Ex Parte Uytdehaag et al

Patent Trial and Appeal Board

Feb 29, 2016

11731246 (P.T.A.B. Feb. 29, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
111731,246 03/30/2007 Alphonsus G.C.M. Uytdehaag
24247 7590 03/02/2016
TRASKBRITT, P.C.
P.O. BOX 2550
SALT LAKE CITY, UT 84110
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
2578-6448.2US 7866
EXAMINER
POPA, ILEANA
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
03/02/2016 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):
USPTOMail@traskbritt.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ALPHONSUS G.C.M. UYTDEHAAG and
DIRK J.E. OPS TEL TEN
Appeal2013-008310
Application 11/731,2461,2
Technology Center 1600
Before DONALD E. ADAMS, RICHARD M. LEBOVITZ, and
RICHARD J. SMITH, Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
This appeal involves claims directed to an immortalized human
embryonic retina cell. The Examiner has finally rejected the claims as
obvious under 35 U.S.C. § 103(a). We have jurisdiction under 35 U.S.C.
§ 134. The Examiner's rejection is affirmed.
STATEMENT OF CASE
The claims are directed to process for producing a protein of interest
in an immortalized human embryonic retina ("HER") cell, where the cell
1 "The '246 Application."
2 According to Appellants, the real party in interest is Crucell Holland B.V.
Appeal Br. 2.
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Application 11/731,246
expresses an adenoviral E 1 A protein, a protein of interest under control of a
heterologous promoter, and a glycosyltransferase under control of a
heterologous promoter. The cell is cultured in suspension in serum-free
medium. In some claims, the HER cells are PER.C6. The PER.C6 cells
have been deposited and are described in the Fallaux patent, 3 which is prior
art to the '246 Application. '246 Application, i-f 33. According to the '246
Application, the methods are useful for producing human recombinant
proteins that are modified by glycosylation. Id. i-f 10. Glycosylation is the
process by which sugars are added to proteins. A glycosyltransferase is an
enzyme that adds sugar residues to proteins or other sugars. Zhang 442.4
Appellants appeal from the Examiner's final rejection of claims 58-
78. Appeal Br. 2.
Also pending before the Board is an appeal in related case,
Application Serial No. 11/026,518 (Appeal No. 2013-007755). The '246
Application is a divisional application of Application Serial No. 11/026,518.
3 Fallaux et al., US 5,994,128 issued Nov. 30, 1999 (hereinafter "Fallaux").
4 Xiaoqian Zhang et al., Stable Expression of Human a-2, 6-Sialyltransferase
in Chinese Hamster Ovary Cells: Functional Consequences for Human
Erythropoietin Expression and Bioactivity, 1425 Biochimica et Biophysica
Acta 441 (1998) (hereinafter "Zhang").
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The claims stand rejected by the Examiner as follows:
Claims 58-78 under 35 U.S.C. § 103(a) (pre-AIA) as obvious in view
ofBerg,5 Yan,6 Louis,7 Zhang, Chitlaru,8 and Fallaux.
Claim 58 is the only independent claim on appeal. Claim 58 is
reproduced below:
58. A process for producing a protein of interest in an immortalized
human embryonic retina cell, said cell expressing at least an adenoviral ElA
protein and expressing said protein of interest from a polynucleotide
encoding said protein of interest, said polynucleotide being under control of
a heterologous promoter, said cell further expressing at least one
glycosyltransferase from a polynucleotide encoding said glycosyltransferase
under control of a heterologous promoter, said protein of interest comprising
at least one N-linked glycan, said process comprising:
culturing said cell in suspension in a serum-free culture medium and
allowing expression of the protein of interest in said cell.
5 David T. Berg et al., High-Level Expression of Secreted Proteins from
Cells Adapted to Serum-Free Suspension Culture, 14 BioTechniques 972
(1993) (hereinafter "Berg").
6 S. Betty Yan et al., Novel Asn-Linked Oligosaccharides Terminating in
GalNAcjS(l-*4)[Fuca(l-*3)}GlcNAc/3(fl'<<) are Present in Recombinant
Human Protein C Expressed in Human Kidney 293 Cells, 3 Glycobiology
597 (1993) (hereinafter "Yan").
7 Nathalie Louis et al., Cloning and Sequencing of the Cellular - Viral
Junctions from the Human Adenovirus Type 5 Transformed 293 Cell Line,
233 Virology 423 (1997) (hereinafter "Louis").
8 Theodor Chitlaru et al., Modulation of Circulatory Residence of
Recombinant Acetylcholinesterase Through Biochemical or Genetic
Manipulation of Sialylation Levels, 336 Biochem. J. 647 (1998) (hereinafter
"Chitlaru").
