Ex Parte 6924264 et al

Patent Trial and Appeal Board

Nov 23, 2013

95000276 (P.T.A.B. Nov. 23, 2013)

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.
95/000,276 07/09/2007 6924264 11767-104-999 2035
107505 7590 11/25/2013
Womble Carlyle Sandridge & Rice, LLP
Attn: IP Docketing
P.O. Box 7037
Atlanta, GA 30537-7037
EXAMINER
TURNER, SHARON L
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
11/25/2013 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
____________

CONJUCHEM, LLC
Requester and Cross-Appellant

v.

AMYLIN PHARMACEUTICALS, INC.
Patent Owner and Appellant
____________

Appeal 2013-004331
Inter Partes Reexamination Control 95/000,276
U.S. Patent 6,924,264 B1
Technology Center 3900
____________

Before TONI R. SCHEINER, RICHARD M. LEBOVITZ, and
JEFFREY B. ROBERTSON, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on the appeal by the Patent Owner from the Patent
Examiner‟s decision to reject pending claims 24 and 26-36 in the above-
identified inter partes reexamination of U.S. Patent No. 6,924,264 B1. The
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Board‟s jurisdiction for this appeal is under 35 U.S.C. §§ 6(b), 134, and 315.
We affirm-in-part.
I. BACKGROUND
The patent in dispute in this appeal is U.S. Patent No. 6,924,264 B1,
issued August 2, 2005 (“the ‟264 patent”). The Patent Owner (“PO”) and
Real Party in Interest is Amylin Pharmaceuticals, Inc. (PO Appeal Br. 1,
dated February 15, 2012). A request for inter parte reexamination of the
‟264 patent was made on July 9, 2007 by third party requester Conjuchem
Biotechnologies Inc.
Claims 24 and 26-36 are pending and stand rejected by the Examiner.
Claims 24 and 26-36 are not original claims but were added by amendment
during the reexamination proceeding. Patent Owner appealed all the
rejections.
A Respondent Brief (March 15, 2012) and Cross-Appeal (February
15, 2012) were filed on behalf of ConjuChem, LLC, located at 11755
Wilshire Blvd., Suite 2000, Los Angeles, CA 92005 who was listed as the
Third Party Requestor and real party in interest in the respective briefs.
However, the Third Party Requestor that filed the original Request for
Reexamination leading to this appeal is ConjuChem Biotechnologies Inc.,
located at 225, President-Kennedy Avenue, Montreal, QC H2X3Y8. The
parties therefore appear to be different. There does not appear to be any
documentation in the record before us to indicate how, when, and why the
real party in interest, or a person in privity thereto, may have changed since
the filing of the Request. There also does not appear to be a change in
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correspondence or an appointment of power attorney to the attorney who
filed the Respondent and Cross-Appeal briefs.
An Order To Show Cause was mailed on October 18, 2013 giving the
Requester two weeks to clarify the discrepancy between the real party in
interest identified in the request for inter partes reexamination and the real
party in interest set forth in Requester‟s Respondent brief. Otherwise, the
cross-appeal would be dismissed. The attorney who filed the Respondent
Brief and Cross-Appeal was contacted by the PTAB on October 31, 2013,
but she informed the PTAB that she has not been involved with the case for
over a year. No response to the Order To Show Cause was received.
Accordingly, as the party filing the Respondent Brief and Cross-Appeal is
unauthorized, the Cross-Appeal is dismissed and consideration will not be
given to the Respondent Brief to Patent Owner‟s Appeal. See 37 C.F.R. §§
41.60, 1.915(b)(8), and 1.957(a).

Claimed subject mater
The claimed subject matter relates to exendin-4 conjugated to albumin
or PEG. Exendin-4 is a known peptide found in the salivary secretions of
the Gila monster (‟264 patent, col. 1, ll. 34-48). Exendin-4 is related to
members of the glucagon-like peptide (GLP) family (id. at col. 1, ll. 49-54),
such as GLP-1. Exendin-4 was known to have an insulinotropic effect in
stimulating insulin secretion from pancreas cells (id. at col. 1, ll. 54-56) and
to be useful for treating diabetes (id. at col. 2, ll. 53-56). Exendin-4 was also
reported to have a longer duration of action than GLP-1 (id. at col. 2, ll. 47-
51). Exendin-4 and its analogs were known prior to the filing date of the
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‟264 patent (id. at col. 3, ll. 13-28). The patent describes conjugating
Exendin-4 to PEG or albumin (id. at col. 4, ll. 36-57; col. 24, ll. 58-65).
Such conjugates are described by the ‟264 patent as having a kidney
clearance less than unmodified exendin-4 (id. at col. 4, ll. 65-67; col. 24, ll.
58-65; col. 31).
Claims 24 and 26 are representative of the appealed claims and read
as follows:
24. A pharmaceutical composition for use in humans
comprising a pharmaceutically acceptable carrier and a
therapeutically effective amount of exendin-4 or an agonist
analog of exendin-4 linked through the C-terminal amino acid
to one polymer selected from the group consisting of
polyethylene glycol and albumin.

