Ex Parte 6455275 et al

Board of Patent Appeals and Interferences

Jul 23, 2012

90006953 (B.P.A.I. Jul. 23, 2012)

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.
90/006,953 02/27/2004 6455275 17668-A7B 7971
23432 7590 07/23/2012
COOPER & DUNHAM, LLP
30 Rockefeller Plaza
20th Floor
NEW YORK, NY 10112
EXAMINER
QIAN, CELINE X
ART UNIT PAPER NUMBER
1636
MAIL DATE DELIVERY MODE
07/23/2012 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
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.
10/870,229 06/18/2004 Richard Axel 17668-A7-B 1533
23432 7590 07/23/2012
COOPER & DUNHAM, LLP
30 Rockefeller Plaza
20th Floor
NEW YORK, NY 10112
EXAMINER
QIAN, CELINE X
ART UNIT PAPER NUMBER
1636
MAIL DATE DELIVERY MODE
07/23/2012 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 The Trustees of Columbia University
____________

Appeal 2011-012149
Reexamination Control 90/006,953
Application 10/870,229
Patent 6,455,275 B1
Technology Center 1600
____________

Before RICHARD E. SCHAFER, ROMULO H. DELMENDO, and
RICHARD M. LEBOVITZ, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on the appeal by the Patent Owner of U.S. Patent
No. 6,455,275 B1 from the Patent Examiner’s rejections of claims 3, 5-13,
15, 19, 39-41, 44-77, 80-83, 85-100, 104-105, 112, 116-119, 121, 125-128,
130 and 134-137 in a merged reissue and ex parte reexamination
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proceeding. The Board’s jurisdiction for this appeal is under 35 U.S.C. §§
6(b), 134(b), and 306. We affirm.

STATEMENT OF THE CASE
This a merged reissue and ex parte reexamination proceeding of U.S.
Patent 6,455,275 B1 (hereinafter, “the ‘275 patent”), which issued on
September 24, 2002. A request for ex parte reexamination was filed by a
third party requester, Public Patent Foundation, Inc., on February 27, 2004,
and was assigned control No. 90/006,953. An application for reissue,
assigned application No. 10/870,229, was filed by the patent owner on June
18, 2004. The two proceedings were merged pursuant to 37 C.F.R. §
1.565(d) (Decision Merging Reexamination and Reissue, January 2005).
The real party-in-interest is The Trustees of Columbia University in
the City of New York (hereinafter, “Columbia”). The ‘275 patent has been
involved in a number of litigations, all of which we have been informed
have been terminated (App. Br. 8-13; Appendix C6-C19).
An oral hearing was held January 18, 2012. A written transcript of
the hearing has been entered into the record.
The ‘275 patent is a descendant of a patent application filed on
February 25, 1980 by inventors Dr. Richard Axel, Michael Wigler, and Saul
Silverstein. The latter application, Application No. 06/124,513 (“the ‘513
application”), resulted in the issuance of U.S. Patent No. 4,399,216 (“the
‘216 patent”) on August 16, 1983. The ‘513 application is also the ancestor
of several other patent applications that have resulted, to date, in the
issuance of three additional patents, including the ‘275 patent, subject of this
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appeal, and U.S Pat. No. 5,179,017 (“the ‘017 patent”), which issued on
January 12, 1993. See Biogen Idec MA, Inc. v. Trustees of Columbia Univ.,
332 F.Supp.2d 286 (D. Mass 2004).
There are two specific grounds of rejection appealed by Columbia:
whether claims 3, 5-13, 15, 19, 39-41, 44-77, 80-83, 85-100, 104-105, 112,
116-119, 121, 125-128, 130 and 134-137 of the ‘275 patent are unpatentable
for obviousness-type double patenting over (a) previously patented claims
54-73 of the ‘216 patent, or (b) previously patented claims 1-5 of the ‘017
patent (Answer 3 & 7).
The non-statutory double patenting rejection is based on a judicially
created doctrine to prevent the unjustified or improper time-wise extension
of the “right to exclude” granted by a patent and to prevent possible
harassment by multiple assignees (see Answer 3 & case law cited therein).
A non-statutory obviousness-type double patenting rejection is appropriate
where the conflicting claims are not identical, but at least one examined
application claim is not patentably distinct from the patented claim(s)
because the examined application claim is either anticipated by, or would
have been obvious over, the patented claim(s) (see Answer 3 & case law
cited therein).
In addition, the claims are rejected under 35 U.S.C. § 251 because the
oath/declaration filed with the reissue application purportedly does not state
that every error arose without deceptive intent on the part of the applicant.
Columbia is not requesting review of this 35 U.S.C. § 251 rejection, but
asserted it will submit an appropriate declaration upon allowance of the
reissue application pursuant to M.P.E.P. § 1444 (App. Br. 22; Answer 2-3).
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Claim 3 is representative and reads as follows (underlining indicates
amendments relative to the original claim):
(Amended) A transformed Chinese Hamster Ovary (CHO) cell
which comprises amplified foreign DNA I encoding a
proteinaceous material portion of a glycoprotein and amplified
DNA II encoding a dihydrofolate reductase not expressed by the
transformed CHO cell prior to transformation, both amplified
DNA I and amplified DNA II being stably incorporated into the
chromosomal DNA of the transformed CHO cell, which cell
produces multiple copies of the proteinaceous material portion of
the glycoprotein from amplified DNA I and a sugar and
synthesizes or assembles multiple copies of biologically active
glycoprotein therefrom.
CLAIMS
Pertinent limitations of the claims which are in dispute in this appeal
are summarized below. This summary is not a word-for-word reproduction
of the language that appears in the claims, but rather is intended to convey
the key concepts in dispute.
’275 patent claims
• All claims drawn to CHO cells and involve stable DNA encoding a
glycoprotein
• Claims 3, 5, 15, and others require the glycoprotein to be
“biologically active”

