Ex parte Rasmussen et al.

Board of Patent Appeals and Interferences

Jan 30, 2001

08442603 (B.P.A.I. Jan. 30, 2001)

The opinion in support of the decision being entered today was not written for
publication and is not binding precedent of the Board.

Paper No. 20

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte JAMES RASMUSSEN,
GARY BARSOMIAN and MICHEL BERGE
__________

Appeal No. 1998-1719
Application No. 08/442,603
__________

ON BRIEF
__________

Before WINTERS, ADAMS and GRIMES, Administrative Patent Judges.

GRIMES, Administrative Patent Judge, issued a concurring opinion.

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on the appeal under 35 U.S.C. § 134 from the examiner’s final
rejection of claim 14. Claim 14 is the only claim pending in this application, and is
reproduced below:

14. A CHO cell comprising nucleic acid encoding enzymatically active
human glucocerebrosidase, said cell being transformed with any
plasmid selected from the group pGB20, pBG371 and pGB42.

1 We note the following typographical error in appellants’ Appendix, “pBG37”
should read – pGB37 --. This typographical error is corrected herein.
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The references relied upon by the examiner are:

Clark et al. (Clark) 4,675,285 Jun. 23, 1987

Levinson et al. (Levinson) 4,713,339 Dec. 15, 1987

Martin et al. (Martin), “Glycosylation and Processing of High Levels of Active Human
Glucocerebrosidase in Invertebrate Cells Using a Baculovirus Expression Vector,”
DNA, Vol. 7, No. 2, pp. 99-106 (1988)
GROUND OF REJECTION

Claim 14 is rejected under 35 U.S.C. § 103 as obvious over Martin in view of
Levinson and Clark.
We reverse.
THE REJECTION UNDER 35 U.S.C. § 103:
In reaching our decision in this appeal, we have given careful consideration
to the appellants’ specification and claims, and to the respective positions
articulated by the appellants and the examiner. We make reference to the
examiner’s Answer2 for the examiner’s reasoning in support of the rejection. We
further reference appellants’ Brief3 for the appellants’ arguments in favor of
patentability.
The initial burden of presenting a prima facie case of obviousness rests on
the examiner. In re Oetiker, 977 F.2d 1443, 1445, 24 USPQ2d 1443, 1444 (Fed.
Cir. 1992).

2 Paper No. 18, mailed December 11, 1996.
3 Paper No. 16, received August 19, 1996.
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In the Final Office Action4 (page 4), the examiner finds that the combination
of Martin in view of Levinson and Clark teach the pGB20 plasmid. The examiner
relies (Answer, pages 4-5) upon Martin to teach the glucocerebrosidase gene. The
examiner states (Answer, bridging paragraph, pages 6-7) that:
Appellants argue that the glucocerebrosidase gene of Martin et al. is
not the functional equivalent of applicant’s gene segment. This is not
persuasive because applicants have failed to show that the
glucocerebrosidase gene of appellants is different in an unobvious
manner from the gene of Martin et al. Appellants argue that their
original gene segment was extensively modified but fail to show how
the modified segment (included within the claimed plasmids) differs
from the gene segment of Martin et al. … Martin et al. state on page
100 that “the cDNA for human glucocerebrosidase was obtained from
plasmid pUC19/GC … This cDNA contained 5’ and 3’ untranslated
sequences as well as the complete coding region for
glucocerebrosidase.” … The nucleotide sequence of pUC19/GC is
not given so it is not clear that the Eco RI – Xba I fragment of the
cDNA insert of this plasmid contains the complete 5’ and 3’ non-
coding regions of the human GCR gene but merely that at least some
of these sequences are present.

Appellants’ specification (page 18, lines 5-26) discloses:

To optimize expression of GCR in mammalian cells, we further
modified the GCR.D21 … the modifications were made using
oligonucleotide directed mutagenesis … to alter the nucleotide
sequence near the GCR translation start to match the consensus
sequence (CCACCATGG) for optimal translation in mammalian cells
… and to delete the excess sequence 3’ of the gcr.D21C stop codon.
… A bicistronic gcr-dhfr expression vector for CHO cells was
constructed as shown in Fig. 7 … This vector, pGB20, contained
gcr.D21C ….