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OBVIOUSNESS REJECTION
The Examiner rejected all the claims based on the combination of
Berg, Yan, Louis, Zhang, Chitlaru, and Fallaux. As explained in the Final
Office Action ("Final Rej."), Fallaux describes immortalized HER cells
which comprise ElA and ElB polynucleotides in their genome. Final Rej.
4. The ElA and ElB proteins were known to transform and immortalize
cells. Louis 293; Fallaux, col. 6, 11. 21-24. Fallaux specifically describes
the PER.C6 cells of dependent claim 60. Fallaux, however, utilizes the HER
and PER.C6 cells to package adenoviral vectors. Final Rej. 4; Answer 18-
19; Fallaux, col. 5, 11. 51-61, col. 6, 11. 30-41.
However, the Examiner found that a human embryonic kidney cell
line containing polynucleotides encoding the ElA and ElB proteins ("293
cells") had been used by Berg to produce human protein C. Final Rej. 4.
The Examiner found that the 293 cells in Berg have a heterologous promoter
operably linked to a nucleic acid encoding human protein C in their genome.
Id. Yan was also cited by the Examiner for the same teaching. Id. The
Examiner concluded that it would have been obvious to one of ordinary skill
in the art to have used PER.C6 for expression of a heterologous protein
because they express ElA/ElB, as do the 293 cells, and thus would have
been recognized as a predictable alterative to 293 cells. Final Rej. 5;
Answer 19-20.
With respect to the expression of the glycosyltransferase in the
claimed cell, the Examiner found Chitlaru teaches that sialylation - which
utilizes the glycosyltransferase called sialyltransferase - is important for
"the in vivo stability of recombinant human glycoproteins" and that "the
abundance of sialyltransferases in the host cells determines the
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pharmacokinetic profile of synthesized recombinant proteins." Final Rej. 5.
The Examiner further found that expressing sialyltransferase in 293 cells
"results in high levels of expression of recombinant proteins with adequate
pharmacokinetic characteristics." Id. at 6. Based on this teaching, the
Examiner concluded that it would have been obvious to one of ordinary skill
in the art to introduce and express a nucleic acid encoding a sialyltransferase
in HER and PER.C6 cells to obtain recombinant human proteins with "better
pharmacokinetic[] characteristics." Id. at 6.
Substitution of HER cells for 293 cells
Appellants contend that the Examiner's finding that one of ordinary
skill in the art would have been motivated to substitute the claimed HER
cells for 293 cells in order to express a protein of interest is not supported by
the record. Appeal Br. 14, 16. Appellants argue it was unpredictable that
HER cells could be used to express a protein and that it is a "time-
consuming and laborious process ... rife with uncertainty." Id. at 14.
Furthermore, Appellants state that HER' s suitability to serve as a viral
packaging cell line does not predict its suitability to express a recombinant
protein because "these different processes require and depend upon different
and sometimes contradictory features of the cell used." Id. Appellants
specifically argue on pages 14--18 of the Appeal Brief:
• The ability of a cell to produce a recombinant protein depends on its
ability to process the protein correctly (glycosylation, sialylation, post-
translational modifications) and it was unpredictable that PER.C6 would
produce a glycosylated recombinant protein with a desirable glycosylation
pattern.
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• It took seven years of research to make kidney 293 cells suitable for
recombinant protein expression and thus the work in 293 cells does not
predict success in other cell lines.
• The PER. C6 cells were optimized for viral packaging, not
recombinant protein expression, and the amplification of a transgene needed
to obtain high levels of protein expression in 293 cells would have been
unnecessary, problematic, and undesirable in HER packaging cells.
Kidney cell optimization
Appellants cite Grinnell9 and Walls10 to support their contentions that
Berg was "the result of several years of optimization efforts with the 293 cell
line in combination with a specific vector." Appeal Br. 14--15; Feb. 2010
Remarks 8.
We are not persuaded by this evidence that such alleged
"optimization" establishes difficulty and uncertainty in obtaining HER cells
which produce recombinant proteins. Specifically, Appellants have not
pointed to any difficulties identified in Grinnell, Walls, or Berg over the "7
years of research." Appeal Br. 15. Grinnell, published in 1987, describes
protein C expression in 293 cells and production of stable 293 cell lines
secreting protein C. Grinnell 1189-90. It is not evident how Grinnell
supports Appellants' argument regarding the difficulty and unpredictably of
9 Brian W. Grinnell et al., Trans-Activated Expression of Fully Gamma-
Carboxylated Recombinant Human Protein C, An Antithrombotic Factor, 5
Biotechnology 1189 ( 1987) (hereinafter "Grinnell").