Claim 3
• CHO cell
• Stable amplified DNA (“stably incorporated”) encoding
proteinaceous portion of a glycoprotein
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• Synthesizes multiple copies of biologically active glycoprotein

Claim 5
• CHO cell
• Stable amplified DNA encoding proteinaceous portion of a
glycoprotein
• Cell produces “an appropriate sugar”
• Synthesizes multiple copies of biologically active glycoprotein

Claim 15
• A method of producing a glycoprotein comprising culturing CHO
cells of claims 3 or 5

Claim 19
• CHO cell
• Stable amplified DNA encoding glycoprotein

‘216 patent claims
• No CHO cell claims
• No recitation that the foreign DNA is stable in the eukaryotic cells
• No recitation that the foreign DNA codes for a glycoprotein
• No recitation that produced protein is biologically active

Claim 1
• A process for inserting a foreign DNA into a eukaryotic cell
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• where the foreign DNA codes for interferon (claim 3), insulin (claim
4), growth hormone (claim 5), a clotting factor (claim 6), a viral antigen or
antibody (claim 7), or an enzyme (claim 8)

‘017 patent claims
• All claims drawn to CHO cells and involve stable DNA
• No recitation that the foreign DNA codes for a glycoprotein
• No recitation that produced protein is biologically active

Claim 1
• CHO cell
• Stable amplified DNA corresponding to a gene of interest

Claim 3 (depends on claim 2, which depends on claim 1)
• CHO cell
• Stable amplified foreign DNA corresponding to a gene of interest
• DNA encodes a proteinaceous material which is “interferon protein,
insulin, a growth hormone, a clotting factor, a viral antigen, an antibody, or
an enzyme.”

The Examiner regarded the ‘275 patent claims as species of the claims
of the ‘216 and ‘017 patents.
The ‘216 patent claims are drawn to a process and are not limited to
CHO cells as are the ‘275 patent claims, but rather the ‘216 patent claims are
drawn to eukaryotic cells in independent claim 1 and mammalian cells in
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dependent claim 12. The ‘216 patent also does not require the DNA to be
stable in the cell, as does the ‘275 patent. Thus, the Examiner properly
concluded that the ‘275 patent claims are a species of the ’216 patent claims
with respect to these claim limitations.
All the claims of the ‘017 patent are drawn to CHO cells, as are the
claims of the ‘275 patent. Independent claim 1 of the ‘017 recites that the
foreign DNA is “corresponding to a gene of interest,” and thus is a broader
genus than the claims of the ‘275 patent which require the DNA to code for
a glycoprotein (e.g., claims 3, 5, 15, 19, 93) or a biologically active
glycoprotein (claim 3, 5, and 15). Thus, with respect to the glycoprotein
limitation, all claims (e.g., independent claims 3, 5, 15, 19, and 93) of the
‘275 patent are a species of claim 1 of the ‘017 patent.
Both the ’216 patent and ‘017 patent have claims which are drawn to
specific classes of proteins. As summarized above, dependent claims of the
‘216 and ‘017 patent recite that the protein can be interferon, insulin, a
growth hormone, a clotting factor, a viral antigen, an antibody, or an
enzyme. There is evidence that at least some of the proteins in these protein
classes are glycoproteins. However, there is insufficient evidence that all
proteins in the ’216 patent and ‘017 patent claims are glycoproteins as
required by the claims of the ‘275 patent.