Appellants’ figure 6 illustrates the modifications made to obtain gcr.D21C,
including the oligonucleotide directed mutagenesis of the GCR translation start to
match the consensus sequence described on page 18 of the specification. Figure

4 Paper No. 13, mailed October 4, 1995.
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7 of the specification illustrates the ligation of gcr.D21C into the pGB14 plasmid to
obtain pGB20.
Obviousness can only be established by combining or modifying the
teachings of the prior art to produce the claimed invention where there is some
teaching, suggestion, or motivation to do so found either in the references
themselves or in the knowledge generally available to one of ordinary skill in the art.
See In re Fine, 837 F.2d 1071, 1075, 5 USPQ2d 1596, 1598 (Fed. Cir. 1988). The
examiner merely argues (Answer, page 8) that it would have been obvious to “trim
the amount of untranslated sequences of a gene for optimization of the expression
of the encoded protein….” The examiner fails to identify a teaching, and we find no
such teaching of record, that would suggest to a person of ordinary skill in the art to
modify the translation start site of the glucocerebrosidase gene as was done in
appellants’ pGB20 construct. Levinson and Clark, relied upon by the examiner to
teach other components of the plasmid, e.g., ampicillin resistance and a
polyadenylation signal, fail to make up for the deficiencies found in Martin.
On these facts, we are constrained to reach the conclusion that the examiner
failed to provide the evidence necessary to support a prima facie case of
obviousness. Where the examiner fails to establish a prima facie case, the
rejection is improper and will be overturned. In re Fine, 837 F.2d 1071, 1074,
5 USPQ2d 1596, 1598 (Fed. Cir. 1988). Accordingly, we reverse the examiner’s
rejection of claim 14 under 35 U.S.C. § 103 as obvious over Martin in view of
Levinson and Clark.
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The concurrence believes that the examiner has met her burden because
“[a]ppellants have admitted that the modification they made to the pGB20 translation
start site was known in the art to optimize expression in mammalian cells.” The
concurring opinion refers to a passage of appellants’ specification (page 18) finding
that “[t]his passage is an admission that a consensus translation start site had been
disclosed in the prior art and that such a translation start site was known to provide
optimal translation in mammalian cells.” In support of this opinion, the concurrence
relies upon In re Nomiya, 509 F.2d 566, 570-71, 184 USPQ 607, 611 (CCPA 1975)
for the proposition that “[i]nformation that an applicant admits is in the prior art ‘may
be considered ‘prior art’ for any purpose, including use as evidence of
obviousness.’” The concurrence also relies on, In re Hedges, 783 F.2d 1038, 1039,
228 USPQ 685, 687 (Fed. Cir. 1986) for the proposition that “the prior art as a
whole must be considered [and] … the teachings are to be viewed as they would
have been viewed by one of ordinary skill.” We disagree with this line of reasoning.
We first note that our concurring colleague’s reasoning bears little
relationship to the reasoning presented to us on the record by the examiner.
Nevertheless, assuming arguendo that appellants’ statements at page 18 of the
specification constitute admitted prior art5, we find no reason, suggestion or
motivation stemming from the prior art to modify Martin, in the manner proposed by
the examiner. Pro-Mold & Tool Co. v. Great Lakes Plastics, Inc., 75 F.3d 1568,
1573, 37 USPQ2d 1626, 1629 (Fed. Cir. 1996). In our judgment, the only reason or

5 We do not find it necessary to determine if, or to what extent, the statements at
page 18 of the specification constitute admitted prior art.
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suggestion to modify the references, as suggested by the concurrence, to arrive at
the present invention comes from appellants’ specification. As our appellate
reviewing court noted in In re Shuman, 361 F.2d 1008, 1012, 150 USPQ 54, 57
(CCPA 1966) “[i]t is impermissible to first ascertain factually what appellants did
and then view the prior art in such a manner as to select from the random facts of
that art only those which may be modified and then utilized to reconstruct appellants’
invention from such prior art.”
On this record, the examiner acknowledges (Answer, page 7) that “the
disclosure of Martin et al. is unclear.” Then, after recognizing that the teachings in
the Martin reference were less than clear, the examiner states (Answer,
page 8):
Even if the gene fragments of Martin et al. differ from
appellants gene fragment as stated in the appeal brief, this is not an
unobvious difference. The disclosure of a gene clearly suggests to
the ordinary skilled artisan additional fragments of nucleic acid which
encode the same nucleotide sequence with less non-coding
sequence as, absent evidence to the contrary, the skilled artisan
would clearly consider all gene fragments which include the entire
coding sequence to be functionally equivalent for the expression of the
encoded protein. Furthermore, it was well known in the art to trim the
amount of untranslated sequences of a gene for optimization of the
expression of the encoded protein as such untranslated sequences
can include sequences which produce plasmid or message instability
or introduce elements such as upstream ATG codons which decrease
the amount of protein produced but are not necessary for expression
of the desired protein.

