Ex Parte Salfeld et al

Patent Trial and Appeal Board

May 12, 2017

13738432 (P.T.A.B. May. 12, 2017)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/738,432 01/10/2013 Jochen G. Salfeld 3685.001000D/EKS/KRM 6558
135005 7590 05/12/2017
STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C.
1100 NEW YORK AVENUE, N.W.
WASHINGTON, DC 20005
EXAMINER
ROMEO, DAVID S
ART UNIT PAPER NUMBER
1647
MAIL DATE DELIVERY MODE
05/12/2017 PAPER
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte JOCHEN G. SALFELD, DEBORAH J. ALLEN,
HENDRICUS R.J.M. HOOGENBOOM, ZEHRA KAYMAKCALAN,
BORIS LABKOVSKY, JOHN A. MANKOVICH,
BRIAN T. MCGUINNESS, ANDREW J. ROBERTS,
PAUL SAKORAFAS, DAVID SCHOENHAUT, TRISTAN J. VAUGHAN,
MICHAEL WHITE, and ALISON J. WILTON1
____________

Appeal 2015-004473
Application 13/738,432
Technology Center 1600
____________

Before FRANCISCO C. PRATS, JEFFREY N. FREDMAN, and
RYAN H. FLAX, Administrative Patent Judges.

FLAX, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134(a) involving
claims directed to a method for producing a human anti-TNFα antibody, or
antigen-binding portion thereof, for therapeutic use in a human subject.
Claims 20–30 are on appeal as rejected under the doctrine of non-statutory
obviousness type double patenting. We have jurisdiction under 35 U.S.C.
§ 6(b). We affirm.

1 The Real Party in Interest is AbbVie Biotechnology Ltd. App. Br. 3.
(“App. Br.” refers to Appeal Brief dated Sept. 2, 2014). This appeal is
related to Appeal No. 2015-007511 (App. Ser. No. 13/736,931). App. Br. 4.
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STATEMENT OF THE CASE
Antibodies are proteins (also called immunoglobulins) normally
produced by certain white blood cells (plasma cells) in response to entry into
the body of a foreign substance (antigen) in order to render it harmless.2
The Specification states, “[t]umor necrosis factor α (TNFα) is a
cytokine produced by numerous cell types, including monocytes and
macrophages, that was originally identified based on its capacity to induce
the necrosis of certain mouse tumors.” Spec. 1:16–18. Further,
[b]ecause of the harmful role of human TNFα (hTNFα) in a
variety of human disorders, therapeutic strategies have been
designed to inhibit or counteract hTNFα activity. In particular,
antibodies that bind to, and neutralize, hTNFα have been sought
as a means to inhibit hTNFα activity. Some of the earliest of
such antibodies were mouse monoclonal antibodies (mAbs),
secreted by hybridomas prepared from lymphocytes of mice
immunized with hTNFα.
Id. 1:27–32.
“Th[e] invention provides human antibodies, preferably recombinant
human antibodies, that specifically bind to human TNFα.” Id. 3:13–14.
Appellants explain that the claimed invention “relate[s] to the production of
a human antibody having light and heavy variable regions corresponding to
adalimumab (sold under the trade name HUMIRA®), which was the first
fully human monoclonal antibody approved by the United States Food and
Drug Administration (FDA).” App. Br. 11 (internal footnotes omitted).

2 Oxford Dictionary of Biology 7th ed., antibody (2015), available at
http://www.oxfordreference.com/view/10.1093/acref/9780198714378.001.0
001/acref-9780198714378-e-262?rskey=hYIlYh&result=301 (visited May
10, 2017).
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HUMIRA® is approved for use in the treatment of
multiple diseases, including moderate to severe rheumatoid
arthritis, psoriatic arthritis, ankylosing spondylitis, moderate to
severe Crohn’s disease, moderate to severe polyarticular juvenile
idiopathic arthritis, and moderate to severe plaque psoriasis, and
has proven to be highly effective and safe as a therapeutic
antibody due, at least in part, to its minimal levels of
immunogenicity in human patients.
Id.
The appealed claims can be found in the Claims Appendix of the
Appeal Brief. Claims 20, 21, 29, and 30 are the independent claims. Claim
20 is representative and reads as follows:
20. A method for producing a human anti-TNFα antibody, or
antigen-binding portion thereof, suitable for therapeutic use in a
human subject, comprising an IgG1 heavy chain constant region
and a kappa light chain constant region, comprising
a) culturing a Chinese Hamster Ovary (CHO) host cell
transfected with
i) a recombinant expression vector encoding a light chain
variable region (LCVR) comprising a CDR3 domain
comprising the amino acid sequence of SEQ ID NO: 3, a
CDR2 domain comprising the amino acid sequence of
SEQ ID NO: 5, and a CDR1 domain comprising the amino
acid sequence of SEQ ID NO: 7, and
ii) a recombinant expression vector encoding a heavy
chain variable region (HCVR) comprising a CDR3
domain comprising the amino acid sequence of SEQ ID
NO: 4, a CDR2 domain comprising the amino acid
sequence of SEQ ID NO: 6, and a CDR1 domain
comprising the amino acid sequence of SEQ ID NO: 8
for a sufficient time to allow for expression of the antibody, or
antigen-binding portion thereof; and
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b) isolating said antibody, or antibody-binding portion thereof.
App. Br. 44 (Claims App’x).
The following rejections are on appeal:
Claims 20–30 are rejected on the ground of nonstatutory double
patenting over claims 1–20 of Salfeld.3 Final Act. 2.

FINDINGS OF FACT
Unless otherwise indicated herein, we adopt the Examiner’s findings
of fact, reasoning on scope and content of the prior art, and conclusions set
out in the Final Action and Answer regarding the rejection. We set forth the
following findings of fact to highlight certain evidence.
FF1. Claims 18–20 of Salfeld recite:
18. A recombinant expression vector encoding:
a) an antibody light chain having a variable region
comprising the amino acid sequence of SEQ ID NO: 1;
and
b) an antibody heavy chain having a variable region
comprising the amino acid sequence of SEQ ID NO: 2.
19. A host cell into which the recombinant expression vector of
claim 18 has been introduced.