OBVIOUSNESS-TYPE DOUBLE-PATENTING
In rejecting the claims of the ‘275 patent as unpatentable for
obviousness-type double patenting in view of the claims of the ‘216 and
‘017 patents, the Examiner referred to the common specification of the ‘216
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patent. For the CHO cell limitation, the Examiner found that CHO cells
were described as preferred for transformation in the ‘216 patent disclosure
and could have been claimed (Answer 14). Based on this disclosure, the
Examiner concluded that CHO cells were therefore an obvious species of the
claimed eukaryotic cells in the ‘216 patent (Answer 14). The Examiner did
a similar analysis for other limitations recited in the ‘275 patent claims, but
lacking from the claims of the ‘216 and ‘017 patents (Answer 14-15).
The Examiner quoted from In re Vogel, 422 F.2d 438 (CCPA 1970) to
support his analysis. Vogel, 422 F.2d. at 441-42, permitted the use of a
patent disclosure to determine whether an application claim was merely an
obvious variation of an invention claimed in a patent, a principle that was
reaffirmed in In re Basell Poliolefine Italia S.P.A., 547 F.3d 1371 (Fed. Cir.
2008).
Indeed, our predecessor court stated that a patent's disclosure
may be used to determine whether an application claim is
merely an obvious variation of an invention claimed in a patent.
Vogel, 422 F.2d at 441-42. The court stated that the disclosure
may be used to learn the meaning of terms and in “interpreting
the coverage of [a] claim.” Id. at 441. It may also be used to
answer the question whether claims merely define an obvious
variation of what is earlier disclosed and claimed.
Basell, 547 F.3d at 1378.
In Vogel, the broadest claims of the patent application were directed to
process of preparing a meat product, with narrower claim 11 reciting that the
meat is beef. The claims of the earlier issued patent were drawn to a related
meat processing method, but limited to pork. The patent application claims
were rejected for obviousness-type double patenting over the patent claims.
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One of the issues was whether the beef method claims were obvious in view
of the issued pork method claims. The court held at 422 F.2d at 442:
The specification then states how the process is to be carried
out with pork. This portion of the specification supports the
patent claims and may be considered. It describes in tabular
form the time and temperature limits associated with the pork
process. Appealed claim 11, reciting beef, does not read on the
pork process disclosed and claimed in the patent. Further, we
conclude that claim 11 does not define merely an obvious
variation of the pork process. The specific time and temperature
considerations with respect to pork might not be applicable to
beef. There is nothing in the record to indicate that the
spoliation characteristics of the two meats are similar.
Accordingly, claim 11 does not present any kind of double
patenting situation.
The court used the patent disclosure in two ways: 1) to determine the
scope of the claim and 2) and to determine whether one claimed process was
obvious in view of the other. After reading the description of the invention
in the patent disclosure, the court found that the process described in the
patent disclosure for pork had different parameters from the process used to
make beef. Based on the described differences, the court concluded that the
beef process did not “read” on the pork process and was not an obvious
variant of the pork process.
The Examiner in this case looked at the ‘216 patent disclosure to see
what species of eukaryotic cells were described. The Examiner found that
CHO cells were a preferred species, and concluded they were obvious
variants of the claimed genus of eukaryotic cells. Apparently, the Examiner
was using the ‘216 patent disclosure to determine whether there was
anything different about using CHO cells as a host cell as compared to the
broader class of eukaryotic cells – in the same way Vogel used the patent
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disclosure to compare the pork and beef processes. Having not found
anything in the ‘216 patent disclosure to distinguish using CHO cells from
other eukaryotic cells, the Examiner concluded that CHO cells were an
obvious species of eukaryotic cells to use as an expression host.
Based on Vogel and Basell, it was proper for the Examiner to consult
the ‘275 patent disclosure to determine whether CHO cells were an obvious
variation of the earlier patented claims. It does not appear from the ‘275
patent disclosure that CHO cells were discovered by the inventors. For
example, the inventors used CHO cells as a source of a mutant DNA in their
experiments, citing a previously published journal article for the description
of the DNA. ‘275 patent, col. 14, ll. 45-50; col. 27, ll. 7-11; col. 28, 1-5.
None of the examples in the ‘275 patent utilized CHO cells as an expression
host. There also does not appear to be any evidence in the ‘275 patent that
practicing the invention with CHO cells as an expression host is different
from practicing it with any other eukaryotic or mammalian cell lines
described in the ‘275 patent. Consequently, the Examiner had basis to
conclude that the claimed CHO cells were an obvious variation of the earlier
patented claims to eukaryotic cells, shifting the burden to Columbia to rebut
they were not.
Columbia did not meet that burden. Columbia did not appear to
identify CHO cells as a patentable difference between the ‘275 claims and
those of the ‘216 patent (App. Br. 33-36). Moreover, expert testimony by
Drs. Dolnick and Lodish (see infra.) established persuasive fact-based
reasons as to why CHO cells would have been obvious to one of ordinary
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skill in the art in view of the claims of the ‘216 patent. (Dolnick Expert
Report1 ¶¶ 23-26; Lodish Expert Report2 ¶¶ 144-149).
In addition to this, the CHO cell claims are a species in some respects
to the broader claims of the ‘216 patent which are directed to eukaryotic
cells. Since the broader claims of the ‘216 patent issued first, it would
therefore conceivably be extending the term of the ‘216 patent as to the
CHO cell claims, a situation that obvious-type double-patenting was
intended to prevent. In re Metoprolol Succinate Patent Litigation, 493 F.3d
1011 (Fed. Cir. 2007).

