Ex Parte Bonny

Patent Trial and Appeal Board

Jul 25, 2017

13244582 (P.T.A.B. Jul. 25, 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.
13/244,582 09/25/2011 Christophe Bonny 067802-5006-11 3261
MORGAN LEWIS & BOCKIUS LLP (WA)
1111 PENNSYLVANIA AVENUE NW
WASHINGTON, DC 20004
EXAMINER
LEE, JAE W
ART UNIT PAPER NUMBER
1656
NOTIFICATION DATE DELIVERY MODE
07/27/2017 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
patents @ morganlewis.com
karen.catalano @ morganlewis.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte CHRISTOPHE BONNY
Appeal 2015-008223
Application 13/244,582
Technology Center 1600
Before CHRISTOPHER G. PAULRAJ, TAWEN CHANG, and
RYAN H. FLAX, Administrative Patent Judges.
PAULRAJ, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims to a D-
enantiomeric peptide. The Examiner rejected the claims for obviousness.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
Background
The invention described in the Specification “relates generally to
protein kinase inhibitors and more specifically to inhibitors of the protein
kinase c-Jun amino terminal kinase,” which are “implicated in the control of
1 Appellant identifies the Real Party in Interest as Xigen Inflammation, Ltd.
See Appeal Br. 4.
Appeal 2015-008223
Application 13/244,582
cell growth and differentiation, and, more generally, in the response of cells
to environmental stimuli.” Spec. 1,11. 6-10. “The JNK inhibitor peptides
can be polymers of L-amino acids, D-amino acids, or a combination of
both,” and “in various embodiments, the peptides are D retro-inverso
peptides.” Id. at 6,11. 14-16. According to the Specification:
The term “retro-inverso isomer” refers to an isomer of a linear
peptide in which the direction of the sequence is reversed and
the chirality of each amino acid residue is inverted. . . . The net
result of combining D-enantiomers and reverse synthesis is that
the positions of carbonyl and amino groups in each amide bond
are exchanged, while the position of the side-chain groups at
each alpha carbon is preserved. Unless specifically stated
otherwise, it is presumed that any given L-amino acid sequence
of the invention may be made into an D retro-inverso peptide
by synthesizing a reverse of the sequence for the corresponding
native L-amino acid sequence.
Id. at 6 11. 16-23.
As one such example, the Specification identifies the retro-inverso
peptide analog of the naturally occurring “TAT” protein (SEQ ID NO: 8),
and notes that such an “all-D retro-inverso peptide of the invention would
provide a peptide with functional properties similar to the native peptide,
wherein the side groups of the component amino acids would correspond to
the native peptide alignment, but would retain a protease resistant
backbone.” Id. at 32,11. 7-29 (Example 9).
The Claims
Claims 38, 39, 41, and 44 are under appeal, and are reproduced in the
Claims Appendix of the Appeal Brief. Independent claim 38 is
representative, and reads as follows:
38. A D-enantiomeric peptide comprising the amino
acid sequence of SEQ ID NO: 8, wherein each of the amino
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Application 13/244,582
acids in the amino acid sequence of SEQ ID NO:8 is in the D-
enantiomeric configuration, and said D-enantiomeric peptide
facilitates transport across a biological membrane.
Appeal Br. 24 (Claims App’x).
The Rejection
The Examiner has rejected the claims under 35 U.S.C. § 103(a) as
being unpatentable over the combination of Piwnica-Worms,2 Huq,3 and
Wang.4
FINDINGS OF FACT
We adopt the Examiner’s findings of fact. We highlight the following
for emphasis.
FF1. Claimed SEQ ID NO:8 is as follows: RRRQRRKKRG.
Spec. 5 (Table 1).
FF2. Piwnica-Worms is directed to membrane-permeable
peptide complexes for medical imaging, diagnostics,
pharmaceutical therapy. Piwnica-Worms, Title. One preferred
embodiment of a peptide taught by Piwnica-Worms comprises
Tat protein residues 48-57 (GRKKRRQRRR) (SEQ ID NO:7).
Id. at col. 13,11. 49-50.
FF3. Piwnica-Worms teaches:
The incorporation of non-natural amino acids, including
synthetic non-native amino acids, substituted amino acids, or
2 Piwnica-Worms (US 6,348,185 Bl, iss. Feb. 19, 2002).
3 Huq et al., Specific Recognition of HIV-1 TAR RNA by a d-Tat Peptide,
Nature Publishing Group, 4 Nature Structural Bio. 881-82 (Nov.
1997).
4 Wang (WO 98/47913, pub. Oct. 29, 1998).
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Application 13/244,582
one or more D-amino acids into the peptides (or other
components of the complexes) of the present invention
(subsequently referred to herein as ‘D-peptides’) is
advantageous in a number of different ways. D-amino acid-
containing peptides exhibit increased stability in vitro or in vivo
compared to L-amino acid-containing counterparts. Thus, the
construction of peptides incorporating D-amino acids can be
particularly useful when greater intracellular stability is desired
or required. More specifically, D-peptides are resistant to
endogenous peptidases and proteases, thereby providing better
oral transepithelial and transdermal delivery of linked drugs and
conjugates, improved bioavailability of membrane-permeant
complexes, and prolonged intravascular and interstitial lifetimes
when such properties are desirable. The use of D-peptides can
also enhance transdermal and oral transepithelial delivery of
linked drugs and other cargo molecules. Additionally, D-
peptides cannot be processed efficiently for major
histocompatibility complex class II-restricted presentation to T
helper cells, and are therefore less likely to induce humoral
immune responses in the whole organism.
Id. at col. 14,11. 5-27.
FF4. Piwnica-Worms states:
While the literature teaches that Tat peptide constructs and
similar membrane permeant peptides readily translocate into the
cytosolic and nuclear compartments of living cells, little is
known regarding the cellular retention characteristics over time
once the permeant peptide constructs are no longer in contact
with the cell surface from the extracellular fluid spaces.
Id. at col. 4,11. 52-58
FF5. Huq teaches a 36 amino acid D-Tat peptide, Tat (37-72),
with specific binding recognition of HIV-1 TAR RNA. Huq,
881. According to Huq, “the D-Tat peptide was able to bind
TAR RNA and failed to bind a mutant TAR RNA without the
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bulge residues” in a manner similar to the L-Tat. Id. at 882; see
also id. (“These findings show that a small Tat-derived D-Tat
peptide binds TAR RNA specifically and interacts in the
widened major groove of TAR RNA in a similar fashion to that
observed for L-Tat.”).
FF6. Huq teaches that “[sjince D-peptide ligands are resistant
to degradation by naturally occurring enzymes and do not
induce a vigorous humoural immune response, they may be
applied to control protein-nucleic acid interactions in vivo.” Id.
at 881.
FF7. Wang teaches a TAT RNA-binding domain peptide
analog wherein:
This compound is composed of all D-amino acids for the
purpose of stability against degradation; that is, to make it long-
lasting in vivo. Since the side chains are all pointing in the
wrong direction when L-amino acids are replaced by D-amino
acids (inverso or enantio effect), the side chains can be
reoriented to their correct positions by reversing the sequence
(retro effect). Another way to look at it is that all the side
chains in the retro-inverso peptide are in the correct spatial
positions when binding to their target, which is TAR RNA of
HIV-I, but the underlying peptide backbone is in the opposite
direction. The retro-inverso approach works when only the side
chains are important for interacting with the target and the
peptide backbone is not important for interacting with the
target, which appears to be true in this case.
Wang, 12.
FF8. Brugidou teaches that the retro-inverso form of a
homeobox-derived short peptide is rapidly internalized by
cultured neurons. Brugidou, Title. Brugidou further states that
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“[w]ith a cholesteryl moiety attached to the C-terminus to
increase its lipophilicity, the retro-inverso peptide was
internalized 8 times better than the L-form.” Id., Summary.