3 U.S. Patent No. US 6,258,562 B1 (issued July 10, 2001) (“Salfeld”).
USPTO records indicate Salfeld was assigned to AbbVie Biotechnology Ltd.
on June 25, 2012 (recorded Jan. 29, 2014 at reel/frame: 032134/0935). As
support for the determination of obviousness over the Salfeld claims, the
Examiner also cites: U.S. Patent No. 5,644,036 (issued July 1, 1997)
(“Ramage”); U.S. Patent No. 6,113,898 (issued Sept. 5, 2000) (“Anderson”);
U.S. Patent No. 5,652,138 (issued July 29, 1997) (“Burton”); U.S. Patent
No. 5,561,053 (issued Oct. 1, 1996) (“Crowley”); and U.S. Patent No.
5,698,195 (issued Dec. 16, 1997) (“Le”).
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20. A method of synthesizing a human antibody that binds
human TNFα, comprising culturing the host cell of claim 19 in a
culture medium until a human antibody that binds human TNFα
is synthesized by the cell.
Salfeld 66:10–22; see also Final Action 3–8, 11, and 14, and Ans. 3–4
and 12–13 (discussing Salfeld).
FF2. It is not disputed that the “human antibody that binds
human TNFα” recited by the claims of Salfeld and the “human anti-
TNFα antibody” recited by the appealed claims are the same,
including any amino acid sequences thereof also recited by the Salfeld
or appealed claims. See generally App. Br. and Reply Br.
FF3. Salfeld disclosed, “[p]referred mammalian host cells for
expressing the recombinant antibodies of the invention include
Chinese Hamster Ovary (CHO cells).” Salfeld 17:38–40; see also id.
19:45–60; see also Final Action 3–8, 11, and 14, and Ans. 3–4 and
12–13 (discussing Salfeld). Thus, regarding Salfeld’s claim 20 (see
FF1, supra), the scope of the limitation “a host cell” is interpreted to
include, inter alia, CHO cells.
FF4. Ramage “relates to a purified preparation of monoclonal
antibodies against the antigen CDw52, to their use in therapy and to
processes for their production” (Ramage 1:9–11), in particular, to “an
IgG 1 antibody, [which] has been humanized[,] . . . known as
Campath 1H” (id. 2:1–3) (a lymphoma cancer treatment). See also
Final Action 3–7, 12, and 14–17, and Ans. 3–4, 6–7, 9–11, and 14–15
(discussing Ramage). Ramage discloses “the purified anti-CDw52
antibody of the invention may be a . . . human antibody.” Ramage
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6:9–10; see also Final Action 3–7, 12, and 14–17, and Ans. 3–4, 6–7,
9–11, and 14–15 (discussing Ramage).
FF5. Ramage discloses that “[a]ntibodies which are intended for
use in medical therapy may need to be administered repeatedly, so the
need to remove foreign immunoglobulins is important as such
administration may produce an immune response and induce
nephrotoxicity, serum sickness and in severe cases anaphylactic
shock.” Ramage 2:15–20; see also Final Action 3–7, 12, and 14–17,
and Ans. 3–4, 6–7, 9–11, and 14–15 (discussing Ramage).
FF6. Ramage discloses that “[a]ntibodies according to the
invention may be prepared using a recombinant expression system,
the preferred system is a mammalian expression system using Chinese
hamster ovary (CHO) cells.” Ramage 3:52–55; see also Final Action
3–7, 12, and 14–17, and Ans. 3–4, 6–7, 9–11, and 14–15 (discussing
Ramage).
FF7. Anderson discloses using CHO cells to express antibodies
“to be used, e.g., as immunosuppressants, i.e., to block antigen driven
immune responses, to treat autoimmune diseases such as psoriasis,
rheumatoid arthritis, systemic erythematosus (SLE), type 1 diabetes
mellitus, idiopathic thrombocytopenia purpura (ITP), and to prevent
organ rejection,” in human patients, via “pharmaceutical
compositions” containing the antibodies. Anderson 8:63–9:2, 9:26–
30, 12:8–10; see also Final Action 4–7, and Ans. 3–4 (discussing
Anderson).
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FF8. Crowley is directed to “[a] method for selecting
recombinant host cells expressing high levels of a desired protein”
(Crowley Abstract), and identifies several “[e]xamples of useful
mammalian host cell lines [including] . . . Chinese hamster ovary
cells/ -DHFR (CHO. . .);[and] dp12.CHO cells . . . ” (Crowley 16:10–
17). See also Final Action 4–7, and Ans. 3–4 (discussing Crowley).
FF9. Crowley disclosed expressing TNFr-IgG capable of
binding tumor necrosis factor (TNF) using dp12.CHO cells. Crowley
20:28–57 (Example 2); see also Final Action 4–7, and Ans. 3–4
(discussing Crowley).
FF10. Crowley disclosed that “[a] stable expression system for
CHO cells has been developed that produces high levels of
recombinant proteins rapidly and with less effort than that required by
other expression systems.” Crowley 23:11–14); see also Final Action
4–7, and Ans. 3–4 (discussing Crowley).
FF11. Le is directed to “[a]nti-TNF antibodies, fragments and
regions thereof which are specific for human tumor necrosis factor-α
(TNFα) and are useful in vivo for diagnosis and therapy of a number
of TNFα-mediated pathologies and conditions, including rheumatoid
arthritis . . . .” Le Abstract; see also Final Action 4, and Ans. 3–4
(discussing Le).
FF12. Le discloses that, in expressing anti-TNF peptides of Ab
fragments,
[p]referred hosts are bacterial or eukaryotic hosts including
bacteria, yeast, insects, fungi, bird and mammalian cells either in
vivo, or in situ, or host cells of mammalian, insect, bird or yeast
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origin. It is preferred that the mammalian cell or tissue is of
human, primate, hamster, rabbit, rodent, cow, pig, sheep, horse,
goat, dog or cat origin, but any other mammalian cell may be
used.
Le 26:57–67; see also Final Action 4, and Ans. 3–4 (discussing Le).
FF13. Further to the immediately preceding finding of fact, Le
discloses:
Preferred hosts are mammalian cells, grown in vitro or in
vivo. Mammalian cells provide post-translational modifications
to immunoglobulin protein molecules including leader peptide
removal, folding and assembly of H and L chains, glycosylation
of the antibody molecules, and secretion of functional antibody
protein.
Mammalian cells which can be useful as hosts for the
production of antibody proteins, in addition to the cells of
lymphoid origin described above, include cells of fibroblast
origin, such as Vero (ATCC CRL 81) or CHO-Kl (ATCC CRL
61).
Le 30:47–58; see also Final Action 4, and Ans. 3–4 (discussing Le).
FF14. Neither Appellants nor the Examiner identify or contest the
relevant level of ordinary skill in the art in this Appeal. However,
Appellants identify that U.S. Patent Application 13/736,931, also on
appeal before the Board under Appeal No. 2015-007511, is related to
this appeal; and we agree with Appellants to the extent that the two
claimed inventions are similar and directed to the same general field
of technology. In that related case, Appellants contend the person of
ordinary skill in the art:
in February 1996, is a Senior Scientist with experience in the
discovery, production and characterization of therapeutic
antibodies, including murine, chimeric or humanized
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monoclonal antibodies. This hypothetical person of ordinary
skill in the art also has experience with research-scale
manufacturing, ultimately leading to commercial scale
manufacturing (given that the antibody is part of a
pharmaceutical composition). This ordinarily skilled person is
either: (A) a person with at least a Bachelor's degree in biology,
chemistry, biochemistry, chemical engineering, or a related field