26. The pharmaceutical composition of claim 24, wherein
the polymer is albumin.

Rejections
The claims stand rejected by the Examiner as follows (PO Appeal
Br.):
1

A. Claims 24 and 26-36 under 35 U.S.C. § 103(a) as obvious in view
of Eng
2
in combination with Drucker III,
3
Davis,
4
Poznansky I (1984),
5

Gombotz,
6
Shearwater,
7
or Poznansky II (1988).
8

1
Rejections A through D were listed by Patent Owner as rejecting claim 25.
However, claim 25 is canceled.
2
Eng, US 5,424,286, issued June 13, 1995.
3
Drucker, WO 98/52600, published November 26, 1998.
4
Davis et al, Reductions of Immunogenicity and Extension of Circulating
Half-Life of Peptides and Proteins, in Peptide and Protein Drug Delivery
831-864 (Vincent H. L. Lee ed., 1991).
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B. Claims 24 and 26-36 under 35 U.S.C. § 103(a) as obvious in view
of Eng in combination with Knudsen II ‟872, Davis, Poznansky I (1984),
Gombotz, Shearwater, or Poznansky II (1988).
C. Claims 24 and 26-36 under 35 U.S.C. § 103(a) as obvious in view
of Eng in combination with Chang I,
9
Davis, Poznansky I (1984), Gombotz,
Shearwater, or Poznansky II (1988).
D. Claims 24 and 26-36 under 35 U.S.C. § 103(a) as obvious in view
of Knudsen I ‟990
10
in combination with Davis, Poznansky I (1984),
Gombotz, Shearwater, or Poznansky II (1988).
E. Claims 24, 26-31, 35, and 36 under 35 U.S.C. § 103(a) as obvious
in view of Syed
11
in combination with Eng or Knudsen I ‟990.
F. Claims 24, 26, 27, and 29-36 under 35 U.S.C. § 103(a) as obvious
in view of Eng, Chang II,
12
and Harlow and Lane.
13

G. Claims 24, 26, 27, and 29-36 under 35 U.S.C. § 103(a) as obvious
in view of Eng, Bernard,
14
and Harlow and Lane.

5
Poznansky & Juliano, Biological Approaches to the Controlled Delivery of
Drugs: A Critical Review, 36(4) Pharmacological Reviews, 277-336 (1984).
6
Gombotz & Pettit, Biodegradable Polymers for Protein and Peptide Drug
Delivery, 6 Bioconjugate Chem., 332-351 (1995).
7
Shearwater Polymers, Inc., Polyethylene Glycol Derivatives (June 1983)
8
Poznansky et al., Growth hormone-albumin conjugates: Reduced renal
toxicity and altered plasma clearance, 239 (1) FEB, 18-22 (October 1988).
9
Chang, US 5,149,782, issued September 22, 1992.
10
Knudsen, US 7,226,990 B2, issued Jun. 5, 2007.
11
Syed et al., Potent Antithrombin Activity and Delayed Clearance From the
Circulation Characterize Recombinant Hirudin Genetically Fused to
Albumin, 89(9) Blood, 3243-3252 (May 1, 1997).
12
Chang, US 5,274,075, issued Dec. 28, 1993
13
Harlow & Lane, Antibodies: A Laboratory Manual 55-137 (1988).
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H. Claims 24, 26, 27, and 29-36 under 35 U.S.C. § 103(a) as obvious
in view of Edwards
15
in combination with Chang II, Harlow and Lane, and
Poznansky I (1984).
I. Claims 24, 26, 27, and 29-36 under 35 U.S.C. § 103(a) as obvious
in view of Edwards in combination with Bernard, and Harlow and Lane.

1. REJECTIONS BASED ON KNUDSEN I ‟990
Rejection D
Claims 24 and 36-36 stand rejected under 35 U.S.C. § 103 as obvious
in view of Knudsen I ‟990 in combination with Davis, Gombotz,
Shearwater, Poznansky I (1984), or Poznansky II (1988).

Findings of Fact
Knudsen I ‟990
KI1. Knudsen I ‟990 describes exendins which “are useful in
treatment of diabetes mellitus (types I and II) and prevention of
hyperglycaemia.” (Col. 19, ll. 57-58.)
KI2. Knudsen I ‟990 also describes truncated exendins disclosed in
WO 9746584 which “[c]ompared with GLP-l and the known exendins, . . .