EXPERT TESTIMONY
The Examiner relied upon expert reports filed during the litigation
related to the ‘275 patent. These experts are: Dr. Harvey Lodish, a
professor of Biology at the Massachusetts Institute of Technology and lead
author of the textbook Molecular Cell Biology (Lodish Expert Report ¶¶ 1-
2); Dr. Bruce J. Dolnick, Professor of Pharmacology in the Pharmacology
and Therapeutics Department and a Member of the Roswell Park Cancer
Institute (Dolnick Expert Report ¶ 1); and Dr. Rodney E. Kellems.
Columbia argues that the opposing expert reports were filed during
litigation of the ‘275 patent and are unsworn assertions in litigation reports
which relate to different claims than those presently on appeal (App. Br. 58).
Columbia states “the Reports do not consider the claim limitations and
issues of unpredictability which are at the center of this proceeding.” (App.

1 Expert Report of Bruce J. Dolnick, Aug. 27, 2004.
2 Initial Expert Report of Harvey F. Lodish, Ph.D., Aug. 27, 2004.
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Br. 24.) For these reasons, Columbia contends the expert reports cannot
serve as a basis for rejecting the claims (App. Br. 58).
We do not agree with Columbia’s position. First, all the reports were
submitted during litigation and were executed and dated by each declarant;
we therefore reasonably presume them to be authentic. Secondly, Columbia
did not establish that Drs. Lodish, Dolnick, and Kellems were unqualified as
experts to testify on the issues relevant in this proceeding. It is
commonsense that such reports should therefore be acceptable as evidence
in a proceeding before the USPTO when the reports are relevant to the
disputed issues. Second, while it is true that the claims involved in the
litigation were different from those in the present appeal, we have reviewed
the reports thoroughly and find that they contain opinion and factual
evidence pertinent to the patentability issues before us. In sum, we discern
no error on the Examiner’s part in relying on the expert reports by Drs.
Lodish, Dolnick, and Kellems in reaching his obviousness determination.
Columbia stated:
Each expert expressly admitted, however, that they did not
consider whether it would be predictable that a person of
ordinary skill in the art could predict whether mammalian cells
could be properly engineered and manipulated to create a
biologically active glycoprotein or a glycoprotein with its
appropriate sugar. Pending claims, now under appeal, recite
these limitations.
(App. Br. 24.)
However, Columbia does not direct us to where such admissions are
made by the opposing experts, and our own review of the testimony by the
opposing experts leads us to an opposite conclusion. We explain our
reasoning in more detail below.
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PATENTABLE DIFFERENCES ARGUED BY COLUMBIA
Columbia contends that there are at least five patentable differences
between the claims on appeal and claims 54-73 of the ‘216 patent and claims
1-5 of the ‘017 patent (App. Br. 33-36). Stated differences 1)-4) each
generally relate to expression of a foreign DNA in a CHO, and the issue of
whether there would have been a reasonable expectation of success that such
a foreign DNA would be glycosylated in CHO cells. Dependent claims
recite that the foreign DNA is “heterologous” (claims 45-53, etc.) or
“synthetic” (claims 39, 41, etc.). Claims 3, 5, 15, and others also require the
glycoprotein to be biologically active. Difference 5) relates to the cells
producing multiple copies of a foreign glycoprotein (App. Br. 35-36), a
limitation that appears in independent claims 3, 5, and 15, but not in
independent claim 19. We address Columbia’s arguments below.

GLYCOPROTEIN & BIOLOGICAL ACTIVITY LIMITATIONS (’216 AND
‘017 CLAIMS)
All the claims in the ‘275 patent require CHO cells comprising a
foreign DNA coding for a glycoprotein. The term “glycoprotein” does not
appear in the claims of the ’216 or ‘017 patent. A glycoprotein is a protein
with sugar residues attached to it. The sugar residues are attached during a
process called glycosylation (Ruddle 1 Decl.3 ¶ 9-a). Columbia did not
appear to dispute the obviousness of choosing a glycoprotein for expression

3 Declaration of Francis H. Ruddle, Ph.D., Jan. 19, 2006 [hereinafter
“Ruddle 1”].
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in a CHO cell, but rather argued that it could not have been predicted
whether a CHO cell would glycosylate a protein coded for by a foreign DNA
as required by the claims, particularly to produce a biologically active
glycoprotein as recited in independent claims 3 and 5 (App. Br. 39 & 42).
Columbia’s unpredictability arguments are based mainly on two
declarations by Dr. Francis Ruddle, a professor emeritus at the Department
of Molecular, Cellular, and Development Biology at Yale University who
was working in the field at the time of the invention (Ruddle 1 Decl. ¶ 2).
Dr. Ruddle testified in his written declarations that it was unpredictable that
a CHO cell would manufacture a glycoprotein.
The Examiner argued that glycosylation would have occurred by the
normal pathway present in the cells (Answer 10, ll. 12-15). The Examiner
rejected Dr. Ruddle’s opinion in favor of the opinions of “Drs. Dolnick,
Rodney E. Kellems, etc. which were part of litigation in the ‘275 patent,”
which the Examiner found rebutted each of Dr. Ruddle’s arguments (Answer
17). Columbia complains that the Examiner did not properly consider Dr.
Ruddle’s two declarations (App. Br. 56-58). However, the Examiner simply
found the testimony by the opposing experts (Drs. Dolnick, Kellems, and
Lodish) more persuasive than Dr. Ruddle’s (Answer 17). For the reasons
given below, we agree with the Examiner’s determination. Yorkey v. Diab,
601 F.3d 1279, 1284 (Fed. Cir. 2010) (Board has discretion to give more
weight to one item of evidence over another “unless no reasonable trier of
fact could have done so”).