who has multiple years of experience in antibody production in
an industrial setting; or (B) a person with an advanced degree
(M.S. or Ph.D.) in biology, chemistry, biochemistry, chemical
engineering, or a related field who has at least 2–3 years of
experience in antibody production in an industrial setting.
See Declaration Under 37 C.F.R. § 1.132 of Dr. Peter Mezes (dated
Sept. 4, 2014), submitted by Appellants in related Appeal No.
2015-007511. We accept this as representative of the relevant person
of ordinary skill in the art in this case.
FF15. Appellants state, “Appellants do not dispute that it was
known in the prior art that CHO cells did not express α-1,3-
galactosyltransferase” (App. Br. 33), and further concede, “[t]he
person of ordinary skill may have even been motivated to try CHO
cells given the fact that CHO cells lack α-1,3-galactosyltransferase”
(Reply Br. 12).
FF16. As of February 9, 1996, there would have been motivation
to produce a human anti-TNFα antibody according to appealed claim
20 using Chinese Hamster Ovary (CHO) cells as host cells and the
skilled artisan would have had a reasonable expectation of
successfully so doing. See findings of fact, supra.
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DISCUSSION
“[T]he law of obviousness-type double patenting looks to the law of
obviousness generally,” such that, “if the later expiring patent is ‘merely an
obvious variation of an invention disclosed and claimed in the [reference]
patent,’ the later expiring patent is invalid for obviousness-type double
patenting.” AbbVie Inc. v. Mathilda and Terence Kennedy Inst. of
Rheumatology Trust, 764 F.3d 1366, 1378–79 (Fed. Cir. 2014) (citing
Amgen Inc. v. F. Hoffman-La Roche Ltd., 580 F.3d 1340 (Fed. Cir. 2009)
and Eli Lilly & Co. v. Teva Parenteral Meds., Inc., 689 F.3d 1368 (Fed. Cir.
2012), and quoting In re Vogel, 422 F.2d 438, 441 (CCPA 1970)). “[T]he
nonclaim portion of the earlier patent ordinarily does not qualify as prior art
against the patentee.” Id. at 1379 (quoting Eli Lilly, 689 F.3d at 179
(internal quotation marks omitted).
“[O]bviousness is not demonstrated merely by showing that an earlier
expiring patent dominates a later expiring patent” and “a narrow species can
be non-obvious and patent eligible despite a patent on its genus.” Id.
However, “not every species of a patented genus is separately patentable,” as
they may be anticipated or obvious over the prior art. Id. For example, as is
well established in the law of obviousness, where “prior art references
‘provide[d] ample motivation to narrow the [a previously patented] genus
. . . to a few [species]’ . . . [the Federal Circuit] concluded that the species at
issue . . . was unpatentable.” Id. (citing and quoting Pfizer, Inc. v. Apotex,
Inc., 480 F.3d 1348, 1366 and 1372 (Fed. Cir. 2007), bracketing original).
Also well established in the law of obviousness is that “[a] species
contained in a previously patented genus may be patentable if the species
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manifests unexpected properties or produces unexpected results.” Id. at
1380. However, even though “evidence of unexpected results [must] be
[considered] . . . even if that evidence was obtained after the patent’s filing
or issue date,” Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc., 769
F.3d 1339, 1342 (Fed. Cir. 2014) (denying reh’g en banc) (quoting Genetics
Inst., LLC v. Novartis Vaccines Diagnostics, Inc., 655 F.3d 1291, 1307 (Fed.
Cir. 2011)), “[m]ere recognition of latent properties in the prior art does not
render nonobvious an otherwise known invention,” In re Baxter Travenol
Labs., 952 F.2d 388, 392 (Fed. Cir. 1991). “[A]dditional unexpected
properties, however, d[o] not upset an already established motivation to
modify a prior art compound [or method to make the compound] based on
the expected properties of the resulting compound.” Bristol-Myers, 752 F.3d
at 976 (reh’g en banc denied) (citing In re Dillon, 919 F.2d 688, 693 (Fed.
Cir. 1990)).
There are no disputes here on the interpretation of the claims, either
those appealed or those over-which the appealed claims are rejected. Thus,
the claim language is accorded its plain meaning under the broadest
reasonable interpretation of the claims. Cuozzo Speed Tech., LLC v. Lee,
136 S. Ct. 2131, 2145 (2016) (the Patent Office, for more than 100 years,
has applied the broadest reasonable construction standard in proceedings).
The Examiner determined the Salfeld patent’s claims and the appealed
claims are directed to producing “the same antibody.” See FF1 and appealed
claim 20, supra; see also FF2 (fact is undisputed). While the Salfeld patent
claims are directed to producing the relevant antibody using “a host cell,”
appealed claim 20 recites “culturing a Chinese Hamster Ovary (CHO) host
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cell.” Although these separately claimed inventions are not identical in this
regard, the Examiner determined that they are not patently distinct due to
this difference because using CHO cells as host cells to produce such an
antibody would be obvious (suitable and, in fact, preferred) in view of
Ramage, and also Anderson, Burton, Crowley, and Le. See Final Action 3–
4, 6 (“Recombinant synthesis of the human anti-TNFα antibody is an
obvious variant of claims 1–19 of the ’562 [Salfeld] patent. CHO cells are
suitable hosts for recombinant antibody synthesis, and preferred by the ’036
[Ramage] patent.”), 9, 16–17; see also Ans. 3–4, 7 (“CHO cells are suitable
hosts for recombinant antibody synthesis, and are preferred by the ’036
[Ramage] patent.”), 9, 11 (“The selection of CHO cells by the ’036
[Ramage] patent for the production of Campath [1H], based on their
suitability and preference for antibody production, supports a determination
that their selection for the production of the adalimumab is prima facie
obviousness.”); see also FF1–FF16, supra. We discern no error in, and
agree with, the Examiner’s determinations.
We find the Examiner has established that the appealed claims would
have been obvious over the claims of Salfeld. Appellants have submitted
arguments and associated evidence in the form of literature and declarations
under 37 C.F.R. § 1.132. Having carefully considered this, we find
Appellants have not produced evidence showing, or persuasively argued,
that the Examiner’s determinations on obviousness-type double patenting
are incorrect. Only those arguments made by Appellants in the Briefs have
been considered in this Decision. Arguments not presented in the Briefs are
waived. See 37 C.F.R. § 41.37(c)(1)(iv) (2015). We have identified claim
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20 as representative and Appellants argue all claims as a group; therefore, all
claims fall with claim 20.
Appellants’ arguments focus on the claim element, “culturing a
Chinese Hamster Ovary (CHO) host cell.” See claim 20, supra. The
question on appeal is whether the evidence supports the Examiner’s
determination that using CHO cells as host cells in the methods claimed in
Salfeld would have been obvious. We find the preponderance of the
evidence supports this determination. We address Appellants’ arguments
below.
Appellants’ First Argument: mouse myeloma cells
Appellants argue CHO cells, as recited by claim 20, would not be an
obvious host cell for production of a human antibody because of
immunogenicity concerns. App. Br. 13. Appellants cite Jenkins,4 Pietersz,5