14
Bernard et al, Synthesis of conjugates between luteinizing hormone
releasing hormone (LH-RH) and N-acetyl-muramyl-L-alanyl-D-
isoglutamine (MDP) models of totally synthetic vaccines, 29 Int. J. Pept.
Protein Res. 455-463 (April 4, 1987).
15
Edwards et al, Glucagon-like peptide 1 has a physiological role in the
control of postprandial glucose in humans: studies with the antagonist
exendin 9-39, 48(1) Diabetes, 86-93, 1999.
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are more active (effective at lower doses), more stable to degradation and
metabolism and have a longer lasting effect.” (Col. 20, ll. 2-5.)
KI3. However, Knudsen I 990 states “the high clearance limits the
usefulness of these compounds, and thus there still is a need for
improvements in this field.” (Col. 20, ll. 6-8.) “Accordingly, it is one object
of the present invention to provide derivatives of exendin and analogues
thereof which have a protracted profile of action relative to native exendin.”
(Id. at col. 20, ll. 8-11.)
KI4. To address this need, Knudsen I ‟990 teaches “an exendin
derivative wherein at least one amino acid residue of the parent peptide has a
lipophilic substituent attached.” (Col. 20, ll. 12-14.)
KI5. Knudsen I ‟990 describes preferred embodiments where the
lipophilic constituent is attached to the N-terminal or C-terminal position,
among other preferences (col. 20, ll. 17-23).
KI6. Knudsen I ‟990 teaches that its exendin derivatives modified as
described above have a protracted profile of action (col. 22, ll. 34-43).

Gombotz
G1. Gombotz discloses many clinically useful proteins and peptides
that have been cloned and become commercially available (Gombotz, p.
332, col. 2).
G2. Gombotz teaches that efforts have been made to address some of
the problems associated with proteins and peptides when administered
therapeutically, including “research [which] has focused on the development
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of dosage forms which . . . prolong the activity of the protein in vivo”
(Gombotz, p. 332, col. 2).
G3. Gombotz reviews “the various types of degradable polymers that
have been used for the delivery of proteins and peptides.” (Gombotz, p. 333,
col. 2.)
G4. Gombotz teaches protein-polymer conjugates, stating that there
are many potential advantages, including altering the circulation
pharmacokinetics, reducing renal clearance, and prolonging circulation half-
life (Gombotz, p. 344, col. 2).
G5. Gombotz acknowledges that conjugating polymers to proteins
can inactivate or alter protein activity (Gombotz, p. 344, col. 2).
G6. Gombolz teaches:
For many protein-polymer conjugation schemes, a balance
between the desirable effects of conjugation and the loss of
bioactivity must be established. Recently, investigators have
attempted to avoid the problem of inactivation by the use of
site-specific conjugation strategies.
(Gombolz, p. 345, col. 1, first paragraph.) Site specific methods are
described which utilize N- and C-terminal amino acids (id.)
G7. Gombolz describes protein conjugates with albumin which
showed increased stability and a significant increase in circulation half-life
(Gombotz, p. 345, col. 1). “Albumin has been used as a pharmaceutical
carrier to enhance circulation half-lives of peptides . . . .” (Id. at p. 345, cols.
1-2).

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Poznansky I (1984)
PI1. Poznansky I (1984) teaches enzyme-albumin conjugates which
stabilize the enzyme, mask antigenic determinants on the enzyme, and
increase half-life (Poznansky I (1984), pp. 288 and 319, col. 1).
PI2. Poznansky I (1984) teaches that a reactive group available for
cross-linking is the “epsilon amino group of lysine residues.” (Poznansky I
(1984), p. 290, col. 1.)

Poznansky II (1988)
PII1. Poznansky II (1988) teaches that growth hormone (GH) is
rapidly cleared by the kidney. “The rapid renal clearance of the peptide
resulting in accumulation in the kidney will have to be resolved before
growth hormone and other similar peptides are used effectively.”
(Poznansky II (1988), p. 18, col. 2).
PII2. Poznansky II (1988) found that insulin conjugated to albumin
retained its biological activity:
We rationalize that if insulin can be conjugated to albumin
while retaining its biological activity then the same should be
true of a number of other small peptide hormones. Conjugation
might therefore be used to dramatically alter the
pharmacokinetics and potential usefulness of administered
hormones such as growth hormone.
(Poznansky II (1988), p. 19, col. 1)
PII3. Poznansky II (1988) reported that growth hormone conjugated
to albumin had an extended half-life and “clearly bypasses the kidneys and
is cleared from the circulation largely by the liver.” (Poznansky II (1988), p.
19, col. 2). The data also showed that “that the conjugated GH retains much
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of the activity of the native hormone and may show increased potency in the
conjugated form.” (id. at pp. 19-20)
PII4.
This paper has demonstrated the possibility of altering
small peptides by simple conjugation methods to larger
molecules (such as homologous albumin) in the first instance to
merely alter the pharmacokinetics by simply avoiding the
kidneys. This has profound effects in terms of altered
clearance, altered tissue deposition and reduced nephrotoxicity
for OH and other bioactive peptides such as cytokines [citation
omitted].
(Poznansky II (1988), p. 21, col. 2.)
PII5.
The fact that so many of the activities of growth hormone are
maintained is both fortuitous and of great interest; although the
trial and error nature of the cross-linking procedure required to
find conditions to retain hormone activity should be
emphasized.
(Poznansky II (1988), p. 21, col. 2.)
PII6. Poznansky II (1988) reported that although the albumin-GH
conjugate retained several biological activities, it did not stimulate growth in
hypophysectomized rats (Poznansky II (1988), p. 21, col. 2.) Yet,
Poznansky II (1988) stated that this fact “does not detract from the
observation that small active peptides may be engineered in such a way as to
enhance their suitability as therapeutic agents.” (Id. at pp. 21-22.)