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Dr. Ruddle
In considering the conflicting testimony in this appeal, Dr. Ruddle
correctly observed that “the relevant question is whether as of February
1980, a person of ordinary skill in the art would consider it obvious that a
eukaryotic cell (or in specific a CHO cell) possesses and can effectively use
the enzymes and other structures sufficient to post-translationally process a
foreign polypeptide effectively.” (Ruddle 2 Decl.4 ¶ 9-d). We have
considered Dr. Ruddle’s evidence, but do not find it persuasive when
weighed against the evidence provided by the opposing expert testimony.
Dr. Ruddle outlined five reasons in his declaration as to why it would
not have been obvious to produce a glycoprotein in CHO cells. We have
considered each reason in light of the opposing expert testimony and Dr.
Ruddle’s own rebuttal.

Signal structure recognition (i)
With regard to the presence of machinery in the CHO cell to process
and glycosylate foreign polypeptides expressed in CHO cells, Dr. Ruddle
testified that there was doubt about the ability of a CHO cell to process a
foreign protein’s signal structures properly (Ruddle 1 Decl. ¶ 9, p. 6).
However, Dr. Ruddle did not provide supporting evidence nor establish that
so-called proper processing of the structure was necessary to manufacture a
glycoprotein in a CHO cell expressing a foreign DNA.

4 Second Declaration of Francis H. Ruddle, Ph.D., Sept. 17, 2007
[hereinafter “Ruddle 2”].
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Dr. Lodish testified that signal sequences were known as of February
1980, to be found at the beginning of all proteins secreted by mammalian
cells (Lodish Expert Rebuttal Report5 ¶ 22). Dr. Lodish acknowledged that
these sequences “differ slightly from one secreted protein to another” but
stated that “all of them direct the protein, as it is being made on the
ribosome, into the endoplasmic reticulum.” (Lodish Expert Rebuttal Report
¶22.) Dr. Lodish testified that the enzymes required to process signal
sequences were also well known prior to February 1980. Dr. Lodish
supported his opinion with numerous pre-filing date publications (Lodish
Expert Rebuttal Report ¶22.) Based on this knowledge, Dr. Lodish
concluded the signal sequences would function in transformed CHO cells
(Lodish Expert Rebuttal Report ¶¶ 22 & 23.) Dr. Lodish’s testimony is fact-
based and credible; for the foregoing reasons, we find it rebuts Dr. Ruddle’s
statements to the contrary, which lacked factual support.

Specific glycosylation structures (ii)
Dr. Ruddle also provided testimony on the ability of CHO cells to
glycosylate proteins. Dr. Ruddle testified in his first written declaration that
specific enzymes control the addition of sugar residues to proteins in a
complex process (Ruddle 1 Decl. ¶ 9, p. 7). Dr. Ruddle stated that a “cell
that has been transformed with foreign DNA encoding a polypeptide does
not necessarily possess the specific enzymes required to glycosylate the
foreign polypeptide” (Ruddle 1 Decl. ¶ 9, p. 7). Citing a pre-filing date
scientific publication, Dr. Ruddle testified that CHO mutant cells had been

5 Rebuttal Expert Report of Harvey F. Lodish, Ph.D., Sept. 16, 2004.
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studied which lacked “specific processes that normally exist in CHO cells,”
resulting in a difference in glycosylation as compared to non-mutant CHO
cells (Ruddle 1 Decl. ¶ 9, p. 7). Based on this evidence, Dr. Ruddle
concluded that “in February 1980 scientists understood that small
differences in the enzymes available in a cell could have significant effects
on the ability of a cell to perform post-translational modifications.” (Ruddle
1 Decl. ¶ 9, p. 8.)
Dr. Dolnick contested Dr. Ruddle’s testimony about the
unpredictability of glycosylation in CHO cells. Dr. Dolnick correctly noted
that the claims are not limited to a particular pattern of glycosylation
(Dolnick Expert Rebuttal Report6 ¶ 15). Thus, whether there are differences
in the glycosylation pattern between the normal protein made in its native
environment and that made in CHO cells according to the claimed invention
is irrelevant with respect to those claims which only require a glycoprotein
to have been produced.
Moreover, as noted by Dr. Dolnick, Dr. Ruddle did not state that
CHO’s cells were incapable of glycosylating proteins (Dolnick Expert
Rebuttal Report ¶ 18). The evidence establishes that CHO cells were well
known prior to February 1980 to be capable of glycosylating proteins.
Dr. Dolnick cited two publications available prior to February 1980 that
established that persons of ordinary skill in the art had knowledge of
enzymes expressed by CHO cells that were required for protein
glycosylation (Dolnick Expert Rebuttal Report ¶ 19). Consistently, Dr.
Lodish provided evidence that glycosylation pathways in CHO cells were