4 Nigel Jenkins et al., Getting the Glycosylation right: Implications for the
Biotechnology Industry, 14 NATURE BIOTECH. 975–81 (1996) (“Jenkins”).
5 Geoffrey A. Pietersz et al., In Vitro and in Vivo Antitumour Activity of a
Chimeric Anti-CD19 Antibody, 41 CANCER IMMUNOL. IMMUNOTHER 53–60
(1995) (“Pietersz”).
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Gramer,6 Logan,7 Poul,8 Potter,9 Hiatt 1989,10 Hiatt 1993,11 Ma,12 Dolezal,13
Ridder,14 and Page15 for the proposition that, human cell lines were not well
enough understood to be hosts in 1996, so similar mammal cells would be
looked to for host cells, and that mouse myeloma cells, not CHO cells,
would have been the well-known choice (from a variety of host choices).
App. Br. 15–17. Appellants cite Ghaderi16 and contend that there were

6 Michael J. Gramer & Charles F. Goochee, Glycosidase Activities of the 293
and NS0 Cell Lines, and of an Antibody-Producing Hybridoma Cell Line, 43
BIOTECH. & BIOENGINEERING 423–28 (1994) (“Gramer”).
7 John S. Logan, Transgenic Animals: Beyond ‘Funny Milk,’ 4 CURRENT OP.
IN BIOTECH. 591–95 (1993) (“Logan”).
8 Marie-Alix Poul et al., Design of Cassette Baculovirus Vectors for the
Production of Therapeutic Antibodies in Insect Cells, 1 IMMNOTECHNOLOGY
189–96 (1995) (“Poul”).
9 Kathleen N. Potter et al., Antibody Production in the Baculovirus
Expression System, 10 INTERN. REV. IMMUNOL. 103–12 (1993) (“Potter”).
10 Andrew Hiatt et al., Production of Antibodies in Transgenic Plants, 342
NATURE 76–78 (1989) (“Hiatt 1989”).
11 Andrew Hiatt & Julian K-C Ma, Characterization and Application of
Antibodies in Plants, 10 INTERN. REV. IMMUNOL. 139–52 (1993) (“Hiatt
1993”).
12 Julian K.-C. Ma et al., Generation and Assembly of Secretory Antibodies
in Plants, 268 SCIENCE 716–19 (1995) (“Ma”).
13 Olan Dolezal et al., Escherichia coli Expression of a Bifunctional Fab-
Peptide Epitope Reagent for the Rapid Diagnosis of HIV-l and HIV-2, 1
IMMUNOTECHNOLOGY 197–209 (1995) (“Dolezal”).
14 Rudiger Ridder et al., Generation of Rabbit Monoclonal Antibody
Fragments from a Combinatorial Phage Display Library and Their
Production in the Yeast Pichia pastoris, 13 BIOTECH. 255–60 (“Ridder”).
15 U.S. Patent No. 5,545,403 (issued Aug. 13, 1996) (“Page”).
16 Darius Ghaderi et al., Implications of the Presence of N-
Glycolylneuraminic Acid in Recombinant Therapeutic Glycoproteins, 28
NATURE BIOTECH. 863–67 (2010) (“Ghaderi”). While not within the prior
art timeframe and, therefore, not particularly relevant and not relied upon in
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limited (just 2) therapeutic antibodies approved by the FDA in 1996 and
each was produced in myeloma-based cells. We do not find these arguments
persuasive.
Having considered Appellants’ evidence, we find the references cited
by Appellants do not support the proposition that mouse myeloma cells
would be especially preferred over CHO cells as hosts for producing human
antibodies or, for that matter, that the skilled artisan would be dissuaded
from using CHO cells as hosts. Moreover, and contrary to Appellants’
position, several of Appellants’ cited references support the Examiner’s
position that CHO cells were suitable or preferred for the task. For example,
Jenkins indicates that CHO cell lines were used for recombinant protein
synthesis (an antibody is a protein), that CHO cell lines can be genetically
modified to resemble the human glycan profile, and that CHO cells may
prove useful hosts. Jenkins 977. Also, Gramer indicates that “Chinese
hamster ovary (CHO) cells have been widely used to produce recombinant
glycoproteins.” Gramer 423 (right col.). And, Page discloses that its
invention relates to “a CHO cell-line capable of producing a human
antibody.” Page Abstract. In view of such disclosures, Appellants’
evidence is inconsistent, at best.
Also, Appellants focus their contentions and arguments on the
premise that the appealed claims and their defined invention must be
considered through the lens of “an industrial setting,” of a desire for a host
cell “suitable for commercial purposes,” and of ultimate “approv[al] by the

