Ex Parte Niklason et al

Board of Patent Appeals and Interferences

Sep 29, 2010

10388588 (B.P.A.I. Sep. 29, 2010)

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.
10/388,588 03/17/2003 Laura E. Niklason 1579-800 9304
23117 7590 09/30/2010
NIXON & VANDERHYE, PC
901 NORTH GLEBE ROAD, 11TH FLOOR
ARLINGTON, VA 22203
EXAMINER
NGUYEN, QUANG
ART UNIT PAPER NUMBER
1633
MAIL DATE DELIVERY MODE
09/30/2010 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 BOARD OF PATENT APPEALS
AND INTERFERENCES
___________________

Ex parte LAURA E. NIKLASON,
J. ANDREW MCKEE,
and
CHRISTOPHER M. COUNTER,
Appellants1
____________________

Appeal 2010-001967
Application 10/388,588
Technology Center 1600
____________________

Before CAROL A. SPIEGEL, JEFFREY N. FREDMAN, and
STEPHEN WALSH, Administrative Patent Judges.

SPIEGEL, Administrative Patent Judge.

DECISION ON APPEAL2
Appellants appeal under 35 U.S.C. § 134(a) from an Examiner's final
rejection of all pending claims, claims 1, 2, 7, 15-18, 20-30, 33, and 34 (Br.
5; Ans. 2). We have jurisdiction under 35 U.S.C. § 134. We REVERSE.

1 The real party in interest is DUKE UNIVERSITY (Amended Appeal Brief
filed 22 June 2009 ("Br.") at 3. This decision also cites to the Examiner's
Answer mailed 13 August 2009 ("Ans.").
2 The two-month period for filing an appeal or commencing a civil action, as
recited in 37 C.F.R. § 1.304, or for filing a request for rehearing, as recited
in 37 C.F.R. § 41.52, begins to run from the "MAIL DATE" (paper delivery
mode) or the "NOTIFICATION DATE" (electronic delivery mode) shown
on the PTOL-90A cover letter attached to this decision.
Appeal 2010-001967
Application 10/388,588

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I. Statement of the Case
Claims 1 and 29, the only independent claims on appeal, are
illustrative and read (Br. 18, 20):
1. A method of producing a vascular graft comprising:
i) introducing into constituent cells obtained from a
human, said constituent cells comprising smooth muscle cells,
a construct that comprises a nucleic acid sequence encoding a
lifespan extending or immortalizing protein product having
telomerase catalytic activity, under conditions such that said
nucleic acid sequence is expressed and said protein product is
thereby produced, and
ii) engineering said cells resulting from step (i) into
said vascular graft.

29. An isolated vascular graft comprising smooth muscle
cells obtained from a human and comprising a recombinant
molecule comprising a nucleic acid sequence encoding a
lifespan extending or immortalizing protein product having
telomerase catalytic activity.

The Examiner rejected
claims 1, 2, 7, 15-18, 20-24, 26, 27, 29, 30, 33, and 34 under 35
U.S.C. § 103(a) as obvious over Niklason3 in view of Westerman4 and
Minamino5 as evidenced by Clontech6 (Ans. 4-8);