Davis
D1. Davis teaches methods to improve the circulating half-life of
peptide and proteins.
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D2. Davis teaches “[a]lbumin has also been conjugated to a variety of
therapeutically useful proteins,” disclosing that cross-linked albumin
enzyme conjugates were made in 1974, and describes a number of such
examples (Davis, p. 838). Davis concluded that “[i]n all cases, the
attachment of albumin resulted in an adduct with improved therapeutic
characteristics.” (Id.)
D3. Davis summarizes results using albumin-protein conjugates,
describing loss of activity in some cases, but with retention of biological
activity when administered, and improved circulating half-life (Davis, p.
839-840).
Rejection
The Examiner found that Knudsen I ‟990 teaches exendin-4 and
agonist analogs linked to lipophilic polymers via a C-terminal lysine residue,
citing paragraphs 62, 484, 489, 500-504, 525, and 548-60
16
(RAN 11). The
Examiner acknowledged that Knudsen I ‟990 does not teach that the
polymer is PEG or albumin as required by claim 24 (id.). However, the
Examiner found that Davis, Gombotz, Shearwater, and Poznansky I and II
teach peptide polymer conjugates with PEG and albumin for enhanced
delivery (id.), providing a reason to have made such modification to
Knudsen I ‟990 (id.). The Examiner found that the “cited prior art
establishes addition of C-terminal Lys for ease of conjugation and polymer
carriers PEG and albumin as standard polymers to achieve enhanced drug
delivery.” (Id.)

16
The citations are to the published application which corresponds to the
issued patent.
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Patent Owner
First, Patent Owner contends that one of ordinary skill in the art
would not have looked to extend the half-life of exendin-4 because it has a
long half-life (Appeal Br. 6). To support this position, Patent Owner cited
Greig:
17

Grieg reports that the half-life of GLP-1 is “too short to achieve
good 24-h metabolic control” but exendin-4 has a “prolonged
effect of lowering blood glucose.” Greig goes on to state that
exendin-4 “could therefore be preferable to glucagon-like
peptide-1 as a long-term treatment for Type II diabetes.”
(PO Appeal Br. 6 (citation footnote omitted).)
Second, Patent Owner argues that enzymatic degradation is the
primary mode of clearance for all small human regulatory peptides, and
“that on average, proteolytic degradation is over 7 fold more important than
renal filtration for clearance of regulatory peptides.” (PO Appeal Br. 7.)
The inventors of the „264 patent discovered that exendin-
4, unlike GLP-1 and the other regulatory peptides, is cleared
exclusively (or nearly exclusively) by glomerular filtration, not
enzymatic degradation. This was a surprising and unusual
discovery, which is described in the „264 patent[.]
(PO Appeal Br. 7.)
Patent Owner contends that increasing the molecular size of peptides
by conjugating them to polymers would be accomplished to prevent them
being cleared by glomerular filtration, but since the extent to which exendins
were cleared by glomerular filtration was not known, the skilled worker
would not have reason to conjugate exendin to PEG or albumin (id. at 8).

17
Greig et al., "Once Daily Injection of Exendin-4 to Diabetic Mice
Achieves Long-Term Beneficial Effects of Blood Glucose Concentrations,"
Diabetologia, 42, 45-50 (January 1999).
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Third, Patent Owner argues unpredictability. Patent Owner cites
evidence from Gombotz that linking large molecular weight polymers to
therapeutic proteins could adversely affect their activity, making it
unpredictable (id. at 8-9). With respect to Poznansky II (1988), Patent
Owner states that “[b]y linking the growth hormone to albumin, they
achieved a longer circulating half-life, but the growth hormone conjugate
lost all therapeutic activity–it failed to promote any weight gain.” (PO
Appeal Br. 9.)
Finally, Patent Owner contends that the claimed conjugate
unexpectedly reduces the incidence of vomiting and nausea in Type 2
Diabetic patients as compared to unconjugated exedin-4 (PO Appeal Br. 15)