our decision, we note Ghaderi does identify an FDA-approved, fully human
antibody produced in CHO cells, i.e., Vectibix (panitumumab).
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FDA for therapeutic use.” App. Br. 12, 16–17. However, the claims do not
require such features, but only “producing a human anti-TNFα antibody, or
antigen-binding portion thereof, suitable for therapeutic use in a human
subject,” which we find does not invoke such concerns. Thus, Appellants’
identifying that, in 1996, the two FDA-approved therapeutic antibodies were
derived only from myeloma-based cells is not determinative on obviousness.
Moreover, Appellants’ adduce no evidence that FDA would have
categorically refused to approve antibodies derived from CHO cells.
Appellants’ Second Argument: general teaching away in 1996
Appellants argue the prior art in 1996 taught away from using CHO
cells as host cells because they were understood to be inefficient and
unstable and, so, not suited to produce an antibody for therapeutic use. App.
Br. 13, 17. Appellants cite Brown17 and Trill18 as support for this
contention. Appellants argue Brown “calls into question the ability of CHO
cells to stably produce antibodies on a scale suitable for the production of
human therapeutics” (e.g., on an industrial scale, taking into consideration,
e.g., production costs and product yields) because “stability needs to be
demonstrated for at least 60 [cell] generations” and Brown indicated stability
for only 20–25 generations. App. Br. 18 (citing Brown 232). Appellants
also argue that Trill “indicates that there is variability in the levels of
expression obtained for different humanized antibodies” in CHO cells. Id.

17 M.E. Brown et al., Process Development for the Production of
Recombinant Antibodies Using the Glutamine Synthetase (GS) System, 9
CYTOTECH. 231–36 (1992) (“Brown”).
18 John J. Trill et al., Production of Monoclonal Antibodies in COS and CHO
Cells, 6 CURRENT OP. IN BIOTECH. 553–60 (1995) (“Trill”).
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18–19 (citing Trill 557). Appellants (again) assert that, as of February 1996,
there were two products produced using myeloma-based cells: ReoPro®
and Orthoclone®, which also supports that CHO cells would not be chosen
for production of “the first fully human therapeutic antibody made in an
industrial setting.” App. Br. 19 (emphasis added).
A “teaching away” requires a reference to actually criticize, discredit,
or otherwise discourage the claimed solution. See In re Fulton, 391 F.3d
1195, 1201 (Fed. Cir. 2004). “The prior art’s mere disclosure of more than
one alternative does not constitute a teaching away from . . . alternatives
because such disclosure does not criticize, discredit, or otherwise discourage
the solution claimed.” Id.
Claim 20 recites “producing a human anti-TNFα antibody, or antigen-
binding portion thereof, suitable for therapeutic use in a human subject”; it
does not require production on an industrial scale or commercially. We do
not interpret “therapeutic use” to invoke an industrial or commercial use or
production, but understand this term in accordance with its plain meaning,
which is of or relating to the treatment of disease or disorders by remedial
agents or methods.19 As we stated above, industrial, commercial, and FDA-
approval concerns are not limitations of appealed claim 20 and are not
properly considered in analyzing the appealed claims. Appellants’
argument, however, is based on the proposition that one would not have
used CHO host cells for industrially or commercially producing human

19 See Merriam-Webster, therapeutic, available at https://www.merriam-
webster.com/dictionary/therapeutic (visited May 3, 2017).
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antibodies for human therapy in 1996 and, therefore, we find it
unpersuasive.
Regarding Brown, the reference discusses stability experiments on
CHO host cell expression and reported, “[w]ith the presence of 250 µM
MSX in the culture medium, the CHO cell line stably secreted product for
35 generations although subsequent experiments have determined stability in
excess of 60 generations thereby meeting production criteria.” Brown 232
(contrasting this success with the more limited result of 20–25 generations
without methotrexate). This evidences that CHO production can be stable
enough to produce a product and does not support Appellants’ contentions
that the skilled artisan would not select CHO cells as host cells over stability
concerns. Brown reported similar success in product yield using CHO host
cells and methotrexate. Brown 334. Again, Brown shows that it does not
support Appellants’ contentions that CHO would not be selected as host
cells.
Regarding Trill, the reference discloses:
In order to meet the demand for clinical supplies, a gradual
increase has occurred in the usage of dihydrofolate reductase
negative (DHFR-) Chinese hamster ovary (CHO) cells for large-
scale antibody production. Using a variety of mammalian
expression vectors and selection/amplification protocols, CHO
cell lines capable of producing monoclonal antibodies at levels
exceeding 1 gl-1 can now be obtained in an almost routine
fashion,
and even calling “CHO cells . . . the expression system of choice to generate
intact biologically active functional mAbs.” Trill 553 (abstract and right
col.). Trill further discloses:
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Like myeloma cells, CHO cells offer the advantages of being
readily transfectable, able to grow in suspension and serum-free
medium, and capable of growth at high densities. All of the data
obtained thus far indicate that no differences exist in the function
of mAbs produced in either myeloma or CHO cells.
Trill 555 (right col.). Such disclosures do not support Appellants’
contention that CHO cells would not have been considered appropriate for
the invention defined by appealed claim 20 or the Salfeld claims, but
supports the opposite. Indeed, Trill evidences that therapeutically relevant
amounts may be produced. Trill 553.
As we indicated above, the FDA’s approval of mouse-myeloma-cell-
produced pharmaceuticals is not determinative regarding whether using
CHO cells as host cells is obvious here.
Appellants’ Third Argument: Ramage and uncertainty regarding
producing Campath 1H teaches away
Appellants argue Ramage teaches away from using CHO cells as host
cells because, in describing Campath 1H production, the reference “reveals
challenges with cell line stability and antibody amounts (or titre).” App. Br.
14, 19. Appellants also cite Raper,20 in view of Ramage, as undermining the
use of the CHO cell line referenced in Ramage because it “produced
decreasing levels of Campath over time.” Id. at 20 (emphasis original), 22.
Appellants argue that the prior art’s disclosure of a genus of cell types
for hosting expression of antibodies is not sufficient to establish a prima
facie case of obviousness. App. Br. 21 (citing MPEP § 2144.08 and In re