3 Niklason et al., Functional Arteries Grown in Vitro, 284 SCIENCE 489-493
(April 1999) ("Niklason").
4 Karen A. Westerman and Philippe Leboulch, Reversible immoralization of
mammalian cells mediated by retroviral transfer and site-specific
recombination, 93 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES
USA 8971-8976 (August 1996) ("Westerman").
5 Minamino et al., Hypoxia Extends the Life Span of Vascular Smooth
Muscle Cells through Telomerase Activation, 21 MOLECULAR AND
CELLULAR BIOLOGY 3336-3342 (May 2001) ("Minamino").
6 Clontech pLNCX Retroviral Vector product information (GenBank
Accession #: M28247), PR99507, published 17 January 2000 ("Clontech").
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claim 25 under 35 U.S.C. § 103(a) as obvious over Niklason in view
of Westerman and Minamino as evidenced by Clontech as applied to claims
1, 2, 7, 15-18, 20-24, 26, 27, 29, 30, 33, and 34 above, and further in view of
Anderson7 (id. at 8-9); and,
claims 1, 2, 7, 15-18, 20-24, and 28-30 under 35 U.S.C. § 103(a) as
obvious over McAllister8 in view of Westerman and Minamino as evidenced
by Clontech (id. at 9-13).9
The Examiner found that Niklason teaches a method of making a
vascular graft comprising culturing smooth muscles cells in a tubular
structure followed by injection of endothelial cells into the lumen to make a
tubular vascular graft (id. at 4). The Examiner also found that McAllister
teaches forming a vascular graft comprising culturing endothelial cells and
smooth muscles cells into a cellular sheet wherein the endothelial cells are

