed. Cir. 1985)
(“[E]ven though product-by-process claims are limited by and defined by the
process, determination of patentability is based on the product itself.”).
Consequently, we agree with Examiner’s determination not to adopt the
rejection under 35 U.S.C. § 101.

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Summary
In sum, claims 11-24 presented under 37 C.F.R. §41.77(b)(1) are not
patentable under § 112, 2nd (claims 11–24) and the prior art teachings of
Zilberfarb (claims 11–24), and Van (claims 11–15, 17, 18, and 21–24).
Thus, Patent Owner has not overcome the rejections presented in our
original decision consistent with 37 C.F.R. § 41.77 by its amendments to
claims 11-24.

TIME PERIOD
In accordance with 37 C.F.R. § 41.79(a)(4), the “[p]arties to the
appeal may file a request for rehearing of the decision within one month of
the date of: . . . [t]he new decision of the Board under § 41.77(f).” A request
for rehearing must be in compliance with 37 C.F.R. § 41.79(b). Comments
in opposition to the request and additional requests for rehearing must be in
accordance with 37 C.F.R. §§ 41.79(c) and (d), respectively. Under
37 C.F.R. § 41.79(e), the times for requesting rehearing under paragraph (a)
of this section, for requesting further rehearing under paragraph (d) of this
section, and for submitting comments under paragraph (c) of this section
may not be extended.
An appeal to the United States Court of Appeals for the Federal
Circuit under 35 U.S.C. §§ 141–144 and 315 and 37 C.F.R. § 1.983 for an
inter partes reexamination proceeding “commenced” on or after November
2, 2002, may not be taken “until all parties’ rights to request rehearing have
been exhausted, at which time the decision of the Board is final and
appealable by any party to the appeal to the Board.” 37 C.F.R. § 41.81.
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In the event neither party files a request for rehearing within the time
provided in 37 C.F.R. § 41.79, and this Decision becomes final and
appealable under 37 C.F.R. § 41.81, a party seeking judicial review must
timely serve notice on the Director of the United States Patent and
Trademark Office. See 37 C.F.R. §§ 90.1 and 1.983.

AFFIRMED

PATENT OWNER:
LEYDIG VOIT & MAYER, LTD
TWO PRUDENTIAL PLAZA, SUITE 4900
180 NORTH STETSON AVENUE
CHICAGO, IL 60601-6731

THIRD PARTY REQUESTER:
ROBERT A. SALTZBERG
MORRISON & FOERSTER LLP
425 MARKET STREET
SAN FRANCISCO, CA 94105-2482