6 Rebuttal Expert Report of Bruce J. Dolnick, Sept. 17, 2004.
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known and thus were “not so poorly understood as Professor Ruddle
suggests.” (Lodish Expert Rebuttal Report ¶ 33.) Dr. Ruddle criticized this
testimony as relating to native processes in CHO, rather than to the issue of
glycosylation of a foreign protein in CHO cells. However, in fact, the expert
testimony of Drs. Dolnick and Lodish were responsive to issues raised by
Dr. Ruddle who was describing deficiencies of certain CHO cell mutants
expressing native proteins, not foreign DNAs.
Dr. Lodish acknowledged that there were mutant CHO cells known in
the prior art which produced proteins with altered glycosylation patterns
(Lodish Expert Rebuttal Report ¶ 44). However, Dr. Lodish reasonably
concluded that the skilled worker, aware that these cells had an altered
glycosylation pattern, would not have used them as host cells (Lodish Expert
Rebuttal Report ¶ 44).
As to the expression of a foreign polypeptide in CHO cells, Dr.
Lodish testified that the same sugar precursors were produced in yeast, plant
and animal cells, and that the peptide sequences were known that dictated
the glycosylation pattern, supporting his conclusion that glycosylation of a
foreign protein would have been expected in CHO cells (Lodish Expert
Rebuttal Report ¶¶ 25-27). That is, given the similarities between
glycosylation in yeast, plants, and animals, it would have been expected that
a CHO cell could glycosylate a protein from a source other than a CHO cell.
Dr. Dolnick concurred with Dr. Lodish’s opinion, and cited evidence that it
was “recognized that there were amino acid motifs within proteins which
could be recognized by the CHO cell glycosylation machinery, and the
glycosylating enzymes would recognize these motifs during translation
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regardless of the origin of the DNA encoding the protein.” (Dolnick Expert
Rebuttal Report ¶ 20.).
Dr. Dolnick provided further evidence that it would have been
reasonably expected that a foreign polypeptide would be glycosylated in
CHO cells. Dr. Dolnick cited a pre-filing date publication reporting that the
viral VSV-G protein, expressed in CHO cells, was glycosylated (Dolnick
Expert Report ¶ 25; Dolnick Expert Rebuttal Report ¶ 20). That is, the fact
the VSG-G protein was glycosylated in CHO cells reasonably predicted that
other foreign proteins would be glycosylated, as well.
Dr. Ruddle challenged this evidence on the basis that viral protein
expression in cells is a natural-occurring and common event, and therefore
not operatively a “foreign” DNA (Ruddle 2 Decl. ¶ 9-b). However, Dr.
Ruddle did not show that the VSV-G normally occurred in CHO cells and
thus did not establish that it was naturally-occurring event in CHO cells. To
the contrary, VSV-G is foreign to CHO cells, and thus is a foreign DNA
within the scope of the claims. Accordingly, we do not find Dr. Ruddle’s
rebuttal persuasive.

Effect on culturing cells (iii)
Dr. Ruddle testified that cells have been adapted for research and
cultured for many generations, and it could not be predicted whether the
ability to “to perform a particular function would be retained, modified, or
lost in the course of continuous propagation in culture.” (Ruddle 1 Decl. 8).
These amount to arguments, which are not persuasive. First, the
evidence firmly establishes that CHO cells were able to glycosylate proteins,
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the only requirement of the claims. Second, as testified by Dr. Dolnick. It
was also known that functional enzymes could be obtained from cultured
cells (Dolnick Expert Rebuttal Report ¶ 21). Dr. Ruddle’s position to the
contrary that it would have been unpredictable that a CHO cell would have
retained its ability to perform the glycosylation function is just not
scientifically credible when cultured cells were known sources of complete
and functional enzymes and proteins.

Species and cell type differences in glycosylation (iv)
Citing several publications, Dr. Ruddle testified that there “were
differences in the ability of cells from different tissues and species to
glycosylate” (Ruddle 1 Decl. ¶ 9, p. 9). “Because of this variability,
researchers in February 1980 would not have considered there to be a
reasonable likelihood of success that a given host cell would be able to
reproduce a glycosylation pattern for a foreign glycoprotein.” (Ruddle 1
Decl. ¶ 9, pp. 9-10; footnotes omitted.) Dr. Ruddle also cited a number of
post-filing date publications to support this conclusion, but did not provide
evidence that such facts disclosed in these publications would have been
known to the ordinary skilled worker on earliest filing date of the ‘275
patent (Ruddle 1 Decl. ¶ 9, pp. 10-11).
Again, the claims do not require that the glycosylation pattern be
reproduced for a foreign glycoprotein. Thus, we find these arguments
unavailing.
Dr. Ruddle also contends that the skilled worker “would have been
extremely concerned about whether a host cell that is not known to
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ordinarily perform a particular post-translational modification” would have
been capable of performing that modification on a foreign polypeptide
(Ruddle 1 Decl. ¶ 9, p. 9). As recognized by Dr. Ruddle, the question is
whether it would have been reasonably expected that a CHO cell could
glycosylate a foreign polypeptide. This issue was discussed above and
answered affirmatively.