10 Jenna D. Walls et al., Amplification of Multicistronic Plasmids in the
Human 293 Cell Line and Secretion of Correctly Processed Recombinant
Human Protein C, 81 Gene 139 (1989) (hereinafter "Walls").
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expressing recombinant proteins. Walls, published in 1989, further
characterizes 293 cell lines, finding that the recombinant 293 cells secrete
human protein Cat high levels and had full anticoagulant activity. Walls,
Abstract. Consequently, we do not find Appellants' reliance on Grinnell and
Walls for unpredictability and difficulty in the art in obtaining recombinant
protein producing cell lines to support their position.
As further evidence of unpredictability, Appellants cite the following
Berg statement: "Currently, the 293 cell line is the only line shown to be
capable of efficiently processing this complex molecule [human protein CJ,
as well as others in this class of proteins." Berg 976; Appeal Br. 17-18.
However, Appellants do not explain what is meant by "efficiently
processing" nor direct us to an explanation in Berg. Thus, we do not find
this statement alone to establish unpredictably.
Berg teaches that "[i]nitial clones producing 10 to 15 µg/ml were
easily isolated, with several clones usually producing levels as high as 20-25
µg/ml. However, as with all expression systems, the level of secretion
obtained will depend on the particular protein." Id. at 978. Berg further
discusses the choice of promoter for secreted and cell surface proteins. Id. at
976, 978. Berg also specifically mentions that a Syrian hamster cell line,
A V12-664, produced in excess of 100 mg per liter of recombinant protein.
Id. at 978, Abstract. Thus, it would be reasonably expected at the time of the
invention that different cell lines and different proteins would have different
levels of expression. The claims do not require a specific level of
recombinant protein expression.
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Viral packaging
Appellants also argue that it was unpredictable that the viral
packaging HER cell lines could be used for recombinant protein production.
Appeal Br. 16. Appellants contend that 293 cells were unique in their
expression capacity, and that "specialized cell lines with rare and
documented utility in recombinant protein expression did not include HER
cells or PER.C6® cells prior to the applicants' invention." Id.
The Examiner explained why the skilled worker would have chosen
PER.C6 cells to express recombinant protein with a reasonable expectation
of success:
Fallaux et al. specifically teach PER.C6 cell line as stably
expressing ElA/ElB genes (column 6, lines 30-41; column 17,
lines 1-9). Berg et al. teach that all that is required for a cell to
be a host for their expression vector is the stable expression of
ElA/ElB genes (Abstract; p. 972, column 2, first and second
paragraphs). Importantly, ... Berg et al. also teach that the
advantage of using their host/vector system is the rapid
adaptation of clones to serum-free suspension cultures (seep.
977, column 2, Discussion).
Answer 12.
Appellants did not identify a flaw in the Examiner's fact-finding or
reasoning. Appellants also have not directed us to any difficulty in adapting
the PER. C6 cells to recombinant expression.
Unexpected advantages
Appellants contend that the claimed subject matter is patentable
because "advantages of the claimed processes that are attributable to the
recited cells with regard to recombinant protein production ... were entirely
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unknown, unpredictable, and unexpected at the time the invention was
made." Appeal Br. 18.
A showing of "unexpected results" can be used to demonstrate the
non-obviousness of a claimed invention. In re Soni, 54 F.3d 746, 750 (Fed.
Cir. 1995) ("One way for a patent applicant to rebut a prima facie case of
obviousness is to make a showing of 'unexpected results,' i.e., to show that
the claimed invention exhibits some superior property or advantage that a
person of ordinary skill in the relevant art would have found surprising or
unexpected."). These results must be "surprising or unexpected" to one of
ordinary skill in the art when comparted to closest prior art. Soni, 54 F .3d at
750. Unexpected results must also be "commensurate in scope with the
degree of protection sought by the claimed subject matter." In re Harris,
409 F.3d 1339, 1344 (Fed. Cir. 2005).
Appellants contend that glycosylation pattern, cell density,
recombinant protein levels, and stability were unexpected advantages of the
claimed cell lines and processes. However, Appellants have not provided
adequate evidence that the advantages attributed to the claimed cells would
have been unexpected by one of ordinary skill in art. We have not been
directed to statements by one of ordinary skill in the art that such results
were "unexpected" or "surprisingly" as required under Soni.
Motivation
At the onset, we note that the Examiner provided adequate reasoning
to have utilized Fallaux's HER cells to express a recombinant protein,
namely, the fact that cells had been immortalized using ElA/ElB, the same
system used in 293 cells - making it obvious to have used the cells in the
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same way that 293 cells are used to express protein as described in Berg.
Appellants contend that the PER.C6 cells had heretofore only been used to
package viral vectors, but this fact alone does not establish that one of
ordinary skill would have been dissuaded from using them to express
recombinant proteins. Fallaux teaches that the PER cells produced yields of
recombinant vector as least as high as cell lines existing at that time,
including 293 cells. Fallaux, col. 17, 11. 43--45; Table II, cols. 29-30. The
favorable comparison between 293 cells and PER cells provides further
reason to have used them in the same way that 293 had been used, to express
recombinant proteins. The properties described by Appellants, including
glycosylation patterns, high expression levels, and cell densities are a
consequence of following the conventional procedures in the prior art for
creating cell lines capable of producing high levels of recombinant protein.
As stated in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007),
[I]f a technique has been used to improve one device, and a
person of ordinary skill in the art would recognize that it would
improve similar devices in the same way, using the technique is
obvious unless its actual application is beyond his or her skill .
. . . [A] court must ask whether the improvement is more than
the predictable use of prior art elements according to their
established functions.
Glycosylation
With regard to glycosylation, Appellants relied on a Declaration by
Dr. Alphonsus G.C.M. UytdeHaag, a co-inventor of the '246 Application.
Dr. UytdeHaag states that the properties of the cells in "suspension culture
devoid of any human- or animal-derived proteins, such as growth factors,
that are superior to the cell lines available for use in recombinant protein
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production at the time the invention claimed in the '246 application was
conceived." UytdeHaag Deel. i-f 4. However, Dr. UytdeHaag did not
provide evidence of the superiority of the cell lines, and thus his statement
carries little weight.
Dr. UytdeHaag also describes the uncertainty about how a cell line
would glycosylate and the problems with inappropriate glycosylation. Id.
i-fi-15-7. However, Dr. UytdeHaag did not address the teachings in Yan,
Zhang, and Chitlaru which describe glycosylation patterns of recombinant
proteins in expression cells lines. For example, Zhang teaches:
Among several factors which determine the selection of an
expression system for human proteins is whether the
recombinant protein to be expressed requires post-translational
modification for bioactivity and stability, and identification of
host cells capable of catalyzing such modifications.
Glycosylation is an important post-translational modification
although the precise requirement varies with the recombinant
protein in question. Among recombinant human proteins of
medical importance; some require glycosylation for bioactivity
and/or stability in vivo, e.g. erythropoietin, while others do not,
e.g. insulin. Hamster cell lines such as Chinese hamster ovary
(CHO) and baby hamster kidney (BHK) are common host cells
for the production of recombinant human proteins intended for
therapeutic use. Although CEO cells glycosylate recombinant
proteins in a qualitatively similar manner as native human
proteins [1], certain differences nonetheless exist [2,3].
Zhang 441--442. Zhang then explains efforts to improve glycosylation
patterns in CHO cells. Id. at 442. Chitlaru also discusses differences in
glycosylation patterns between 293 cells and CHO cells. Chitlaru 657
(col. 2).
Consequently, based on the evidence, it was well-known and expected
that different cell lines would have different glycosylation patterns, some of
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which were more advantageous when expressing human proteins in a
recombinant cell line. The claims, however, are not limited to human
proteins.
Dr. UytdeHaag's statement that "one of ordinary skill in the art could
not have reliably predicted the cells claimed in the '246 application would
exhibit their favorable glycosylation characteristics with respect to
recombinant proteins produced therein" is not supported by the evidence
with respect to predictability. UytdeHaag Deel. i-f 7 (emphasis added). Dr.
UytdeHaag did not provide evidence of a favorable glycosylation pattern nor
point to the Specification of the '246 Application where such evidence can
be found. Yallop, 11 a post-filing date publication, describes favorable
glycosylation patterns when antibodies are produced by cells, but the claims
are not limited to antibody expression and it is not evident that such
favorability, or superiority, would be achieved with other proteins, human
and non-human, and in all cell lines covered by the claims. Thus, the results
shown in Y allop are not commensurate with the full scope of the claims.
Furthermore, Appellants have not presented evidence that such glycosylation
results would have been unexpected or surprising to one of ordinary skill in
the art.
Cell density
Appellants also assert, based on Yallop, that higher cell densities have
been achieved which are "novel in the industry." Yallop, Abstract and 796.
11 Chris Yallop et al., PER.C6® Cells for the Manufacture of
Biopharmaceutical Proteins, 2005 Modem Biopharmaceuticals 779
(hereinafter "Yallop").
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While such cell density may be high, Appellants have not provided a
statement under Soni that the densities would have been unexpected or
surprising to one of ordinary skill in the art.
With respect to the question of whether the cell densities were high,
the Examiner found that PER. C6 cells expressed higher amounts of E 1 B
than 293 cells and that EIB prevents the induction of apoptosis caused by
EIA. Fallaux, col. 2, 11. 43-52; col. 17, 11. 1-3; Answer 16. Based on this
teaching about EIB's high expression in PER.C6 cells and its function to
prevent apoptosis, the Examiner found that "one of skill in the art would
have expected PER.C6 cells to grow at higher densities than the 239 cells."
Answer 15. As noted by the Examiner, the post-filing date publication by
Y all op is consistent with the Examiner's reasoning because Y all op discloses
that the El protein expression characteristic of the cells described by Fallaux
"may be one of the factors that make the PER.C6 cells grow to high cell
densities." Yallop 784. Appellants have the burden to establish that the
high densities were even higher than would be expected, but did not provide
evidence, such as a declaration, that one of ordinary skill in the art would
have found such densities unexpected in view of the teachings in Fallaux.
Thus, we are not persuaded by the weight of the evidence that a skilled
worker who had knowledge of Fallaux would have found the high densities
to be unexpected.
Appellants' argument is also not commensurate in scope with the
claims. Y all op' s results were achieved with PER. C6 cells which comprises
both EIA and EIB proteins. However, independent claim 58 only requires
the presence EIA. Appellants have not established the results with PER.C6
cells would be characteristic of cells expressing only EIA. Furthermore,
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Y all op' s results are for PER. C6 cells and claim 5 8 is not limited to this cell
line.
Recombinant protein levels
With respect to protein production, Appellants cited to page 804 of
Yallop which states that the antibody levels are "on a par with levels
obtained in industry with CHO and other cell lines." Appeal Br. 22.
Appellants did not establish that the protein levels obtained with the PER.C6
cells would have been "unexpected" by, or "surprising" to, one of ordinary
skill in the art, a necessary finding to establish unexpected results under
Soni. To the contrary, the Examiner provided evidence that it was routine in
the art to select high protein producers as demonstrated by Berg at pages 973
and 976. Answer 16.
Furthermore, the results are not commensurate in scope with the
claims because Y all op' s results were achieved with PER. C6 cells which
comprises both ElA and ElB proteins. However, independent claim 58
only requires the presence of El A. Appellants have not established the
results with PER.C6 cells would be characteristic of cells expressing only
ElA. Furthermore, Yallop's results are for PER.C6 cells and claim 58 is not
limited to this cell line.
Stability and lack of amplification
Another advantage cited by Appellants is that transgene amplification
did not occur in the highly expressing PER.C6 cells. Appeal Br. 17.
Trans gene amplification leads to a high copy number of the gene. As
explained by Y all op, "high gene copy number is associated with instability
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of expression over time. In contrast, expression from PER.C6 cell lines
producing antibodies is very stable over several months." Y allop 803.
PER.C6 cells had been identified by Fallaux as stable ("We found that
the level of El expression in PER cells remained stable for at least 100
population doublings. We decided to characterize the PER clones in more
detail." Fallaux, col. 17, 11. 1-9.). PER.C6 also had high yields of vector
when used as a packaging cell line ("The results indicate that the yields
obtained on PER cells are at least as high as those obtained on the existing
cell lines." Id. at col. 17, 11. 43--48). Based on these disclosures, the skilled
worker would have reasonably expected PER.C6 cells to be capable of
stably expressing protein. While the mechanism was not known, in our
opinion, discovering the mechanism does not make the cells patentable when
one of ordinary skill in the art would have reasonably expected the cells to
be stable over time in expressing a heterologous gene because the
heterologous E 1A/E1 B was expressed stably by the same cell line.
Appellants also did not provide evidence that the stability observed
with the PER. C6 cells was unexpected by one of ordinary skill in the art,
particularly in view of the teachings in Fallaux.
Appellants also state that obtaining high levels of protein expression
by using transgene amplification "is not only unnecessary for packaging
cells (e.g., PER.C6® cells), it is problematic and undesirable," and cite
paragraphs 3.3.2, 3.3.5, and 3.7.1 of Yallop. Appeal Br. 17.
We do not find Appellants' arguments supported by the weight of
evidence. Appellants have not established the undesirability of gene
amplification in packaging cell lines. Appellants point to three paragraphs
in Y allop in apparent support of this position, but they do not direct our
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attention to any specific sentence in Y allop making such a statement and we
cannot find one. Since Appellants are attempting to establish
unpredictability, it is their burden to do so with factual evidence. Section
3.3.5 states a feature of the PER.C6 cell line is the "the easy and rapid
adaptation to serum-free conditions. While gene amplification does not take
place, this is property of the cell line ("expression in PER.C6 cells does not
involve amplification of gene copy number"). Yallop 789 (col. 1 ). Pointing
vaguely to three paragraphs in Yallop which show the success of PER.C6 in
expressing recombinant protein does not meet this burden.
It is true that Yallop, published after the filing date of the application,
teaches that "expression in PER.C6 cells does not involve amplification of
gene copy number" as in another line of cells used for expression (Y allop
789, col. 1, 11. 6-8). However, Appellants have not demonstrated that the
inventors did anything more than follow standard protocols to adapt the
known cell line PER.C6 to express recombinant proteins.
Finally, as with their other arguments, Appellants have not established
the results observed with PER.C6 are indicative of the full scope of the
claims, particularly cells expressing ElA only.
Growth in serum-free suspension
Appellants contend that PER.C6 cells "'behave significantly better in
the process of upscaling, suspension growth, and growth factor
independence' than 293 kidney cells that comprise adenovirus EIA and EIB
proteins. Specification, at [0033]." Appeal Br. 19. Based on teachings in
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,.. ' r-... .. ' .. .. . '. .. ~ 1") • .... ' ,.. ' ££•' .. .. ' me post-nnng aate puoncauon oy Kyu, ,~ Appeuants argue mat ··n coma not
have been predicted with any reasonable expectation of success that the
claimed HER cells (which were not previously known to be adaptable for
suspension culture) would even be capable of suspension growth and growth
factor/serum independence." Id. at 24.
Berg, as pointed out by the Examiner, expressly teaches conditions to
adapt 293 cells to serum free suspension cultures. Berg 973. Thus, Berg
provided guidance on how to adapt cells to suspension culture. Appellants
have not provided evidence that, following Berg's procedure, it would
require any more than routine experimentation to adapt PER. C6 cells to
grow in suspension. Based on the advantages of serum-free suspension
culture as described in Berg, it would have been obvious to have applied
Berg's procedures to Fallaux's cells and "obvious to try" Berg's method on
Fallaux's cells which were also immortalized by El proteins as were Berg's.
To differentiate between proper and improper applications of
"obvious to try,'' this court outlined two classes of situations
where "obvious to try" is erroneously equated with obviousness
under§ 103. In the first class of cases,
what would have been "obvious to try" would have been
to vary all parameters or try each of numerous possible
choices until one possibly arrived at a successful result,
where the prior art gave either no indication of which
parameters were critical or no direction as to which of
many possible choices is likely to be successful.
[In re O'Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988)] .... In
such circumstances, where a defendant merely throws
metaphorical darts at a board filled with combinatorial prior art
12 Ju Hee Ryu et al., HEK 293 Cell Suspension Culture Using Fibronectin-
Absorbed Polymer Nanospheres in Serum-Free Medium, 2004 Wiley
InterScience 128 (hereinafter "Ryu").
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possibilities, courts should not succumb to hindsight claims of
obviousness. The inverse of this proposition is succinctly
encapsulated by the Supreme Court's statement in KSR that
where a skilled artisan merely pursues "known options" from a
"finite number of identified, predictable solutions," obviousness
under§ 103 arises. 550 U.S. at 421, 127 S.Ct. 1727.
The second class of O'Farrell's impermissible "obvious
to try" situations occurs where
what was "obvious to try" was to explore a new
technology or general approach that seemed to be a
promising field of experimentation, where the prior art
gave only general guidance as to the particular form of
the claimed invention or how to achieve it.
853 F.2d 903.
In re Kubin, 561F.3d1351, 1359 (Fed. Cir. 2009).