20 J Raper et al., Long Term Stability of Expression of Humanized
Monoclonal Antibody Campath 1-H in Chinese Hamster Ovary Cells, The
Wellcome Foundation Ltd. (1992) (“Raper”).
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Baird, 15 F.3d, 380, 382 (Fed. Cir. 1994)). Appellants contend that, because
CHO cells were merely one of many options known in the art, their use
would not have been obvious (over the claim element of Salfeld (FF1)).
Appellants, again, cite Gramer, contending “that while Gramer states
that CHO cells have been ‘widely used,’ Gramer also discusses other useful
production methods,” which would indicate the skilled artisan would not
chose to use CHO cells as hosts. Id. at 22–23. Appellants also cite Lifely21
and discuss Isaacs22 and Lockwood.23 Appellants contend, because, in view
of the objectives of claims 20–30, it would have been critical to maintain a
product free of non-human epitopes and because manufacturing stability and
efficiency must be considered, in 1996, the skilled artisan would not have
used CHO cells.
Appellants do not argue Raper teaches one cannot “produc[e] a human
anti-TNFα antibody, or antigen-binding portion thereof, suitable for
therapeutic use in a human subject” using a CHO cell line, but only that such
production eventually decreases. There is no claim element or limitation
where such an issue would be relevant. Further, Raper evidences that CHO
cell lines do work as hosts for expressing Campath 1-H, even if production

21 M.Robert Lifely et al., Glycosylation and Biological Activity of
CAMPATH-1H Expressed in Different Cell Lines and Grown Under
Different Culture Conditions, 5 GLYCOBIOLOGY 813–22 (1995) (“Lifely”).
22 John D. Isaacs et al., Humanised Monoclonal Antibody Therapy for
Rheumatoid Arthritis, 340 LANCET 748–52 (1992) (“Isaacs”).
23 C. M. Lockwood et al., Remission Induction in Behḉet’s Disease
Following Lymphocyte Depletion by the Anti-CD52 Antibody CAMPATH 1-
H, 42 RHEUMATOLOGY 1539–44 (2003) (“Lockwood”).
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eventually decreases. See, e.g., Raper 52 (Fig. 1). Thus, Appellants’
argument is not persuasive.
Regarding Appellants’ In re Baird argument, the cited prior art
supports the species of host cells recited by the claims. The claims of
Salfeld are directed to the genus of “[a] host cell” that “synthesi[zes] a
human antibody that binds human TNFα” from a vector encoding an
antibody light chain having a variable region comprising the amino acid
sequence of SEQ ID NO: 1 and an antibody heavy chain having a variable
region comprising the amino acid sequence of SEQ ID NO: 2. FF1. As
determined by the Examiner, Ramage (and other identified prior art)
indicates that CHO cells are well suited and even preferred for such
production. Appellants’ argument is not persuasive. Unlike Baird, which
addressed the selection of chemical substituents from a generic formula, the
instant prior art selects CHO cells from small lists of acceptable host cells
(see, e.g., FF8, FF13). Instead, the claim recites CHO cells, which were
known in the prior art, and “all that was required to obtain the claimed
combination was to substitute one well-known . . . [host cell] for another” in
claim 20 of Salfeld. See Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC,
683 F.3d 1356, 1364 (Fed. Cir. 2012).
Appellants’ argument regarding Gramer is not persuasive. Gramer
stands for the proposition that CHO cells as hosts are a reliable baseline
against which other potential host can be measured. Gramer 423. And, as
Appellants concede (App. Br. 22–23), Gramer states, “Chinese hamster
ovary (CHO) cells have been widely used to produce recombinant
glycoproteins,” which evidences that CHO cells are an obvious choice for
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producing recombinant proteins, such as antibodies. That Gramer discusses
other production methods does not make using CHO cells less obvious. See
In re Fulton, 391 F.3d at 1201.
Regarding Lifely, the very first sentence of the reference indicates that
humanized antibodies have been expressed in CHO cells for use in therapy
of lymphoma, leukemia, and rheumatoid arthritis. Lifely 813. Certainty is
not a requirement of obviousness and Lifely does not diminish the
reasonable success that would be expected of using CHO cells to express
antibodies. Appellants’ contention that Lockwood is not prior art is well
taken, but Lockwood is not necessary for the Examiner’s rejection.
Regarding Appellants’ argument (App. Br. 25) that Isaacs teaches
away from the use of CHO cells because it indicates some patients
“developed anti-Campath antibodies,” while it may be true that the reference
identifies some potential drawbacks that might be associated with the use of
animal cell expressed humanized antibodies, it does not strongly teach away
from such a process and makes no definitive conclusions thereon.
“[C]ase law is clear that obviousness cannot be avoided simply by a
showing of some degree of unpredictability in the art so long as there was a
reasonable probability of success.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d
1348, 1364 (Fed. Cir. 2007) (citing In re Corkill, 771 F.2d 1496, 1500 (Fed.
Cir. 1985)). Our review of Appellants’ evidence (including, inter alia,
Jenkins, Pietersz, Gramer, Logan, Poul, Potter, Hiatt 1989, Hiatt 1993, Ma,
Dolezal, Ridder, Page, Ghaderi, Gramer, Brown, Trill, the documents
concerning ReoAPro and Orthoclone, Raper, Lifely, Isaacs, and Lockwood,
etc.) shows that none of it establishes that using CHO cells as hosts for
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production of recombinant human antibodies (e.g., TNFα antibodies) would
not work for producing a human therapeutic composition, or would not be
expected to work, or teaches away therefrom, or otherwise evidences that the
indications of, for example, Ramage, that CHO cells would be a good choice
for such host cells are less than credible. In fact, many of the references
cited by Appellants evidence just the opposite, that in 1996 and prior, CHO
cells were accepted and widely used, successfully, as host cells for
producing recombinant proteins including antibodies like TNFα antibodies.
Further, “a given course of action often has simultaneous advantages
and disadvantages, and this does not necessarily obviate motivation to
combine [or modify].” Medichem, S.A. v. Rolabo S.L., 437 F.3d 1157, 1165
(Fed. Cir. 2006). We acknowledge that there is evidence of some
drawbacks, potential or realized, to using CHO cells as described in the art
and claimed here, but none of this evidence sways the balance against the
Examiner’s determination, and rationale therefor, that the appealed claims
would be obvious over the claims of Salfeld.
Further, Appellants concede, “Campath was produced successfully in
CHO cells and approved by the FDA in 2001, . . . [but contend] there was
uncertainty in the art, at the time of filing of the priority application, as to
which cell line should be used for production.” App. Br. 21. Again, “some
degree of unpredictability in the art [is not determinative of obviousness] so
long as there was a reasonable probability of success.” Pfizer, 480 F.3d at
1364. While we do not rely on Appellants’ concession or the evidence upon
which it is based in affirming the Examiner’s rejection, the concession
stands for the proposition that Appellants’ evidence does not support the
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contention that the skilled artisan would be dissuaded from using CHO cells
to produce human antibodies for pharmaceuticals.
Appellants’ Fourth Argument: unexpected results
Appellants argue the invention of the appealed claims provides
unexpected results in producing a human antibody lacking α-1,3-galactose
glycan (α-1,3-Gal), thus avoiding “severe immune reactions in certain
patients.” App. Br. 14; see also Salfeld Decl. ¶ 5.24 Appellants contend that
use of CHO cells to produce anti-TNFα antibodies results in “a relatively
lower risk of causing certain immunogenicity problems in [human]
recipients” and “this benefit is unexpected inasmuch as it was not recognized
or appreciated in the art as of the priority date.” App. Br. at 27. As support,
Appellants cite the declarations of Chumsae25 and Salfeld.
Appellants’ argument regarding unexpected results can be
summarized as follows: post-invention, it was discovered that adalimumab
(Humira®), produced in CHO cells, unexpectedly avoids potentially serious
immune reactions in patients because the antibodies do not include
potentially immunogenic α-1,3-Gal; and, despite the fact that it was known
in 199626 that CHO cells naturally do not express α-1,3-galactostransferase