Discussion
Claim 24 is drawn to exendin-4 conjugated to albumin. As discussed
above, the Examiner found that one of ordinary skill in the art would have
had reason to have made such conjugate to achieve enhanced delivery.
Patent Owner contends that exendin-4 already had a long half-life and that it
was known to have a prolonged glucose lowering effect. We have
considered this evidence but do not find it persuasive.
Firstly, Knudsen I ‟990 expressly teaches modifying exendins to
“have a protracted profile of action relative to native exendin.” (KI3 and
KI6.) Thus, despite Patent Owner‟s argument to the contrary, Knudsen I
‟990 expressly recognized the need to improve the activity of an exendin by
modifying it. And even if this teaching is not explicit, in view of the art-
recognized need to prolong the activity of therapeutic proteins as taught by
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Gombotz (G1-G2), the skilled worker would have had reason to improve
exendin-4 even if it did have a “long” half-life because there is always a
desire by scientists to improve upon what is already known.
Despite Patent Owner‟s arguments and evidence about clearance of
exendin from plasma not being a consideration (PO Appeal Br. 7), Knudsen
I ‟990 mentions it as a concern (KI3). Patent Owner cited evidence that
clearance by kidney glomerular filtration would not have been a concern for
exendin-4 because proteolytic degradation was the main cause of clearance
of regulatory peptides from plasma (PO Appeal Br. 7; Declaration of
Andrew A. Young, M.D., Ph.D.; ‟264 patent at col. 31). Yet, Poznansky II
(1988) teaches that renal clearance was a concern for another small protein,
growth hormone (PII1 and PII3). Gombolz also mentions renal clearance as
a reason for making peptide and protein conjugates (G4). Moreover,
Gombolz (G7), Poznansky I (1984) (PI1), Poznansky II (1988) (PII3 and
PII4), and Davis (D1-D3) provide evidence that it was well-known to use
albumin to prolong the half-life of proteins, addressing the problem of “high
clearance” identified by Knudsen II ‟990 for exendin (KI3). Consequently,
there was more than sufficient reason for one of ordinary skill in the art to
have conjugated albumin to exendin-4.
We agree with Patent Owner that there was a degree of
unpredictability in whether conjugating albumin to exendin-4 would
improve its half-life without affecting its activity. However, there are
numerous examples in which conjugated albumin worked in imparting
stability and increasing half-life of proteins (G7, PI1, PII2, PII3, and D2). In
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fact, Davis stated that “[i]n all cases, the attachment of albumin resulted in
an adduct with improved therapeutic characteristics.” (D2.)
As far as the loss of activity, there is evidence that conjugation to
albumin could result in loss of a protein‟s activity and in some cases did
(G5, G6, PII6, and D3). However, growth hormone did not lose all
“therapeutic activity” when conjugated to albumin, as alleged by Patent
Owner (see above). To the contrary, Poznansky II (1988) states that “that so
many of the activities of growth hormone are maintained is both fortuitous
and of great interest.” (PII5.) And even though the growth hormone-
albumin conjugate did not stimulate growth in hypophysectomized rats,
Poznansky II (1988) stated that this fact, nevertheless, “does not detract from
the observation that small active peptides may be engineered in such a way
as to enhance their suitability as therapeutic agents.” (PII6.) Thus, despite
the recognition at the time of the invention that conjugation to a polymer like
albumin could adversely affect a protein‟s activity, it was still considered a
viable strategy for improving a protein‟s half-life in circulation (G6). In
fact, Gombolz suggested that site specific conjugation at the C-terminus was
a strategy to avoid the problem of inactivation of a protein (G6), the exact
approach utilized in the ‟264 patent. Significantly, Knudsen I ‟990 teaches
the exendin is still biologically active when conjugated to a lipophilic
substituent (KI6), giving rise to an expectation that exendin would not lose
activity when joined to a polymer such as albumin or PEG.
It is axiomatic that “[o]bviousness does not require absolute
predictability of success . . . all that is required is a reasonable expectation of
success.” In re O’Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988). Based on
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16
the many teachings in the art of how to conjugate albumin to a peptide and
the success in many cases of making a biologically active peptide, including
of exendin-4 conjugated to a lipophilic group (KI4-KI6), we conclude that a
person in the art would have reasonably expected the claimed conjugate to
possess biological activity. The claim does not require that it possesses a
specific degree of activity, so even if a reduction of activity is observed, the
conjugate of exendin-4 and albumin would still fall within the scope of the
claim.

Secondary considerations
Patent Owner provided evidence of secondary considerations for an
exendin-albumin conjugate known as “PC-DAC
TM
: Exendin-4.” In making
an obviousness determination, secondary considerations must be considered
if present. Graham v. John Deere Co. of Kan. City, 383 U.S. 1, 17-18
(1966); TriMed Inc. v. Stryker Corp., 608 F.3d 1333, 1343 (Fed. Cir. 2010).
The exendin peptide PC-DAC
TM
: Exendin-4 is linked via its C-
terminal amino acid to albumin through a linker (PO Appeal Br. 15). During
prosecution, Patent Owner presented evidence said to show that PC-DAC
TM
:
Exendin-4 “unexpectedly reduces the incidence of nausea and vomiting in
Type 2 diabetic patients as compared to unconjugated exedin-4.” (Id.). The
data showing the reduction in nausea and vomiting said to be unexpected is
from page 17 of U.S. Patent Application No. 2007/0207958 (Application
Serial No. 11/595,576). We reproduce that table below:
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Exentide is synthetic exendin-4 and CJC-1134-PC is PC-DAC
TM
:
Exendin-4 (Patent Owner Remarks, dated May 5, 2009, p. 34). According to
Patent Owner on page 34 of those remarks:
Exenatide (synthetic exendin-4) is the active ingredient
of Byetta®. It is currently used at doses of 10 μg for the
treatment of type 2 diabetes. The table above shows that 35%
of patients receiving a single 10 μg subcutaneous dose of
exenatide experienced nausea and 21% experienced vomiting.
When PC-DAC™:Exendin-4 is dosed at 1250 μg, patients
experienced a glucose lowering response comparable to
exenatide dosed at 10 μg (patients showed a mean glucose
reduction from baseline of 15% to 25%). However, none of
these patients experienced nausea or vomiting. Even at doses
three times this amount (i.e., 3750 μg) the incidence of
nausea and vomiting were still lower than incidence of nausea
and vomiting of exenatide dosed at 10 μg. Furthermore, when
PC-DAC™:Exendin-4 is overdosed at 5000 μg, it still exhibits
fewer incidents of nausea and vomiting than exenatide that is
overdosed at 100 μg. Based on these unexpected results, any
indicia of obviousness are overcome.