ANALYSIS
Claimed SEQ ID NO:8 is the retro-inverso isomer of SEQ ID NO:7 as
taught by Piwnica-Worms. Appeal Br. 14; Ans. 3; FF1-2. The Examiner
asserts, based on the teachings of Piwnica-Worms, Huq, and Wang, that it
would have been obvious to make a D-enantiomeric peptide comprising the
amino acid sequence of SEQ ID NO:8, wherein said peptide facilitates
transport across a biological membrane, as well as a transport protein
comprising (or consisting of) such a D-entantiomeric peptide. Ans. 3. The
Examiner contends that the skilled artisan would have been first motivated
to make the L-TAT sequence of Piwnica-Worm into the D-configuration “in
order to increase intracellular stability of the peptide by making more
resistant to cellular proteases, and use it to design ‘cell-permeable and stable
molecules for the control of cellular processes involving RNA-protein
interactions in vivo’ as taught by Huq.” Id. at 5. The Examiner also
contends “[o]ne would have been further motivated to reverse the D-TAT
sequence in order to re-orient the side chains of the D-TAT sequence to their
correct positions so that it mimics the orientation of the L-TAT as taught by
Wang.” Id. The Examiner asserts there would have been a reasonable
expectation of success “because the results of Piwnica-Worms, Huq et al.
and Wang et al. positively show that such retro D-TAT sequence can be
made and put on a target protein.” Id.
Appellant argues that Piwnica-Worms “does not teach an all D-
residue peptide as a cell membrane permeant,” and “[wjhile Worms does
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suggest replacing L-residues for D-residues to increase the stability of the
sequence, Worms does not teach any actual D-residue polypeptides being
synthesized or tested for their cell permeability.” Appeal Br. 16. Due to
unpredictability in the art, Appellant contends “it is difficult, if not
impossible, to a priori predict with any degree of certainty, or with any
reasonable expectation of success, whether a particular change in the
primary sequence of a peptide would lead to a functioning or a
nonfunctioning sequence.” Id. Appellant further contends that a “change in
chirality changes the orientation of the residue’s side chain, which can result
in poor or non-existent alignment between the peptide and its target.” Id.
Furthermore, given Piwnica-Worms’ disclosure of 28 different amino acid
sequences, Appellant contends “[tjhere is no guidance in Worms to single
out SEQ ID NO:7 as the starting point of a retro-inverso sequence
synthesis.” Id. at 17. Appellant argues that “Worms at best provides an
invitation for further experimentation,” but “[t]he level of experimentation
that is required to prove the general and vague concept set forth in Worms
by preparing all the various permutations of D- and L-polypeptides would
constitute undue experimentation.” Id.
Appellant also emphasizes that Wang indicates that “[t]he retro-
inverso approach works when only the side chains are important for
interacting with the target and the peptide backbone is not important for
interacting with the target, which appears to be true in this case” i.e., with
respect to RNA binding. Appeal Br. 13 (quoting Wang, 12). Appellant
notes that “[w]ith respect to cell membrane permeability, there is no
teaching in the cited references that it is only the side chain orientation that
is important,” and “[t]he ordinary artisan would not know a priori whether
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the backbone primary sequence is also important in cell membrane
permeability or not.” Id. at 18. Additionally, because a 10 residue
polypeptide is capable of forming secondary structures, such as an a-helix or
a (3-turn, Appellant argues that:
[i]t is a priori unclear to the ordinary artisan whether SEQ ID
NO:7 of Worms forms any secondary structures, whether the
putative secondary structure is required for the cell membrane
permeability of the sequence, and whether the retro-inverso
sequence, i.e., the claimed SEQ ID NO:8, would show the same
secondary structures.
Id.
Finally, with respect to Huq, Appellant argues that the reference does
not teach forming a retro-inverso sequence, and the fact that Huq shows that
RNA binding functionality was not affected for the 36 residue D-peptide
discussed therein as compared to the same 36 residue L-peptide “is not
indicative of the two sequences having the same functionality in cell
membrane permeability.” Id. at 20.
We determine that the Examiner has made a prima facie showing of
obviousness. We have considered Appellant’s arguments, which focus on
whether a skilled artisan would have known, a priori, or been able to
predict, with any degree of certainty or a reasonable expectation of success,
that the conversion of Piwnica-Worms’ SEQ ID NO:7 into its retro-inverso
isomer form (i.e., claimed SEQ ID NO:8) would result in a D-enantiomeric
Tat-peptide that retains cell membrane permeability. We are not persuaded
by these arguments.