24 Declaration Under 37 C.F.R. § 1.132 of Dr. Jochen Salfeld (dated Jan. 10,
2014) (“Salfeld Decl.”).
25 Declaration Under 37 C.F.R. § 1.132 of Christopher Chumsae (dated Jan.
10, 2014) (“Chumsae Decl.”)
26 See Smith et al., Transfer and Expression of a Murine UDP-Gal:β-D-Gal-
αl,3-Galactosyltransferase Gene in Transfected Chinese Hamster Ovary
Cells, 265 J. BIO. CHEM. 6225–34 (1990) (“Smith”), and Jenkins; see also
Ans. 15 and Reply Br. 12 (discussing same). Smith discloses that CHO cells
only express α-1,3-galactosyltranderase when artificially engineered to do so
and, so, normally do not have the capability to transfer Gal from UDP-Gal to
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and, so, the lack of α-1,3-Gal on polypeptides produced by CHO cells was
expected, there was no motivation to use, or an expectation of successfully
using, CHO cells to produce therapeutic human antibodies (“to avoid [such]
potentially harmful immune responses in human patients”) until it was
eventually discovered that a potential immunogenic problem existed because
of α-1,3-Gal. See Reply Br. 11–14.
The “discovery that a claimed composition possesses a property not
disclosed for the prior art subject matter, does not by itself defeat a prima
facie case.” In re Dillon, 919 F.2d 688, 693 (Fed. Cir. 1990). “In
determining whether the subject matter of a patent claim is obvious, neither
the particular motivation nor the avowed purpose of the patentee controls.
What matters is the objective reach of the claim. If the claim extends to
what is obvious, it is invalid under § 103.” KSR Int’l Co. v. Teleflex Inc.,
550 U.S. 398, 419 (2007).
Appellants’ position discounts or disregards the fact that other,
different, but sufficient motivation to produce Humira® (the antibody
constituting the active drug, in the way recited by the appealed claims, i.e.,
using CHO cells as hosts) did exist in the prior art. Appellants also based
their position on considerations for producing an FDA-approved
pharmaceutical on an industrial and commercial scale that are not invoked
based on the claimed invention.