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The Examiner found the evidence of reduced incidence of nausea and
vomiting insufficient to overcome the rejection. The Examiner states:
This finding is not disclosed in the patent specification, the
property is not the subject of the instant claims and there is
insufficient evidence to ascertain whether the property is related
to the specific albumin conjugate or to polymer conjugates in
general. The prior art already establishes a prima facie case for
the claimed compounds for the reasons of extending bioactivity
and half-life. Accordingly, the disclosure of a previously
unrecognized property is insufficient evidence to overcome the
instant prima facie case.
(RAN 20.)
The Examiner‟s failure to consider the evidence is improper.
Evidence of unexpected results does not have to appear in the patent
specification or to have been known at the time the patent application was
filed. Genetics Institute, LLC v. Novartis Vaccines and Diagnostics Inc.,
655 F.3d 1291, 1307 (Fed. Cir. 2011)(“Although the § 103 analysis remains
properly focused „at the time the invention was made,‟ it would be error to
prohibit a patent applicant or patentee from presenting relevant indicia of
nonobviousness, whether or not this evidence was available or expressly
contemplated at the filing of the patent application. . . . Relevant secondary
considerations often are not manifest even until well after the issuance of a
patent.”); Knoll Pharmaceutical Co. v. Teva Pharmaceutical USA Inc., 367
F.3d 1381, 1385 (Fed. Cir. 2004)(“Evidence developed after the patent grant
is not excluded from consideration, for understanding of the full range of an
invention is not always achieved at the time of filing the patent
application. . . . There is no requirement that an invention‟s properties and
advantages were fully known before the patent application was filed, or that
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the patent application contains all of the work done in studying the
invention, in order for that work to be introduced into evidence in response
to litigation attack.”); In re Chu, 66 F.3d 292, 299 (Fed. Cir. 1995)(“We
have found no cases supporting the position that a patent applicant‟s
evidence and/or arguments traversing a § 103 rejection must be contained
within the specification.”)
The results clearly show that the subjects administered a therapeutic
dosage of 1250 μg of PC-DAC
TM
: Exendin-4 experienced no nausea or
vomiting, while at an equivalent therapeutic dosage of 10 μg of exendin-4,
36% experienced nausea and 21% vomiting (above). This result
demonstrates that the albumin linkage of the exendin-albumin conjugate is
responsible for the reduction in nausea and vomiting since such adverse
side-effects were observed with the unconjugated exedin-4 but not with the
conjugate. Thus, the Examiner erroneously dismissed this evidence of
secondary considerations in considering whether the claims were obvious
over the prior art.
Evidence of secondary considerations must be “commensurate in
scope with the degree of protection sought by the claimed subject matter.”
In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005). This does not mean that
evidence must be presented for every embodiment which falls within the
scope of the claim. In re Glatt Air Techniques Inc., 630 F.3d 1026, 1030
(Fed. Cir. 2011) (“To the extent the PTO asserts that Glatt needed to submit
commercial success evidence from multiple embodiments for that evidence
to be commensurate in scope with claim 5, this position is not consistent
with our precedent. . . . Rather, we have consistently held that a patent
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applicant „need not sell every conceivable embodiment of the claims in order
to rely upon evidence of commercial success.‟ In re DBC, 545 F.3d 1373,
1384 (Fed. Cir. 2008)”). “If an applicant demonstrates that an embodiment
has an unexpected result and provides an adequate basis to support the
conclusion that other embodiments falling within the claim will behave in
the same manner, this will generally establish that the evidence is
commensurate with scope of the claims.” In re Kao, 639 F.3d 1057, 1068
(Fed. Cir. 2011).
In this case, claim 24 is drawn to “a therapeutically effective amount
of exendin-4 or an agonist analog of exendin 4 linked through the C-terminal
amino acid to one polymer selected from the group consisting of
polyethylene glycol and albumin.” PC-DAC
TM
: Exendin-4 is an exendin-4
linked at its C-terminal to albumin. Patent Owner has not provided evidence
that PEG, a polymer of ethylene oxide groups, would behave in the same
manner as albumin, a protein which is a polymer of amino acids. We do not
require Patent Owner to show data for every embodiment within the scope
of the claim, but they still must show that the results for the albumin-
exendin-4 conjugate would be reasonably expected for a PEG conjugate.
Such information has not been provided to us. Thus, the data provided by
Patent Owner is not commensurate with the full scope of claim 24.
On the other hand, claim 26 recites that the polymer is albumin. Thus,
with respect to this claim, we conclude that the evidence is sufficient to
show that the subject matter of claim 26 is not obvious in view of Knudsen I
‟990 in combination with Davis, Gombotz, Shearwater, Poznansky I (1984),
or Poznansky II (1988) because there is no evidence in the record that one of
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ordinary skill in the art would have expected that the claimed exendin-4-
albumin conjugate would reduce the symptoms of nausea and vomiting
otherwise experienced with unconjugated exendin-4.