Initially, we believe that it is improper to base a rejection on a reference that
is less than clear. As stated in In re Warner, 379 F.2d 1011, 1017, 154 USPQ 173,
178 (CCPA 1967), cert. denied, 389 U.S. 1057 (1968) “[t]he Patent Office has the
initial duty of supplying the factual basis for its rejection. It may not, because it may
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doubt that the invention is patentable, resort to speculation, unfounded assumptions
or hindsight reconstruction to supply deficiencies in its factual basis.”
In addition, where we need specificity in the examiner’s analysis, to lead us
to the modifications made in pGB20, we are only met with vagueness and
generalities. We find no appreciation in the examiner’s statement that Martin could
or should be modified in the manner suggested in the concurring opinion. It does
not appear to us that the examiner fully appreciated the degree of specificity
required to get from the gene taught by Martin, to the claimed pGB20 construct
claimed.
Furthermore, to the extent that the concurrence relies on Nomiya, we note
that figures 1 and 2 at issue in Nomiya were labeled “prior art”. In Nomiya, the
examiner’s first rejection of the appealed claims identified and specifically
recognized that figures 1 and 2 illustrated the prior art. Nomiya 509 F.2d at 570,
184 USPQ at 611. Thus, from the very first rejection, Nomiya had notice of the
“prior art” relied upon and an opportunity to address this “prior art.” That is not the
case here.
The Nomiya court also recognized, in reversing the examiner’s rejection
under 35 U.S.C. § 103, that “[t]he court must be ever alert not to read obviousness
into an invention on the basis of the applicant’s own statements; that is, we must
view the prior art without reading into that art appellant’s teachings.” Nomiya 509
F.2d at 571, 184 USPQ at 612.
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On the record presented, the examiner failed to meet her burden of
establishing a prima facie case of obviousness within the meaning of 35 U.S.C. §
103.
Having determined that the examiner has not established a prima facie case
of obviousness, we find it unnecessary to discuss the Barsomian Declaration
executed June 10, 1992, relied on by appellants to rebut any such prima facie case.
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Other Issues:
We encourage the examiner to consider whether a deposit of the biological
materials is necessary, in this application, in order to comply with the requirements
of 35 U.S.C. § 112, first paragraph.

REVERSED

Sherman D. Winters )
Administrative Patent Judge ) BOARD OF PATENT
)
) APPEALS AND
)
Donald E. Adams ) INTERFERENCES
Administrative Patent Judge )

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GRIMES, Administrative Patent Judge, concurring.

Although I agree that the obviousness rejection should be reversed, I
respectfully disagree with the majority’s analysis of the prima facie case. The
majority concludes that the prima facie case fails because the examiner “fails to
identify a teaching, and we find no such teaching of record, that would suggest to a
person of ordinary skill in the art to modify the translation start site of the
glucocerebrosidase gene as was done in appellants’ pGB20 construct.” However,
Appellants have admitted that the modification they made to the pGB20 translation
start site was known in the art to optimize expression in mammalian cells.
The modification of the glucocerebrosidase translation start site in pGB20 is
explained in Appellants’ specification as follows:
To optimize expression of GCR in mammalian cells, we further
modified the GCR.D21 BglII cassette containing the gcr gene. In
general, with reference to Fig. 6, the modifications were made using
oligonucleotide directed mutagenesis . . . to alter the nucleotide
sequence near the GCR translation start to match the consensus
sequence (CCACCATGG) for optimal translation in mammalian cells
(as described by Kozak, 1986, 44 Cell 283-292).