7 US Patent Application Publication 2002/0136726 A1, Artery Smooth
Muscle- and Vein Smooth Muscle-Specific Proteins and Uses Therefor,
published 26 September 2002 by Anderson et al., based on US Application
09/988,496 filed 20 November 2001 ("Anderson").
8 US Patent Application Publication 2003/0138945 A1, Tissue Control Rods
for Sheet-Based Tissue Engineering, published 24 July 2003 by Todd N.
McAllister and Nicolas L'Heureux, based on US Application 10/318,279
filed 11 December 2002, which claims benefit under 35 U.S.C. § 119 of the
7 February 2002 and 11 December 2001 filing dates of Provisional
Applications 60/355,283 and 60/340,964, respectively ("McAllister").
9 The Examiner cited US Patent 6,399,384 B1 ("Jat") and International
Application Publication WO 99/35245 ("Newgard") to show the state of the
prior art as of the effective filing date of the instant Application (Ans.
sentence bridging 15-16). Jat and Newgard have not been considered
because the statement of the rejection must expressly contain a mention of
all references applied in the rejection. In re Hoch, 428 F.2d 1341, 1342 n.3
(CCPA 1970). If a reference is important to the rejection, it should be made
a part of the statement of the rejection.
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4
grown on the inner surface of the sheet and the smooth muscle cells are
grown on the outer surface of the sheet, which sheet is then rolled to form a
vascular graft (id. at 10). The Examiner found that neither primary
reference, i.e., neither Niklason nor McAllister, teaches introducing a
lifespan extending or immortalizing protein product having telomerase
catalytic activity into the smooth muscle cells used to make the vascular
graft (id. at 4, 10).
The Examiner found that Westerman teaches a process of reversibly
immortalizing primary cells, including smooth muscle cells, by the transient
expression of an oncogene, but that the resulting immortalized primary cells
exhibited telomere decay leading to senescence (id. at 4-5, 10). According
to the Examiner, Westerman contemplated, but did not demonstrate, using
transient expression of telomerase activity as one possible solution to the
senescence problem (id. at 5, 10-11).
The Examiner found that Minamino teaches that overexpression of
telomerase reverse transcriptase ("TERT") in primary human vascular
smooth muscle cells greatly expands the lifespan of these cells in culture and
that the morphology of TERT lines after extensive passages remained
similar to the morphology of early passage cell populations (id. at 5-6, 11).
The Examiner concluded that it would have been obvious to modify
the method of forming a vascular graft taught by Niklason or by McAllister
by "transiently expressing a TERT protein as suggested by Westerman …
and exemplified by Minamino …[because] [t]he practical and economic
advantages of obtaining more viable and useful cells from a single cell
isolation procedure would be recognized by one of ordinary skill in the art
…" (id. at 6, 11-12).
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Appellants argue that it is only with hindsight that one would have
looked to the Westerman and Minamino to cure the deficiencies of the
primary reference, Niklason or McAllister (Br. 9, 14, 16). Appellants
further argue that even if the combination had been made, there would have
been no basis for a reasonable expectation of success (id.). Appellants also
argue that nothing in Anderson cures the deficiencies of Niklason taken with
Westerman and Minamino (id. at 15).
Thus, the dispositive issue is whether the evidence of record supports
the Examiner's conclusion that it would have been obvious to one of
ordinary skill in the art to modify the method and vascular graft product of
Niklason or McAllister based on the teachings of Westerman and Minamino
absent improper hindsight reconstruction.
II. Findings of Fact
The following findings of fact ("FF") are supported by a
preponderance of the evidence of record.
[1] Niklason teaches producing arteries (vascular grafts) in vitro from
bovine smooth muscle cells grown on a biodegradable polyglycolic
acid matrix, by means of a pulsatile perfusion culture system
(Niklason abstract; ¶ bridging pp. 489-490; Figure 1).
[2] According to Niklason, after 8 weeks of culture, the gross appearance
of vessels cultured under pulsatile conditions was identical to that of
native arteries and their histologic appearance was more similar to
that of native arteries than non-pulsed control vessels (id. at 490, col.
3, ¶ 2).
[3] Table 1 of Niklason summarizes the effects of pulsatile stress and
increasing culture time on the engineered vessels, i.e., the vessel wall
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thickness and collagen content of the engineered vessels grown under
pulsatile conditions were comparable to that of native arteries; and,
while applied pulsatile stress significantly increased the observed
suture retention strengths, the observed suture retention strengths
were less than those observed for native arteries (id. at 491, col. 2, ¶
2; Table 1).
[4] According to Niklason, "[t]issue-engineered arteries were implanted
in miniature swine, with patency documented up to 24 days by digital
angiography" (id. abstract).
[5] According to McAllister, "a stent-less tubular construct can be made
comprising cells grown to a robust tissue sheet" (McAllister 7, ¶ 53).
[6] McAllister teaches forming a vascular graft comprising culturing
mammalian endothelial cells and smooth muscles cells into a cellular
sheet wherein the endothelial cells are grown on the inner surface of
the sheet and the smooth muscle cells are grown on the outer surface
of the sheet, which sheet is then rolled to form a very robust vascular
graft (id. at 3, ¶ 25; 8, ¶¶ 54-5511, ¶ 82).
[7] According to Westerman, "[v]arious research strategies and clinical
applications, such as gene targeting by homologous recombination in
somatic cells, have been hampered by difficulties in obtaining
populations of primary cells that actively divide while maintaining
their stage of differentiation" (Westerman 8971, col. 1, ¶ 1).
[8] Westerman "devised a general gene transfer strategy, referred to as
reversible immortalization, which allows temporary expansion of
primary cell populations by transfer of an oncogene that can be
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subsequently excised by site-specific recombination" (id. at 8971,
sentence bridging cols. 1-2).
[9] Westerman teaches that its "Cre/LoxP reversible immortalization
procedure may facilitate investigations of cell differentiation,
oncogenesis, cell cycle, and senescence by allowing controlled cell
proliferation and accurate on/off studies of various oncogenes in
primary cells" (id. at 8975, col. 2, ¶ 1).
[10] According to Westerman, "our results support the current formulation
of the telomere hypothesis of replicative cell senescence.
Alternatively, it may be advantageous to excise the oncogene in truly
immortal cell lines after M2, when telomeres have been spontanously
[sic] stabilized" (id.).
[11] Westerman suggests that "transient expression of telomerase activity
might also allow in the future the resetting of the mitotic clock during
the Cre/LoxP reversible immortalization procedure to delay
replicative senescence of the cells" (id.).
[12] Minamino reports
that chronic hypoxia can … prolong the growth of
human VSMC [vascular smooth muscle cells] by
inducing telomerase activity and telomere
stabilization. … [I]nhibition of telomerase
shortened cell life span in hypoxic cultures,
whereas constitutive expression of TERT
[telomerase catalytic component] extended the life
span of cells under normoxic conditions. Our data
indicate that hypoxic induction of telomerase
activity could be involved in long-term growth of
VSMC and may thus contribute to human vascular
disorders. [Minamino abstract.]

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III. Discussion
A. Legal principles
The question of obviousness is resolved on the basis of underlying
factual determinations including: (1) the scope and content of the prior art;
(2) the level of ordinary skill in the art; (3) the differences between the
claimed invention and the prior art; and (4) secondary considerations of
nonobviousness, if any. Graham v. John Deere Co., 383 U.S. 1, 17 (1966).
A rejection for obviousness must include "articulated reasoning with some
rational underpinning to support the legal conclusion." KSR Int’l Co. v.
Teleflex Inc., 550 U.S. 398, 418 (2007), quoting In re Kahn, 441 F.3d 977,
988 (Fed. Cir. 2006). While the analysis under 35 U.S.C. § 103 allows
flexibility in determining whether a claimed invention would have been
obvious, KSR, 550 U.S. at 418, "[w]e must still be careful not to allow
hindsight reconstruction of references to reach the claimed invention without
any explanation as to how or why the references would be combined to
produce the claimed invention." Innogenetics, N.V. v. Abbott Labs., 512
F.3d 1363, 1374 n.3 (Fed. Cir. 2008).
B. Analysis
Niklason and McAllister both disclose isolated vascular grafts and
methods of making the grafts from smooth muscle cells (FF 1, 5, 6).
However, it is unclear why one of ordinary skill in the art would have
modified the methods and grafts of Niklason or McAllister by transferring a
gene encoding a protein having telomerase catalytic activity into the smooth
muscle cells used to make the grafts absent Appellants' disclosure. The
Examiner contends that the motivation would be the "practical and economic
advantages of obtaining more viable and useful cells from a single cell
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9
isolation procedure" (Ans. 6, 11-2). The Examiner's rationale ignores a
primary, if not the primary, reason for culturing cells taken from a single cell
isolation procedure to begin with, i.e., to increase the number of viable cells
by expanding the original sample of cells in culture. Neither Niklason nor
McAllister teach or suggest that their respective method of culturing cells to
produce grafts or the product grafts experienced problems, e.g., problems
with cell viability in culture, such as premature senescence, or problems with
faulty graft performance, such as inability to retain a suture when implanted.
To the contrary, Niklason teaches that after 8 weeks of pulsatile culture, the
appearance of the engineered bovine vessels is similar to that of native
arteries (FF 1-3) and that implanted grafts showed patency for up to 24 days
(FF 4). Similarly, McAllister characterized its grafts as robust (FF 5-6).
Therefore, it seems that the Examiner has fallen into the trap of hindsight
reconstruction.
C. Conclusion
Consequently, we will not sustain the rejections under § 103 based on
the combination of Niklason or McAllister with Westerman and Minamino.
The evidence of record fails to support the Examiner's conclusion that it
would have been obvious to one of ordinary skill in the art to modify the
method and vascular graft product of Niklason or McAllister based on the
teachings of Westerman and Minamino absent improper hindsight
reconstruction.

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IV. Order
Upon consideration of the record, and for the reasons given, it is
ORDERED that the decision of the Examiner to reject claims 1, 2, 7,
15-18, 20-24, 26, 27, 29, 30, 33, and 34 under 35 U.S.C. § 103(a) as obvious
over Niklason in view of Westerman and Minamino as evidenced by
Clontech is REVERSED;
FURTHER ORDERED that the decision of the Examiner to reject
claim 25 under 35 U.S.C. § 103(a) as obvious over Niklason in view of
Westerman and Minamino as evidenced by Clontech as applied to claims 1,
2, 7, 15-18, 20-24, 26, 27, 29, 30, 33, and 34 above, and further in view of
Anderson is REVERSED; and,
FURTHER ORDERED that the decision of the Examiner to reject
claims 1, 2, 7, 15-18, 20-24, and 28-30 under 35 U.S.C. § 103(a) as obvious
over McAllister in view of Westerman and Minamino as evidenced by
Clontech is REVERSED.
REVERSED

alw

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