Summary
For the foregoing reasons, we affirm the Rejection D of claim 24, and
claims 27-36 which were not separately argued. We reverse the rejection of
claim 26.
Rejection E
Claims 24, 26-31, 35, and 36 stand rejected under 35 U.S.C. § 103 as
obvious in view of Syed in combination with Eng or Knudsen I. Since we
have affirmed Rejection D of all the claims based on Knudsen I ‟990, it is
unnecessary for us to reach this rejection which is based on the same
teachings in Knudsen I ‟990 (RAN 12). The Examiner alternatively relied
upon Eng, but Eng‟s teaching are not as strong as Knudsen I ‟990‟s because
Eng is not said by the Examiner to teach improving the profile of action of
exendin as taught by Knudsen I ‟990 (KI3-KI6) The latter provides a clear
reason to have modified exendin with a reasonable expectation of success.
Thus, we do not reach Rejection E.

2. REJECTIONS BASED ON EDWARDS
Rejection H
Claims 24, 26, 27, and 29-36 stand rejected under 35 U.S.C. § 103 as
obvious in view of Edwards in combination with Chang II, Harlow and
Lane, and Poznansky I (1984).
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Findings of Fact
Edwards
E1. Edwards teaches synthetic exendin-4 conjugated with
glutaraldehyde to bovine serum albumin (Edwards, p. 87, col. 2, ¶ 4).
E2. The conjugate was used to make antiserum for the purpose of
detecting exendin (Edwards, p. 87, col. 2, ¶ 4).

Chang II ‟075
CII1. When using a peptide as an immunogen to elicit antibodies,
Chang II ‟075 teaches linking the peptide to a carrier protein via a lysine
residue at the peptide‟s C-terminal (Chang II ‟075, col. 7, ll. 23).

Harlow and Lane
HL1. Harlow and Lane is a laboratory manual on antibodies. Harlow
and Lane teach:
Coupling methods should be used that link the peptide to the
carrier via either the carboxy- or amino-terminal residue. When
preparing antibodies against the carboxy-terminal region of the
protein, the coupling should be done through the amino
terminus of the peptide. Similarly, the coupling for amino
terminal fragments should be done through the carboxy-
terminal region of the peptide. For internal fragments, the
major consideration is that the peptide be coupled by an end
and not through a central residue.
(Harlow and Lane, p. 77.)
HL2.
The easiest strategy to manipulate the type of coupling is
to add an extra amino acid on either the amino or carboxyl
terminus to allow simple, one-site coupling to the carrier. Any
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coupling method that potentially can bind to an internal residue
should be avoided.
(Harlow and Lane, p. 77.)
Rejection
Edwards describes exendin-4 joined to albumin, but not linked to a C-
terminal amino acid as recited in claim 24. However, the Examiner
provided evidence that it was conventional in the art to conjugate a carrier,
such as albumin, to the C-terminus of a peptide used to stimulate antibody
production (RAN 15).
Patent Owner contends the rejection is improper because 1) the
references do not account for one PEG or albumin coupled through the C-
terminal to an exendin; 2) based on the properties of glutaraldehyde, it
should not form a conjugate with the C-terminal amino acid of exendin-4;
3) Edwards is directed to a composition for eliciting antibodies and is not a
pharmaceutical composition; 4) the cited prior art does not describe a
linkage through the epsilon amino group of the C-terminal lysine (claims 32-
34) (PO Appeal Br. 27-29).
Discussion
Patent Owner distinguishes the claimed invention from Edwards,
arguing that Edwards‟s glutaraldehyde technique would not result in the
exendin-4 joined to albumin at the exendin‟s C-terminal amino acid.
However, the rejection is not based on Edwards alone. Rather, the Examiner
relied upon Edwards for the teaching of exendin-4 conjugated to albumin,
providing a reason to have made a conjugate of both proteins within the
scope of claim 24. The Examiner explicitly found that coupling to the C-
terminal of a peptide was conventional in the art as taught by both Chang I
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‟075 and Harlow and Lane (RAN 15). Contrary to Patent Owner‟s argument
about the cited prior art not teaching a single albumin or PEG conjugated to
exendin‟s C-terminus, Harlow and Lane teaches that the “easiest strategy to
manipulate the type of coupling is to add an extra amino acid on either the
amino or carboxyl terminus to allow simple, one-site coupling to the
carrier.” (HL2.) Patent Owner did not address this teaching in Harlow and
Lane.
Patent Owner also contends that following Edwards would not result
in the claimed “pharmaceutical composition for use in humans comprising a
pharmaceutically acceptable carrier.” (PO Appeal Br. 28). Patent Owner
contends that the preamble requires the exendin-albumin to be therapeutic
and for the composition to omit components such as adjuvants which are
typically present in compositions for raising antibodies as taught by Edwards
(PO Appeal Br. 28-29)
During reexamination, claims are given their broadest reasonable
interpretation as they would be understood by the skilled worker in light of
the patent specification. The claimed “pharmaceutical composition” is not
expressly defined in the ‟264 patent specification, but one of ordinary skill in
the art would understand that the composition is suitable for administration
to a subject for therapeutic purposes, particularly in view of the recitation
that there must be a “therapeutically effective amount of exendin-4.” Claim
24. The claim does not require the composition to have been administered
therapeutically, only that it be capable of this purpose. Accordingly, even if
the composition is made for a different purpose, it can still meet the
requirements of the claim if it is suitable for therapeutic administration.
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The fact that Edwards‟s conjugates were made as an immunogen to
elicit antibodies does not deter it from reading on claim 24 when modified
by the cited prior art. It is true that an immunogen composition can
comprise adjuvants which might be incompatible with a pharmaceutical
composition, but Harlow and Lane expressly describes compositions for
eliciting antibodies that lack such adjuvants and comprise physiological
buffers and salts (Harlow and Lane, pp. 102 and 110).
Claims 32-34 recite that the exendin “is linked to the polymer” of
claim 1 “through the epsilon amino group of the lysine amino acid.” As
indicated by the Examiner, Poznansky I (1984) teaches that a reactive group
available for cross-linking is the “epsilon amino group of lysine residues.”
(PII7.) Patent Owner did not identify a flaw in this teaching and we find
none.
Secondary considerations
For the reasons discussed above, we conclude that the secondary
considerations are adequate to establish the nonobviousness of claim 26, but
not claim 24 when considered in view of the cited prior art because the
showing is not commensurate in scope with the claimed subject matter.