the α-1,3-linkage (Smith 3225, 3232) and Jenkins discloses that CHO cell
lines used for recombinant protein synthesis have “fortuitously inactivated
the gene for α-1,3-galactosyltranferase” (Jenkins 977).
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“Mere recognition of latent properties in the prior art does not render
nonobvious an otherwise known invention.” In re Baxter Travenol Labs.,
952 F.2d 388, 392 (Fed. Cir. 1991). Here, the evidence shows that the
information the skilled artisan had in 1996 indicated that CHO host cells
were a good choice for producing antibodies for human therapy. FF4–FF13,
FF15, FF16. The fact that, later, we understand an additional reason why
Humira® might be particularly effective is not the type of unexpected result
(as much as it is an uncovered latent property) that can overcome a strong
case for obviousness as of the invention date. See Bristol-Myers, 769 F.3d at
1344 (finding later discovered properties of a compound cannot influence
prior-existing motivations to use it); see also Bristol-Myers, 752 F.3d at 976
(“additional unexpected properties, however, [do] not upset an already
established motivation to modify a prior art compound [or method] based on
the expected properties of the resulting compound.).
The facts identified in the initial Federal Circuit panel’s decision in
Bristol-Myers (752 F.3d 967) nearly parallel those of this case. As here, in
Bristol-Myers, the claimed invention was found to be obvious. The Bristol-
Myers invention was a pharmaceutical compound called “entecavir,” which
was a slightly-altered version of a prior art pharmaceutical compound called
“2#-CDG,” on which there was evidence, as of the invention date, of praise
for its pharmaceutical activity and the promise of therapeutic uses, as well as
evidence of the compound’s actual use in research, which showed enough
success to warrant the aforementioned praise and related high expectations.
Id. at 971–72. Based on this evidence, the Federal Circuit affirmed the
district court’s holding that the skilled artisan would have been motivated to
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modify the prior art compound to form the invention compound and would
have had a reasonable expectation of success in so doing. Id. at 972.
Evidence showed, however, that years later it was discovered that this prior
art compound (2#-CDG) was actually toxic (while, presumably, the
invention compound was sufficiently not), which the patentee asserted
would defeat any motivation to use this compound as a starting point. Id. at
974. Further, the patentee asserted that the claimed compound was
unexpectedly effective to treat hepatitis B (as well as having a high
resistance barrier and a large therapeutic window), without the toxicity
issues of the prior art compound. Id. at 977–78.
In Bristol-Myers, the Federal Circuit thus held that the late-discovered
unexpected results, while advantageous, did not outweigh the prior-existing
motivation to make the invention or the prior-existing reasonable
expectation the skilled artisan would have had for successfully doing so.
This is the scenario the facts present here, with the exception that, unlike the
starting prior art compound found to be toxic and unusable in Bristol-Myers,
here the CHO cells, identified as useful and preferred in the prior art, have
established themselves as such in the industry. Thus, we find the Examiner
presents a strong case for obviousness that is not upset by the late-found,
potentially unexpected results. We find this, without more, is sufficient to
affirm the rejection.
However, we also find the declaration evidence relied upon by
Appellants’ unconvincing. We note the Chumsae Declaration is largely
speculative, indicating that “galactose-α-1,3-galactose . . . can increase the
immunogenicity of the therapeutic antibodies when administered to human
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subjects,” that having α-1,3-Gal on an antibody “could lead to dangerous”
conditions and it is “highly likely” (or just “likely”) that, were the claimed
antibodies produced in a mouse myeloma cell, they would have α-1,3-Gal.
Chumsae Decl. ¶¶ 4, 6, 9, 10 (emphasis added). Chumsae identifies no
testing data to confirm this speculation and never states that producing
antibodies with CHO cells provides unexpected results. Nor does Chumsae
identify prior art evidence that undermines the teachings, discussed above,
as to the desirability of using CHO cells to express recombinant antibodies.
The Salfeld Declaration is also unconvincing. Salfeld states that, “[i]n
my opinion, production of human anti-TNFα antibodies using CHO cells, as
set forth in the pending claims, results in anti-TNFα antibodies that have
unexpected beneficial properties when administered to a human subject, as
compared to antibodies produced in other host cell lines, such as mouse
myeloma cell line” due to the CHO cells-produced antibodies not
“contain[ing] the galactose-α-1,3,galactose glycan.” Salfeld Decl. ¶ 5. But,
like Chumsae, Salfeld’s statements are speculative. Salfeld indicates
“[g]lycosylation of thereapeutic antibodies can have a critical effect on
immunogencity when administered in humans,” that “production in certain
mammalian expression systems can increase the immunogenicity of
therapeutic antibodies,” that “humans may produce antibodies against this
glycan epitope,” and that all these potential effects present an “increased risk
of immunogenicity when administered to humans.” Salfeld Decl. ¶ 6
(emphases added).
Also, the declarants’ use of hedging language to support their
opinions underscores the speculative and non-conclusive determinations of
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the evidence they cite (i.e., Chung, Valliere, Raju, and Ghaderi).27 Chung
identifies potential hypersensitivity to the drug cetuximab due to antibodies
for galactose-α-1,3-galactose, but indicated that the immunogenic reaction to
galactose-α-1,3-galactose is natural in only some people and is also
regionally prevalent, suggesting unknown environmental causation. Chung
1115–16. The Examiner also identifies that Chung’s disclosure of
glycosylation sites may not support Appellants’ contentions. Ans. 17–18.
Valliere discusses why (or why not) glycosylation resulting in incorporation
of galactose-α-1,3-galactose may occur, but does not conclude that inclusion
of α-1,3-Gal will lead to dangerous IgE-mediated anaphylaxis in patients.
See Valliere, generally. As noted above, it was previously understood that
CHO cells do not express α-1,3-galactosyltransferase and that α-1,3-Gal was
not detected in CHO cell expression systems. See Smith and Jenkins. Raju
states, “no evidence in the literature suggests that the presence of α-Gal
epitopes on rIgG is immunogenic to humans.” Raju 44. Ghaderi indicates
“it is likely that most recombinant therapeutic glycoproteins carry some
Neu5Gc” and identifies “the presence of small amounts of Neu5Gc in
recombinant glycoproteins produced in CHO cells,” and concludes,

27 Christine H. Chung, M.D. et al., Cetuximab-Induced Anaphylaxis and IgE
Specific for Galactose-α-1,3-Galactose, 358 N. ENGL. J. MED. 1109–17
(2008) (“Chung”); John F. Valliere-Douglass et al., Glutamine-linked and
Non-consensus Asparagine-linked Oligosaccharides Present in Human
Recombinant Antibodies Define Novel Protein Glycosylation Motifs, 285 J.
BIO. CHEM. 16012–22 (2010) (“Valliere”); T. Shantha Raju, Glycosylation
Variations with Expression Systems and Their Impact on Biological Activity
of Therapeutic Immunoglobulins, BIOPROCESS INT’L 44–53 (April 2003)
(“Raju”).
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“findings suggest that the potential significance of the presence of Neu5Gc
on glycoprotein biotherapeutics should be revisited.” Ghaderi 863, 865–66.
Thus, none of these references definitively supports Appellants’ contentions,
even if they may inferentially do so.

CONCLUSION
Representative claim 20 would have been obvious over the claims of
Salfeld, in view of Ramage, Anderson, Burton, Crowley, and Le. Appellants
have not presented persuasive evidence or argument that the Examiner’s
determination on obviousness is not correct. Appellants’ evidence of
secondary indicia of non-obviousness, specifically of alleged unexpected
results, is not persuasive in demonstrating non-obviousness over the Salfeld
claims because, as of the date of invention, there was sufficient motivation
to modify the invention claimed in Salfeld and a reasonable likelihood of
success in doing so, based on the Examiner’s cited prior art.

SUMMARY
The rejection of the claims under the doctrine of obviousness-type
double patenting over the claims of Salfeld is affirmed.

TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED