Ex Parte Bonny

Patent Trial and Appeal Board

Oct 11, 2018

13141314 (P.T.A.B. Oct. 11, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/141,314 11/14/2011
20999 7590 10/15/2018
HAUG PARTNERS LLP
745 FIFTH A VENUE - 10th FLOOR
NEW YORK, NY 10151
FIRST NAMED INVENTOR
Christophe Bonny
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
A385-14 4298
EXAMINER
NIEBAUER, RONALD T
ART UNIT PAPER NUMBER
1658
NOTIFICATION DATE DELIVERY MODE
10/15/2018 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):
docket@haugpartners.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte CHRISTOPHE BONNY
Appeal2017-004466 1
Application 13/141,314
Technology Center 1600
Before FRANCISCO C. PRATS, JEFFREYN. FREDMAN, and
DEBORAH KATZ, Administrative Patent Judges.
PRATS, Administrative Patent Judge.
DECISION ON APPEAL
This appeal under 35 U.S.C. § 134(a) involves a claim to a
polypeptide transporter construct composed of a combination of D-amino
acids and L-amino acids. The Examiner rejected the claim for obviousness.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
Appellant's invention involves a polypeptide construct that can be
conjugated to a variety of cargo moieties, such as proteins, peptides, nucleic
acids, cytotoxic agents, and organic molecules. Spec. 1. Conjugation to
1 Appellant states that the real party in interest in this appeal is Xigen
Inflammation, Ltd. Br. 1.
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Application 13/141,314
Appellant's polypeptide construct allows the cargo moiety to be transported
"into an organism, a tissue, a cell ( e.g. to be treated), a cellular
subcompartiment [sic] and/or into the nucleus of a cell." Id. at 9.
The Specification discloses that polypeptides capable of traversing
cell membranes include "[t]ranslocatory proteins [which] are considered as a
group of peptides capable of effecting transport of macromolecules between
cells (translocatory proteins), such as HIV-I TAT (HIV) .... " Id. at 5.
Appellant's invention is directed to the finding that configuring a
transport polypeptide, such as the HIV TAT protein, to have a particular
combination of D- and L-amino acids is advantageous in achieving optimal
duration of action of the cargo moiety within the target cell:
This inventive D-/L-pattem allows a skilled person to define the
in vivo or in vitro persistence of the inventive novel transporter
construct as defined above in the cell precisely enough as a time
sufficiently long to ensure administration and entering of the
inventive novel transporter construct into the cell or nucleus
prior to degradation of the inventive novel transporter construct
by proteases within a considerable time limit. This in vivo or in
vitro persistence of the inventive novel transporter construct in
the cell is in fact dependent on the specific content and position
of the D-amino acids in alteration with the specific content of
L-amino acids as defined in generic formula (I).
Id. at 9; see also id. at 8 (showing generic formula (I) of Appellant's
transporter polypeptide).
The Specification discloses:
As surprisingly found by the inventor[], such
advantageous properties may be conferred to a trafficking
sequence, particularly to any trafficking sequence known in the
art only by the inventive pattern (herein also described as D-/L-
pattem) of the above defined generic formula (I), the specific
content and position of the D-amino acids in alteration with the
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specific content of L-amino acids as defined in generic
formula (I).
Id. at 9.
More specifically, the Specification discloses that TAT transport
protein sequences, modified to have a combination of D- and L-amino acids
in accordance with generic formula (I), have a reduced proteolytic resistance
to human serum as compared to a TAT transport protein having all D-amino
acids, but have an increased proteolytic resistance to human serum as
compared to a TAT transport protein having all L-amino acids. Id. at 93,
101; see also Appellant's Figure 3.
Claim 1, the sole claim on appeal, reads as follows:
1. A transporter construct comprising a sequence selected
from the group consisting of an amino acid sequence
comprising rKKRrQRRr (SEQ ID N0:20) and an amino
acid sequence comprising rRRQrRKKr (SEQ ID N0:21 ),
wherein lowercase designations indicate D-amino acids
and uppercase designations indicate L-amino acids.
Br. A-1 (Claims App 'x).
The sole rejection before us for review is the Examiner's rejection of
claim 1, under 35 U.S.C. § I03(a), for obviousness over Hotchkiss. 2 Ans. 2-
3.
OBVIOUSNESS
The Examiner's Prima Facie Case
The Examiner cited Hotchkiss as disclosing membrane-permeant
peptides, including "a preferred embodiment of a peptide comprising
RKKRRQRRR (SEQ ID N0:7) and specifically recit[ing] RKKRRQRRR
(section 0082)," the same sequence as SEQ ID NO: 20 recited in Appellants'
2 US 2006/0166881 Al (published Jul. 27, 2006).
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claim 1, except for the specific pattern of D- and L-amino acids recited in
the claim. Ans. 2.
As to the requirement in Appellants' claim 1 for SEQ ID NO: 20 to be
composed of a specific pattern of D- and L-amino acids, the Examiner found
that Hotchkiss "expressly teach[ es that] incorporating D-amino acids is
particularly useful when stability is desired (section 0085) and suggest[s]
combinations of D and L-amino acids for the peptides (sections 0071 and
0085)." Id.
The Examiner reasoned that, because Hotchkiss "teach[ es] (page 8
section 0082 and example 1) a preferred embodiment of a peptide
comprising RKKRRQRRR (SEQ ID N0:7) one would be motivated to use
such compound as a starting point." Id.
Moreover, the Examiner reasoned, because Hotchkiss "expressly
teach[ es] incorporating D-amino acids is particularly useful when stability is
desired ( section 0085) and suggest[ s] combinations of D- and L-amino acids
for the peptides (section 0071 and 0085) one would be motivated to
incorporate D-amino acids with a reasonable expectation of success." Id. at
2-3.
Accordingly, the Examiner reasoned, an ordinary artisan would have
been motivated to "make a peptide comprising instant SEQ ID N0:20 thus
meeting the limitations as recited in instant claim 1. It is noted that the D
and L amino acids are of the same chemical composition ( compare MPEP
2144.09)." Id.
In particular, the Examiner noted, "[i]n the instant case, there are a
finite number of positions to use either the Dor L-amino acid." Id.
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Analysis
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden ... of presenting a
primafacie case ofunpatentability ....
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
In the instant case, having considered all of the evidence and
arguments presented by Appellant and the Examiner, Appellant does not
persuade us that the preponderance of the evidence fails to support the
Examiner's conclusion of obviousness as to claim 1.
Hotchkiss discloses "compositions for drug delivery by the use of
novel cell membrane-permeant peptide conjugate coordination and covalent
compounds having target cell specificity." Hotchkiss ,r 3.
Hotchkiss discloses that its drug delivery compositions are composed
of three components:
1) a cell membrane-permeant peptide sequence made up of D-
amino acids, L-amino acids or a combination of D- and L-
amino acids; 2) a functional or non-functional linker motif; and
3) a chelator moiety able to coordinate metals useful in medical
imaging and therapy (FIG. 1 ), or other cargo molecule such as a
diagnostic substance or pharmaceutically active agent.
Id. ,r 71 ( emphasis added).
Hotchkiss discloses that a preferred membrane permeant peptide
component of its compositions has the same sequence of amino acids as in
SEQ ID NO: 20 recited in Appellant's claim 1:
A preferred embodiment comprises Tat protein residues 48-57
(GRKKRRQRRR) (SEQ ID NO: 7). Residue number may be
selected or modified to achieve a desired level of cellular
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uptake as there is a correlation between decreased length of at
least some permeation peptides and decrease cellular uptake of
the conjugate. For example, to generate the sequences
identified as 13a, 14a, 15, 16, 17 of Table 2, one additional
amino acid was removed from the N-terminus of the longest
Tat basic domain sequence (RKKRRQRRR) while all other
aspects of the peptide remained the same.
Id. ,I 82.
Hotchkiss' s preferred construct, thus, differs from the construct
recited in Appellant's claim 1 only in that Hotchkiss's membrane permeant
peptide is not composed of the specific pattern of D- and L-amino acids
recited in Appellant's claim 1.
As noted above, however, Hotchkiss expressly discloses that its
membrane permeant peptide may be made up of "a combination of D- and
L-amino acids." Id. ,r 71.
Hotchkiss explains that the "incorporation of non-natural amino acids,
including synthetic non-native amino acids, substituted amino acids, or 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." Id. ,r 85
( emphasis added).
Hotchkiss describes a number of advantages of incorporating D-amino
acids into the membrane permeant peptide component of its constructs:
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
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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. As shown in Example 14, the
use of D-amino acids in the membrane permeant peptide greatly
increases the accumulation of linked drugs or other cargo
molecules into cells. 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. ,I 85.
Hotchkiss discloses that, although inclusion of D-amino acids into its
constructs imparts desirable properties, it is also desirable to include
L-amino acids in its constructs in certain circumstances:
Id.
On the other hand, when it is more desirable to allow the
peptide to remain active for only a short period of time, the use
of L-amino acids in the peptide can allow endogenous
peptidases in a cell to digest the peptide in vivo, thereby
limiting the cell's exposure to the membrane-permeant peptide
covalent and coordination complexes comprising the peptides
disclosed herein.
As to the inclusion of combinations of D- and L-amino acids in its
constructs, Hotchkiss discloses:
It will be apparent that it is possible to construct complexes in
which different portions contain either D- or L-amino acids.
For example and without limitation, it is possible to construct a
complex in which a cell permeant peptide and a metal chelator
comprised of D-amino acids are connected by a functional
linker comprised of L-amino acids. Other such combinations
be readily apparent to those of ordinary skill in the art and are
within the scope of the present invention.
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Id. ( emphasis added)
Given the teachings of Hotchkiss, we agree with the Examiner that an
ordinary artisan would have considered the construct recited in Appellant's
claim 1 prima facie obvious. As seen above, Hotchkiss's preferred
membrane permeant peptide differs from the 9 amino acid polypeptide of
SEQ ID NO: 20 recited in Appellant's claim 1 only in that Hotchkiss's
peptide is not composed of the specific combination of D- and L-amino
acids recited in claim 1. See Hotchkiss ,r 82.
As the Examiner pointed out, however, Hotchkiss states expressly that
its membrane permeant peptide may be composed of a combination of D-
and L-amino acids. Id. ,r 71. As seen above, Hotchkiss' s preferred
membrane permeant peptide sequence has only 9 amino acids, or at most 10
amino acids, each of which may be either a D- or L-amino acid. See id.
,r 82.
Accordingly, because Hotchkiss's preferred membrane permeant
peptide sequence has at most 10 amino acids, and because only two possible
options were available at each position, we agree with the Examiner's
finding that, when following Hotchkiss' s express teaching to prepare a
variant of its membrane permeant peptide composed of a combination of D-
and L-amino acids, an ordinary artisan was presented with a finite number of
options.
Moreover, because Hotchkiss states expressly that its membrane
permeant peptide may be composed of a combination of D- and L-amino
acids, and because the construct recited in Appellant's claim 1 is one species
of the finite set of possible combinations of D- and L-amino acids for
Hotchkiss' s preferred membrane permeant peptide, we discern no error in
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the Examiner's conclusion that the construct recited in Appellant's claim 1
would have been prima facie obvious to an ordinary artisan, particularly in
light of Hotchkiss' s teachings (Hotchkiss ,r 85) regarding the advantages of
using one or more D-amino acids in combination with L-amino acids. See
Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989)
(species claim held obvious where it recited one of 1200 possible
combinations of embodiments disclosed by reference and where reference
suggested no preference for claimed embodiment); see also id. at 808 (That
a reference "discloses a multitude of effective combinations does not render
any particular formulation less obvious.").
We acknowledge, but are unpersuaded by, Appellant's argument that
"Hotchkiss fails to provide any specific direction or guidance as to which
amino acid residues, if any, should be placed in the D configuration and
which amino acid residues, if any, should be placed in the L-configuration of
all of the cell membrane-permeant peptides disclosed." Br. 4--5; see also id.
at 6 ("While Hotchkiss may disclose an amino acid sequence that has the
same residues as the amino acid sequence of SEQ ID N0:20 in the present
application (see ,r 0082), Hotchkiss does not provide the precise arrangement
of D- and L- residues of the sequence.").
That Hotchkiss does not expressly disclose the precise arrangement of
D- and L-amino acids recited in Appellant's claim 1 does not demonstrate
that the construct recited in claim 1 would have been unobvious. See Dann
v. Johnston, 425 U.S. 219,230 (1976) ("[T]he mere existence of differences
between the prior art and an invention does not establish the invention's
nonobviousness. ").
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Moreover, as discussed above, Hotchkiss's preferred membrane
permeant peptide sequence has at most 10 amino acids, and may be
composed of as few as 9 amino acids. See Hotchkiss ,r 82. Only two
possible options were available at each position, either a D- or L-amino acid.
Thus, when following Hotchkiss' s express teaching to prepare a variant of
its membrane permeant peptide composed of a combination of D- and L-
amino acids (see id. ,r 71 ), an ordinary artisan was presented with a finite
number of possible combinations of D- and L-amino acids with respect to
Hotchkiss' s preferred membrane permeant peptide.
As also discussed above, and is undisputed on this record, the
construct recited in Appellant's claim 1 is one species of the finite set of
possible combinations of D- and L-amino acids for Hotchkiss' s preferred
membrane permeant peptide. Thus, rather than using hindsight to arrive at
the construct recited in Appellant's claim 1 based on the teachings in
Hotchkiss, an ordinary artisan need only have selected from the finite set of
possible combinations of D- and L-amino acids from which Hotchkiss' s
preferred membrane permeant peptide could be assembled. Because
arriving at the construct of claim 1 from the teachings of Hotchkiss only
required selecting from a finite set of suitable options, Appellant does not
persuade us that Hotchkiss failed to provide adequate guidance for preparing
Appellant's claimed construct.
We acknowledge Hotchkiss' s express disclosure of membrane
permeant peptides composed of only D-amino acids (see Hotchkiss ,r 83), as
well as the disclosure in Table 2 of Hotchkiss, in which only two of the
membrane permeant peptides, constructs 9i and 1 lk, included a mixture of
D- and L-amino acids (id. ,r 231 (Table 2)). We are not persuaded, however,
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that Hotchkiss teaches away from the construct recited in Appellant's claim
I. See Br. 7.
Specifically, contrary to Appellant's contention that Hotchkiss
suggests membrane permeant peptides composed of only D-amino acids,
Hotchkiss states expressly that its constructs may include "a cell membrane-
permeant peptide sequence made up of D-amino acids, L-amino acids or a
combination of D- and L-amino acids." Hotchkiss ,r 71 ( emphasis added).
Hotchkiss, moreover, discloses that its membrane permeant peptides
may include as few as one D-amino acid, or a simple majority of D-amino
acids. See id. ,r 83 ("In one preferred embodiment any of the
aforementioned membrane peptides may contain at least one D-amino acid.
In another preferred embodiment, a majority of the amino acid residues in
any of the aforementioned peptides can comprise D-amino acids.").
Appellant does not persuade us, therefore, that Hotchkiss teaches away from
the construct in claim 1 on appeal, which recites a construct composed of
three D-amino acids and six L-amino acids. See Br. A-1 (Claims App'x).
We acknowledge, as Appellant contends (see Br. 7), that "patents are
not barred just because it was obvious 'to explore a new technology or
general approach that seemed to be a promising field of experimentation,
where the prior art gave only general guidance as to the particular form of
the claimed invention or how to achieve it."' Procter & Gamble Co. v. Teva
Pharmaceuticals USA, Inc., 566 F.3d 989, 997 (Fed. Cir. 2009) (quoting In
re O'Farrell, 853 F.2d 894,903 (Fed. Cir. 1988)).
In the present case, however, rather than providing only general
guidance, Hotchkiss expressly identifies the amino acid sequence recited in
Appellant's claim 1 as being the sequence of a preferred membrane
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permeant peptide (Hotchkiss ,r 82), and teaches that substituting D-amino
acids for one or more of the amino acids in any of the peptides in its
constructs provides advantages as to therapeutic properties of the resulting
construct (see id. ,r,r 83, 85). Thus, rather than providing only general
guidance, Hotchkiss identifies a specific 9 amino acid transport peptide, and
teaches that any number of the amino acids in that peptide can be either a D-
or L-amino acid, thereby providing a limited and finite set of options from
which to choose, to impart to the preferred transport peptide the therapeutic
advantages taught in the reference.