Summary
For the foregoing reasons, we affirm the Rejection H of claim 24, and
dependent claims 27-36. We reverse the rejection of claim 26.

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Rejection I
Claims 24, 26, 27, and 29-36 stand rejected under 35 U.S.C. § 103 as
obvious in in view of Edwards in combination with Bernard and Harlow and
Lane. Since we have affirmed Rejection H based on Edwards, it is
unnecessary for us to reach this rejection which is based on the same
teachings in Edwards (RAN 15-16) and therefore is redundant and largely
duplicative.
3. REJECTIONS BASED ON ENG
Rejections A, B, and C appear to be substantially the same rejection as
Rejection D, but Eng is being relied upon for the teaching of exendin
conjugated to polymer, rather than Knudsen I ‟990. Eng‟s teachings differ
from Knudsen I ‟990‟s because Eng does not teach improving the profile of
action of exendin as taught by Knudsen I ‟990 (KI3-KI6) The latter
provided a clear reason to have modified exendin with a reasonable
expectation of success.
The Examiner referred to column 4, lines 53-56 of Eng as the reason
to conjugate albumin or PEG to exendin-4. Column 4, lines 53-56 read as
follows: “In addition, the invention also provides for the addition of amino
acids to enhance attachment to carrier molecules, or added to enhance the
insulinotropic effect.”
The Examiner has not provided sufficient evidence that the skilled
worker would have had reason to have utilized albumin or PEG as a “carrier
molecule.” The Examiner states that the skilled worker would be motivated
to modify exendin “for enhanced peptide drug delivery” (RAN 8), but the
Examiner did not provide sufficient evidence that exendin required enhanced
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delivery, would benefit from albumin and PEG, and that there would have
been a reasonable success in doing so.
The Examiner also did not provide evidence that albumin or PEG
would enhance the insulinotropic effect of exendin.
In view of these deficiencies and the showing that an embodiment
within the scope of the claim reduced nausea and vomiting, we will not
sustain these rejections.
Rejections F and G appear to be substantially the same rejection as
Rejection I, but Eng is being relied upon for the teaching of exendin
conjugated to a polymer, rather than Edwards. We affirmed the rejection
based on Edwards, in part because Edwards specifically teaches exendin
conjugated to albumin. This teaching is absent from Eng. Thus, we shall
not sustain Rejections F and G.

Summary
Rejections A, B, C, F, and G are reversed.

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-IN-PART

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28

peb

THIRD PARTY REQUESTER:

RAHUL PATHAK
JONES DAY
222 EAST 41ST STREET
NEW YORK, NY 10017

PATENT OWNER:

CONJUCHEM BIOTECHNOLOGIES INC.
225, PRESIDENT-KENNEDY AVENUE
MONTREAL, QC H2X3Y8