In this case, there is inadequate evidence that the skilled worker would
have had to vary parameters and make numerous unguided choices. Berg
provides explicit guidance on how to adapt cells to suspension culture.
Appellants have not provided adequate evidence to the contrary. The '246
Application describes loosening attached cells and then growing in medium
to form the suspension culture. '246 Application, i-f 180. Berg's procedure
appears to be similar. Berg 973.
There is also no evidence that Appellants are claiming a new
technology. Berg demonstrates that it was known to adapt cells to grow
suspended in serum-free media.
Citing the post-filing date publication by Ryu, Appellants contend:
even as recently as March, 2004 (which is almost four years
after the earliest priority date of the present application), those
of skill in the art understood that adaptation of anchorage-
dependent cells (such as 293 cells and the claimed HER cells)
for suspension growth and growth factor/serum independence
"is time-consuming and costly, and all types of anchorage-
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dependent cells cannot be adapted to grow in suspension.· Id.,
at page 128 (emphasis added).
Appeal Br. 24.
Absolute predictability of success is not required to establish
obviousness. In re Kubin, 561 F.3d at 1360. The fact that Berg teaches a
method to adapt cells to suspension culture, and Appellants have not
identified any problems or difficulties, militates, in our opinion, against a
finding of nonobviousness based on the production of a cell line that could
be grown in serum-free suspension culture.
Invitation to engage in research
Appellants assert that the Examiner's rejection is "a general invitation
to engage in a research program" (Appeal Br. 18), but Appellants have not
provided persuasive arguments or evidence that transforming Fallaux's cell
with a sialyltransferase polynucleotide and then utilizing the cell to make
heterologous proteins was anything more than following the explicit
guidance in the publications cited by the Examiner. Appellants have not
established that it was necessary to "to vary all parameters or try each of
numerous possible choices until one possibly arrived at a successful result,
where the prior art gave" no guidance or direction as to choices to be made
to achieve success. In re 0 'Farrell, 853 F.2d at 903.
Licensing
Appellants provide evidence of "of over 44 separate license
agreements or license extensions between Crucell and DSM Biologics and
leading biotechnology and biopharmaceutical companies for the use of the
PER.C6® cell line as an r-protein production platform," which they contend
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establish commercial success of the claimed invention. Remarks of
September 2010 ("Sept. 2010 Remarks"), 15, References Cl---C44.
Id.
Included amongst the list of industry leaders are well-known
and established companies such as Acambis (reference C36),
Centocor/Johnson & Johnson (reference C5), CSL Behring
(reference C44), Daiichi Sankyo (reference C36), GSK
(reference C43), Merck & Co. (reference C 1 ), Masterclone
(reference C33), MorphoSys (references C12, C26, and C39),
Pfizer (reference C30), Roche (reference C13), Sartorius
Biotech GmbH (reference C32), Talecris Biotherapeutics
(references C40 and C42), and others. Such license agreements
can prove profitable, as demonstrated at least by the separate,
multimillion dollar agreements entered into with Talecris
Biotherapeutics (references C40 and C42) for just two specific
r-proteins and the rights to produce the r-proteins using the
PER.C6® cell line.
We agree with Appellants that the aforementioned licensing is strong
evidence of commercial success of the PER. C6 cell line. See Ins ti tut
Pasteur & Universite Pierre et Afarie Curie v. Focarino, 738 F.3d 1337,
1347 (Fed. Cir. 2013). However, Appellants have not directed us to what
patent or patents have been licensed. The PER.C6 cell line was not invented
by Appellants, but rather was already described in the Fallaux patent, which
was filed prior to the Application and published as a PCT on January 3,
1997, almost two years prior to April 15, 1999, the earliest priority date of
the instant application. The Fallaux patent, US 5,994, 128, is assigned to
Crucell Holland B.V. (Reel/Frame 13828-651 ), which is the same assignee
as the '246 Application (Reel/Frame 19138-898). The '246 Application
claims benefit to applications that matured into two additional patents, US
6,855,544 and US 7 ,504,248. Appellants have not identified what patents or
patent applications have been licensed in the 44 license agreements relied
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upon for commercial success. Appellants have the burden of establishing
commercial success and it is incumbent on them to demonstrate, on the
record, that the '246 Application is the subject of the licensing agreements,
rather than leave it to presumption. This is particularly true in view of the
fact that the PER. C6 cell line mentioned in References C 1---C44 is the
subject of the Fallaux patent.