Piwnica-Worms and Huq both provide a specific motivation to use a
D-enantiomeric Tat-peptide, which is to increase stability and reduce the
humoural immune response as compared to the L-peptide counterpart. FF3;
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FF6. Piwnica-Worms teaches that “Tat peptide constructs and similar
membrane permeant peptides readily translocate into the cystolic and
nuclear compartments of living cells,” and indicates that the use of D-
peptides can also improve bioavailability of such membrane-permeant
complexes. FF3; FF4. Additionally, Huq and Wang both teach that the use
of D-amino acids for Tat peptide analogs did not affect the peptide’s RNA
binding capability. FF5; FF7. In arriving at SEQ ID NO:8, a skilled artisan
would further have taken into account Wang’s teaching that “[sjince the
side chains are all pointing in the wrong direction when L-amino acids are
replaced by D-amino acids (inverso or enantio effect), the side chains can be
reoriented to their correct positions by reversing the sequence (retro effect).”
FF7.
We recognize that Wang indicates that “[t]he retro-inverso approach
works when only the side chains are important for interacting with the target
and the peptide backbone is not important for interacting with the target.”
FF7. Contrary to Appellant’s arguments, however, we do not agree that this
statement would have conferred upon the skilled artisan a lack of reasonable
expectation of success in arriving at the claimed sequence. By suggesting
that the skilled artisan must know “<2 priori” whether the backbone primary
sequence is important in cell membrane permeability and/or whether any
putative secondary structures required for cell membrane permeability will
be retained, Appellant seeks to impose an “absolute predictability”
requirement for obviousness. However, “[ojbviousness does not require
absolute predictability of success”; rather, “all that is required is a
reasonable expectation of success.” In re O'Farrell, 853 F.2d 894, 903-904
(Fed. Cir. 1988).
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In determining there is a reasonable expectation of success, we have
also taken into account the Examiner’s and Appellant’s arguments regarding
the teachings of Brugidou.5 The Examiner cites Brugidou as an “evidentiary
reference” teaching that “when making a retro-inverso form of L-
enantiomeric peptide capable of facilitating transport across a biological
membrane, the resulting D-enantiomeric peptide DOES NOT lose the
original function of facilitating transport across a biological membrane but
rather has increased the function of membrane transport due to being
resistant to proteolytic degradation.” Ans. 9; see also FF8. Appellant argues
that the Examiner misreads the results of Brugidou because, “[wjhile the
abstract does in fact show that a retro-inverso sequence was internalized 8
times faster than the L-form, the body of the reference shows that this is not
the result of a head-to-head study” since “[t]he internalized retro-inverso
sequence was the cholesterol moiety.” Reply Br. 10. Appellant further
argues that “Brugidou identifies at least two other factors besides side chain
orientation, i.e., the chirality and the rigidity of the side chains, that affect
the biological function of the retro-inverso sequence,” and this “add[s] to the
a priori unpredictability of this art.” Id. Appellant additionally contends
that “all of the peptides of Brugidou are biotinylated,” and the skilled artisan
would “immediately realize that cellular uptake can depend on additional
factors, such as the property of other compounds conjugated to the peptide.”
Id. at 10-11. Finally, Appellant contends that “Brugidou is directed to a 16-
mer region of a homeodomain of a 60-mer protein,” which “forms the third
5 Brugidou et al., Is Rapidly Internalised by Cultured Neurones: A New
Basis for an Efficient Intracellular Deliver System, 214 Biochem. and
Biophys. Res. Comms., 685-93 (1995).
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helix of the protein,” whereas “[t]he presently claimed subject matter is
directed to a 10-mer, which forms unstable secondary structures, if any at
all.” Id. at 11.
We are unpersuaded by Appellant’s arguments concerning Brugidou.
Although there may be additional moieties or conjugates included with
Brugidou’s D-enantiomeric peptide that contribute to its improved
membrane transport functionality, the record does not suggest that those
other features must necessarily be present in order for the peptide to be
internalized in the first place. As such, we find that a skilled artisan reading
the prior art relied upon by the Examiner in making the rejection, as
evidenced by Brugidou, would have had a reasonable expectation of success
in applying the retro-inverso approach to Piwnica-Worms’ SEQ ID NO:7 in
order to create a D-enantiomeric peptide that facilitates transport across a
biological membrane (i.e., the claimed SEQ ID NO:8).
SUMMARY
We affirm the rejection of claims 38, 39, 41 and 44 under 35 U.S.C.
§ 103(a) as being unpatentable over the combination of Piwnica-Worms,
Huq, and Wang.
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
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