We acknowledge, but are unpersuaded by, Appellant's contention that
the construct recited in claim 1 has properties that an ordinary artisan would
have considered to be unexpected. See Br. 6-8. In particular, we
acknowledge the data in Appellant's Figure 3, which shows that, when
treated in either 10% or 50% human serum, TAT peptides corresponding to
the sequences in Appellant's claim 1 were essentially undigested for the 28
day treatment period when formed of all D-amino acids, but were entirely
digested after 72 hours by the proteases in the serum when formed of all L-
amino acids. See Appellant's Figure 3.
We acknowledge, as also seen in Appellant's Figure 3, that the TAT
peptides having the specific combination of D- and L-amino acids recited in
Appellant's claim 1 were digested more slowly than the corresponding
peptides formed entirely of L-amino acids, and also that the D- and L-amino
acid combination peptides were ultimately digested by the proteases in the
serum, unlike the peptides formed entirely of D-amino acids. See id.
We further acknowledge Appellant's Specification characterizing
these results as "show[ing] a degradation within a suitable time limit,
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allowing to limit the in vivo stability for therapeutic applications." Spec
101.
We agree with the Examiner, however, that these results would have
been expected in view of Hotchkiss. See Ans. 5.
Specifically, as noted above, Hotchkiss discloses that "D-amino acid-
containing peptides exhibit increased stability in vitro or in vivo compared to
L-amino acid-containing counterparts" whereas "[ o ]n the other hand ... the
use of L-amino acids in the peptide can allow endogenous peptidases in a
cell to digest the peptide in vivo, thereby limiting the cell's exposure to the
membrane-permeant peptide covalent and coordination complexes
comprising the peptides disclosed herein." Hotchkiss ,r 85.
Based on these properties, Hotchkiss explains the desirability of
preparing constructs composed of combinations of D- and L-amino acids in
its constructs:
It will be apparent that it is possible to construct complexes in
which different portions contain either D- or L-amino acids.
For example and without limitation, it is possible to construct a
complex in which a cell permeant peptide and a metal chelator
comprised of D-amino acids are connected by a functional
linker comprised of L-amino acids. Other such combinations
be readily apparent to those of ordinary skill in the art and are
within the scope of the present invention.
Id. ( emphasis added).
Given Hotchkiss' disclosures that incorporating D-amino acids
imparts protease resistance to the transport protein constructs, and
incorporating L-amino acids allows protease digestion of the constructs, we
agree with the Examiner that an ordinary artisan would not have considered
it unexpected that constructs composed of combinations of D- and L-amino
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acids as taught by Hotchkiss would have a protease resistance somewhere
between the construct composed of all D- or all L-amino acids.
It is well settled, moreover, that "when unexpected results are used as
evidence of nonobviousness, the results must be shown to be unexpected
compared with the closest prior art." In re Baxter-Travenol Labs., 952 F.2d
388, 392 (Fed. Cir. 1991).
In the present case, as noted above, the comparison advanced by
Appellant to show unexpected results is between the claimed constructs and
constructs composed of either all D-amino acids, or all L-amino acids. See
Appellant's Fig. 3. As also noted above, and as Appellant concedes (see Br.
5), Hotchkiss discloses two constructs having a combination of D- and L-
amino acids, constructs 9i and 1 lk (see Hotchkiss ,r 231 (Table 2)).
Because Appellant did not compare the claimed constructs to the prior
art constructs having combinations of D- and L-amino acids, we are not
persuaded that Appellant compared the claimed constructs to the closest
prior art.
In sum, for the reasons discussed, Appellant does not persuade us that
Hotchkiss fails to suggest preparing the construct recited in Appellant's
claim 1. Also, for the reasons discussed, Appellant does not persuade us that
the objective evidence of nonobviousness in relation to unexpected results is
sufficient to outweigh the prior art evidence of obviousness. Accordingly,
weighing the evidence of record as a whole, we find that the preponderance
of the evidence supports the Examiner's conclusion of obviousness as to
claim 1. We, therefore, affirm the Examiner's rejection of claim 1 over
Hotchkiss.
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SUMMARY
For the reasons discussed, we affirm the Examiner's rejection of the
Examiner's rejection of claim 1, under 35 U.S.C. § 103(a), for obviousness
over Hotchkiss.
TIME PERIOD
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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