Changes in glycosylation patterns impact a molecule’s function (v)
Dr. Ruddle also testified that differences in glycosylation could affect
the function of a protein (Ruddle 1 Decl. ¶ 9, p. 10). Citing scientific
articles published prior to February 1980, Dr. Ruddle testified that
“researchers understood that glycosylation could play essential roles in the
function of a molecule.” (Ruddle 1 Decl. ¶ 9, p. 10.)
The function recited in claims 3, 5, and 15 is that the glycoprotein is
“biologically active.” The term “biologically active” is not defined in the
‘275 patent. However, in a videotaped deposition of Dr. Ruddle7 on October
3, 2004, Dr. Ruddle testified as to his understanding of the term.
Dr. Ruddle testified that a “[g]lycoprotein is a polypeptide with sugars
attached, which is, in its complete form, and which has activity.” (Ruddle
Dep., p. 91, ll. 15-17). Dr. Ruddle clarified that by “activity” he was
referring to “biological activity.” (Ruddle Dep., p. 99, l. 24-p. 100, l.2.) Dr.
Ruddle gave several examples of what was meant by biological activity:

7 Videotaped Deposition of Francis H. Ruddle, Oct. 3, 2004 [hereinafter
“Ruddle Dep.”].
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Q. Okay. Now let's talk about activity. You mentioned that
earlier as another -- as something that a glycoprotein had to
have.
A. Mm-hmm.
Q. Can you explain what you mean by that?
A. Again, it would be specific for particular glycoproteins. In
some instances it may have to do with the clearance of the
protein, the glycoprotein from the body via the kidney, so that
certain glycosylated forms would be resistant to clearance,
whereas others or non-glycosylated forms would be susceptible
to clearance.
(Ruddle Dep., p. 98, l. 23-p. 99, l. 13.)

A. It could - - another possible measure might be its ability to
be precipitated by particular antibodies.
Q. So that's another aspect of your definition of active?
A. Yes.
Q. Does it have to both be able to be precipitated by particular
antibodies and have something else in order to be biologically
active?
. . .
A. That definition of activity would take into account
combinations of attributes.
(Ruddle Dep., p. 100, l. 13-p. 101, l. 2.)

A. I don't believe that there is a generic definition of activity,
and it is determined by specific tests which indicate the
completeness and the activity of the -- of the molecule.
(Ruddle Dep., p. 101, ll. 21-25.)

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Based on Dr. Ruddle’s testimony in his deposition, we interpret
“biological activity” to be any activity of a glycoprotein which can be
measured by specific tests, including clearance of a glycoprotein from the
body and its ability to be precipitated by antibodies.
As to the claims which require biological activity, Dr. Ruddle testified
“that small changes in the pattern of post-translational modification could
have a significant impact on the function of molecule.” (Ruddle 1 Decl. ¶ 9,
p. 10.) Dr. Ruddle buttressed this opinion by references to the scientific
literature (Ruddle 1 Decl. ¶ 9, p. 10).
We are not convinced that persons of ordinary skill in the art would
have found it unpredictable that a glycoprotein produced in CHO cells
would be biologically active as required by independent claims 3 and 5. As
noted by the Examiner, the claims do not require a specific amount of
activity (Answer 18). Thus, any amount of activity would meet the claimed
requirement. Nor do the claims require a specific biological activity, but
include general activities such as an immunological activity (“precipitated
by particular antibodies”), as testified by Dr. Ruddle, which only require the
glycoprotein to react with an antibody. Dr. Ruddle noted that changes in
“post-translational modification” could impact a molecule’s function, but did
not specifically state, or provide adequate evidence, that such changes would
made it unpredictable whether a foreign glycoprotein, when made in CHO
cells, would be biologically active, such as unable to be precipitated by an
antibody. On the other hand, Dr. Lodish testified that differences in
glycosylation “in some cases” had “little or no effect on the function of the
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protein,” and described an example of such a case (Lodish Expert Report ¶
37).
In view of the breadth of the claim, and testimony by Dr. Lodish, we
conclude that the persons of ordinary skill in the art would have reasonably
expected a foreign glycoprotein, when produced in a CHO cell, would
possess some amount of a biological activity as required by the claims.

Culturing conditions
Dr. Ruddle testified that, when a cell was placed in culture, it might
lack the materials and conditions to glycosylate (Ruddle 1 Decl. ¶ 10, p. 12).
Scientific publications were cited to support this opinion, but the publication
dates were after the earliest filing date of the ‘275 patent and therefore do
not establish what the skilled worker would have believed at the time the
claimed invention was made.
Dr. Lodish acknowledged it “was widely known at the time the
original Axel patent application was filed that culture conditions can affect
many aspects of cell growth and metabolism.” (Lodish Expert Rebuttal
Report ¶ 45.) Dr. Lodish cited pre-filing date publications to support this
opinion and his subsequent conclusions that “[o]ne skilled in the art at the
time the initial Axel application was filed would know to use appropriate
conditions for culturing the cells” and would know not to use conditions “so
sub-optimal” that glycosylation did not occur (Lodish Expert Rebuttal
Report ¶¶ 45 & 46.) We find that this fact-based evidence is sufficient to
rebut Dr. Ruddle’s opinion to the contrary, and conclude the persons of
ordinary skill in the art would reasonably expected that cell culture
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conditions were routinely selected to have produced a biologically active
foreign glycoprotein in CHO cells at the time the application as filed.