Page 18. This passage is an admission that a consensus translation start site had
been disclosed in the prior art and that such a translation start site was known to
provide optimal translation in mammalian cells.
Information that an applicant admits is in the prior art “may be considered
‘prior art’ for any purpose, including use as evidence of obviousness under
35 U.S.C. § 103.” In re Nomiya, 509 F.2d 566, 570-71, 184 USPQ 607, 611
(CCPA 1975). In addition, when considering obviousness, “the prior art as a whole
must be considered. The teachings are to be viewed as they would have been
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viewed by one of ordinary skill.” In re Hedges, 783 F.2d 1038, 1039, 228 USPQ
685, 687 (Fed. Cir. 1986).
Here, even though the references relied on by the examiner do not teach
Appellants’ modification to the translation start site in the pGB20 plasmid,
Appellants have admitted that this modification was known in the art to provide
optimal translation in mammalian cells. Since the prior art as a whole must be
considered in determining the obviousness of a claimed invention, I conclude that
the references relied on by the examiner, viewed as they would have been viewed
by one of ordinary skill, support a prima facie case of obviousness.
“When prima facie obviousness is established and evidence is submitted in
rebuttal, the decision-maker must start over.” In re Rinehart, 531 F.2d 1048, 1052,
189 USPQ 143, 147 (CCPA 1976). “If a prima facie case is made in the first
instance, and if the applicant comes forward with reasonable rebuttal, whether
buttressed by experiment, prior art references, or argument, the entire merits of the
matter are to be reweighed.” In re Hedges, 783 F.2d at 1039,
228 USPQ at 686.
Here, Appellants have provided evidence that the claimed host cells
unexpectedly secrete the recombinant glucocerebrosidase enzyme. In a
declaration under 37 CFR § 1.132, applicant Gary Barsomian states that
[g]lucocerebrosidase is known to be a lysosomal enzyme which, like
other lysosomal enzymes, is targeted to lysosomes within
mammalian cells. This means that one skilled in the art would
normally expect such an enzyme to be retained within the cell once
expressed, and not secreted into the medium in any significant
amounts. Accordingly, it was unexpected to discover that
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glucocerebrosidase could be secreted into a culture medium in
significant amounts by mammalian cells.

Barsomian declaration, ¶ 5.
Declaratory evidence as to issues of fact is entitled to substantial weight. In
re Alton, 76 F.3d 1168, 37 USPQ2d 1578 (Fed. Cir. 1996). The examiner has not
disputed Dr. Barsomian’s statements that a person of ordinary skill in the art would
expect a lysosomal enzyme such as glucocerebrosidase to be targeted to
lysosomes in mammalian cells, and that its secretion from the claimed cells was
unexpected. Rather, she argues that secretion of glucocerebrosidase from the
claimed cells does not overcome the prima facie case because “the skilled artisan
would have expected the claimed CHO cells to be useful regardless of the ability of
the cells to secrete the glucocerebrosidase.”
In order to outweigh a prima facie case of obviousness, evidence of
unobviousness must show unexpected property of a significant aspect of the
invention. See In re Eli Lilly & Co., 902 F.2d 943, 947, 14 USPQ2d 1741, 1745-46
(Fed. Cir. 1990). However, “when an applicant demonstrates substantially
improved results . . . and states that the results were unexpected, this should suffice
to establish unexpected results in the absence of evidence to the contrary.” In re
Soni, 54 F.3d 746, 751, 34 USPQ2d 1684, 1688 (Fed. Cir. 1995) (emphases in
original).
Here, Appellants have presented unrebutted evidence that the claimed cells
display not merely an improvement in a known property, but a property that was
unknown and unexpected based on the prior art. Since the disclosed utility of the
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claimed cells lies their ability to produce recombinant glucocerebrosidase, and
since the improved property relates to production of recombinant
glucocerebrosidase, the unexpected property relates to a significant aspect of the
claimed invention. Therefore, I find it sufficient to overcome the prima facie
obviousness suggested by the prior art.
In sum, I find no defect in the examiner’s prima facie case. I would, however,
reverse on the basis of Appellants’ evidence of unexpected results.

) BOARD OF PATENT
)
Eric Grimes ) APPEALS AND
Administrative Patent Judge )
) INTERFERENCES

Appeal No. 1998-1719
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William G. Gosz
Genzyme Corporation
Legal Department
One Mountain Road
Framingham MA 01701-9322