In addition to this, and an independent reason for finding the licensing
activity insufficient, Appellants have also not identified a nexus between the
claimed subject and the commercial success. All the claims require the cells
to comprise "a polynucleotide encoding said glycosyltransferase under
control of a heterologous promoter." "[I]f the marketed product embodies
the claimed features, and is coextensive with them, then a nexus is presumed
and the burden shifts to the party asserting obviousness to present evidence
to rebut the presumed nexus." Brown & Williamson Tobacco Corp. v.
Philip Morris Inc., 229 F.3d 1120, 1130 (Fed. Cir. 2000) (internal citations
omitted). Appellants have not provided evidence that the licensed subject
matter has all the features of the claims, namely, HER cells which comprise
glycosyltransferase under control of a heterologous promoter. Appellants
refer to statements made by the licensees regarding "the technical and
economic superiority of the as-claimed cells and methods." Sept. 2010
Remarks 16. However, the statements are with regard to the PER.C6 cell
line and there is no evidence that it comprises the claimed
glycosyltransferase polynucleotide under control of a heterologous promoter
as claimed. In addition, PER.C6 cells contain both ElA and ElB, and the
claims only require the presence of El A. Accordingly, Appellants have not
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established a nexus between the claimed subject matter and the licensing
activity.
Claim 60
Claim 60 is drawn to the protein production process of claim 58,
"wherein said cell is a PER.C6® cell (ECACC deposit 96022940) or a cell
of PER. C6® origin."
Appellants provide separate arguments for claim 60, but these
arguments are the same arguments already addressed for claim 58. Appeal
Br. 29.
Since this claim is limited to the PER.C6 cell line, the commensurate
in scope reasoning discussed above does not apply.
With regard to the secondary considerations, Appellants did not
provide statements by one of ordinary skill in the art that results obtained
with PER.C6 were surprising or unexpected as required under Soni. The
comparisons described in Y allop did not appear to be conducted under
comparable conditions or with the closest prior art as noted by the Examiner.
Answer 15, 26 (discussing comparison with CHO cells).
Claim 76
Claim 76 is drawn to protein production process of claim 58, and
further recites that "wherein the cell is cultured in suspension in a serum-free
culture medium to a cell density of at least 10 x 106 cells/mL."
The Examiner found that the claimed cell density is "inherent to the
transformed PER.C6 cell" described in Fallaux. Final Rej. 6.
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Appellants provide separate arguments for claim 7 6 but do not
identify an error in the Examiner's reasoning that cell density is an inherent
characteristic of the PER.C6 cell line. Appeal Br. 35. Rather, in the Appeal
Brief, Appellants repeat the same arguments made for claim 58.
Claim 77
Claim 77 is drawn to the protein production process of claim 58,
"wherein the cell is cultured in suspension in a serum-free culture medium
with a doubling time of about 35 hours." The Examiner found that the
claimed doubling time is "inherent to the transformed PER.C6 cell"
described in Fallaux. Final Rej. 6. Consistent with the Examiner's
statement, the '246 Application states that "following features make PER.C6
particularly useful as a host for recombinant protein production" and list
doubling times of about 35 hours as one of these features. '246 Application,
iT 44.
Appellants provide separate arguments for claim 77 but do not
identify an error in the Examiner's reasoning that doubling time is an
inherent characteristic of the PER.C6 cell line. Appeal Br. 41. Rather, in
the Appeal Brief, Appellants repeat the same arguments made for claim 58.
Claim 78
Claim 78 is drawn to the protein production process of claim 58,
"wherein the cell expresses between 2 to 200-fold more of the protein of
interest than a Chinese hamster ovary (CHO) cell comprising a
polynucleotide encoding the protein of interest under control of the
heterologous promoter." The Examiner found that the claimed protein levels
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are "inherent to the transformed PER.C6 cell" described in Fallaux. Final
Rej. 6. The Examiner also found that it was routine in the art to select high
protein producers as demonstrated by Berg at pages 973 and 97 6. Answer
16. The claim, itself, has no reference standard so the process could be
compared to a process using any CHO cell, including a low producer.
Appellants provide separate arguments for claim 78 but do not
identify an error in the Examiner's reasoning that protein production is an
inherent characteristic of the PER.C6 cell line. Appeal Br. 46. Rather, in
the Appeal Brief, Appellants repeat the same arguments made for claim 58.
Summary
For the aforementioned reasons, we affirm the obviousness rejection
of claims 58-78. To the extent claims were not argued separately, they fall
with claim 58. 37 C.F.R. § 41.37(c).
TIME PERIOD
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l )(iv).
AFFIRMED
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