SYNTHETIC
Dependent claims 39, 41, 44, 119, 128 and 137, and claims dependent
on them, refer to a glycoprotein from a “synthetic” gene. Columbia
contends that “[o]ne of ordinary skill in the art could not predict from any
one of claims 54-73 of the ‘216 Patent or claims 1-5 of the ‘017 Patent that a
‘synthetic’ proteinaceous material expressed from an in vitro constructed
DNA I could be glycosylated in a mammalian or CHO cell.” (App. Br. 50.)
Dr. Ruddle testified that “a researcher in 1980 would not have considered it
obvious that a foreign or heterologous DNA would be expressed and
glycosylated. This concern would be heightened if the DNA used was in-
vitro constructed and synthetic because such a gene would be more alien to
the host cell and its natural processing mechanism.” (Ruddle 2 Decl. p. 10).
The ‘275 patent defines a “synthetic” gene as coding for a protein “not
yet in existence.” (‘275 patent, col. 6, ll. 19-25.) Such a synthetic gene
would include any change to a protein sequence, including a change to a
single amino acid. Dr. Ruddle’s arguments appear directed to largely
synthetic genes, with many amino acid alterations. Dr. Ruddle did not
explain how a native protein with one or two amino acid alterations would
be so alien to the host cell’s processing mechanisms that it would be
unpredictable that it could be glycosylated in a host cell.
A claim is unpatentable under § 103 if any scope of it would have
been obvious to the person of ordinary skill in the art at the time the
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invention was made. See In re Klein, 987 F.2d 1569, 1570 (Fed. Cir. 1993);
In re Muchmore, 433 F.2d 824, 826 (CCPA 1970); Eli Lilly & Co. v. Barr
Labs., Inc., 251 F.3d 955, 971(Fed. Cir. 2001) stating that a later genus
claim limitation is not patentably distinct from an early species claim; In re
Berg, 140 F.3d 1428 (Fed. Cir. 1998), holding genus claims unpatentable
over species claims under the doctrine of obviousness-type double patenting.
Thus, Dr. Ruddle’s arguments did not provide sufficient evidence to
establish that the full scope of the “synthetic” claim would have been non-
obvious to the ordinary skilled worker.

MULTIPLE COPIES
Claim 3 recites that the transformed CHO cell “produces multiple
copies of the proteinaceous material portion of the glycoprotein from
amplified DNA I and a sugar and synthesizes or assembles multiple copies
of biologically active glycoprotein therefrom.” Claim 5 has a similar
limitation.
Dr. Ruddle contends that such limitation would not been obvious to a
person of ordinary skill in the art. Dr. Ruddle testified:
Researchers in February 1980 would have been very concerned
that the volume of foreign polypeptides encoded by all the
multiple copies of the foreign DNA I and DNA II that could be
produced by the host cells would overwhelm the processing
apparatus of the cell and thus prevent the host cell from
producing the “glycoprotein.”
(Ruddle 1 Decl. ¶ 11, p. 16.) Dr. Ruddle referred to this as “squelching” and
wrote that “in 1985, researchers continued to view it as significant enough of
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an issue to merit discussion in a journal publication.” (Ruddle 1 Decl. ¶ 11;
footnote omitted.)
The claims at issue require that multiple copies of the protein be
manufactured, which we interpret to mean more than one protein copy. Dr.
Ruddle’s arguments concern a “volume of foreign polypeptide,” but it is not
clear what amount a “volume” would cover. The claims cover as a little as a
few copies of a foreign glycoprotein, and Dr. Ruddle did not explain how a
few copies of a produced glycoprotein would “overwhelm” the cell. Thus,
Dr. Ruddle’s statements about limiting amounts of enzymes and other
materials (Ruddle 1 Decl. ¶ 11), as well as attorney argument about a “large
volume of foreign polypeptides” (App. Br. 52) are not persuasive because
the claim is not limited to such amounts.
Furthermore, Dr. Dolnick, in rebuttal, refers to knowledge in the art of
cells of overproducing the DHFR protein in transformed cells, giving rise to
an expectation that overproduction would not necessarily overwhelm a cell’s
post-translational machinery (Dolnick Expert Rebuttal Report ¶ 22).

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SUMMARY
For the foregoing reason, we affirm the obviousness-type double
patenting rejection of 3, 5-13, 15, 19, 39-41, 44-77, 80-83, 85-100, 104-105,
112, 116-119, 121, 125-128, 130, and 134-137.

TIME PERIOD FOR RESPONSE
Requests for extensions of time in this ex parte reexamination
proceeding are governed by 37 C.F.R. § 1.550(c). See 37 C.F.R. § 41.50(f)

AFFIRMED

KMF

Patent Owner:
COOPER & DUNHAM, LLP
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New York, NY 10112

Third Party Requester:

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