Ex Parte Bonny

Patent Trials and Appeals Board

Apr 15, 2019

14035450 - (D) (P.T.A.B. Apr. 15, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
14/035,450 09/24/2013
20999 7590 04/17/2019
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.
A385-2.13 3514
EXAMINER
LIEB, JEANETTE M
ART UNIT PAPER NUMBER
1654
NOTIFICATION DATE DELIVERY MODE
04/17/2019 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
Appeal2017-009011
Application 14/035,450 1
Technology Center 1600
Before JEFFREYN. FREDMAN, ELIZABETH A. LA VIER, and DAVID
COTTA, Administrative Patent Judges.
COTT A, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of inhibiting neuronal cell damage in a subject suffering from or being at
risk for developing Alzheimer's disease. The Examiner rejected the claims
on appeal as obvious under 35 U.S.C. § 103(a).
We AFFIRM.
1 According to Appellants, Xigen Inflammation, Ltd. is the real party in
interest. App. Br. 1.
Appeal 2017-009011
Application 14/035,450
STATEMENT OF THE CASE
The Specification discloses that "[t]he c-Jun amino terminal kinase
(JNK) is a member of the stress-activated group of mitogen-activated protein
(MAP) kinases" and that "[t]hese kinases have been implicated in the control
of cell growth and differentiation, and, more generally, in the response of
cells to environmental stimuli." Spec. 1. The Specification also discloses
that "JNK has been implicated in .... oncogenic transformation[,] ...
mediating adaptive responses to environmental stress[,] ... modulating
immune responses, [ and] ... effecting programmed cell death in cells
identified for destruction by the immune system." Id. According to the
Specification, "[t]he present invention is based in part on the discovery of
peptides that are effective inhibitors of JNK proteins." Id. "The invention
... provides a method of preventing or treating neuronal death or brain
lesions in a subject" by "administering to the subject a cell-permeable
bioactive peptide which prevents damage to the neurons or neuronal
apoptosis," including by administering "e.g., a JNK-inhibitor ('JNKI')
peptide." Id. at 3.
Claims 1, 3, 4, 13, 14, 16, 18, and 20-22 are on appeal. Claim 1 is
illustrative and reads as follows:
1. A method of inhibiting neuronal cell damage in a subject
suffering from or being at risk for developing Alzheimer's
disease, comprising administering to the subject prior to
identification of said cell damage a composition comprising a
peptide having an amino acid sequence with at least 95%
sequence identity to SEQ ID NO: 24.
App. Br., Claim App. A-1.
2
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Application 14/035,450
The Examiner rejected claims 1, 3, 4, 13, 14, 16, 18, and 20-22 under
35 U .S.C § I03(a) as obvious over the combination ofBonny2 and Liu. 3
FINDINGS OF FACT
1. The Specification identifies SEQ ID N0:24 as:
TDQSRPVQPF LNL TTPRKPR PPRRRQR RKKRG.
2. Bonny discloses:
Stress conditions and proinflammatory cytokines activate the c-
Jun NH2-terminal kinase (JNK), a member of the stress-
activated group of mitogen-activated protein kinases (MAPKs ).
We recently demonstrated that inhibition of JNK signaling with
the use of the islet-brain (IB) 1 and 2 proteins prevented
interleukin (IL )-1 B-induced pancreatic B-cell death. Bioactive
cell-permeable peptide inhibitors of JNK were engineered ...
Kinase assays indicate that the inhibitors block activation of the
transcription factor c-Jun by JNK .... All-D retro-inverso
peptides penetrate cells as efficiently as the L-enantiomers,
decrease c-Jun activation by JNK, and remain highly stable
inside cells. These latter peptides confer full protection against
IL- I B-induced apoptosis for up to 2 weeks of continual
treatment with IL- I B
Bonny Abstract.
3. Bonny discloses that the L-enantiomer of JNKI 1 has the
sequence: GRKKRRQRRRPPRPKRPTTLNLFPQVPRSQDT. Id. at
78 and Fig. 1.
4. The Examiner finds, and Appellant does not dispute, that the D-
retro-inverso peptide of JNKII is TDQSRPVQPFLNLTTPRKPRPPRRRQ
RRKKRG. Ans. 3. The sequence of the D-retro-inverso peptide of JNKII
2 Bonny et al., Cell-Permeable Peptide Inhibitors of JNK, Novel Blockers of
/J-Cell Death, Diabetes, Vol. 50, 77-82 (2001) ("Bonny").
3 Liu, US 2003/0148395 Al; published Aug. 7, 2003.
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Application 14/035,450
is identical to the sequence of SEQ ID N0:24 of the present application.
5. Bonny discloses:
[W]e obtained chemically synthesized cell-permeable JNK-
ligands that block JNK-mediated activation of c-Jun, penetrate
B-cells throughout the cytoplasm and the nucleus, and prevent
IL-I B-induced apoptosis. Furthermore, we show that synthesis
of the all-D retro-in verso form of these peptides produces
molecules that conserve all of the essential biological properties
of the L-enantiomers. However, their markedly expanded half-
life in vivo allows for the continuous protection against IL- I B-
induced apoptosis for several days to weeks.
Id. at 78.
6. Bonny discloses: "We synthesized an all-D retro-inverso
peptide. Thereafter, this peptide was referred to as D-JNKII to
discriminate it from its L-enantiomeric counterpart .... D-JNKII
inhibited phosphorylation of c-Jun, although at a level that is about 15-
to 20-fold less than that of (L-) JNKII (Fig. 4B)." Id. at 79.
7. Bonny discloses:
The above data indicated that the cell-permeable peptides might
reduce the biological effects of activated JNK. Addition of the
JNKI peptides inhibited IL-IB-induced apoptosis of the insulin-
secreting BTC-3 cells (Fig. 7 A). To achieve this level of
protection, JNKI peptides (1 µmol/1) have to be added every
day during the treatment period with IL-I B. No protection is
observed after 2 days of incubation with one single addition of
peptides ( data not shown). In contrast, one single addition of D-
JNKII (1 µmol/1) completely protected BTC-3 cells for up to 2
weeks of continual incubation with IL- I B (Fig. 7B).
Id. at 80.
8. Bonny discloses that "JNK targets are mainly transcription
factors including c-Jun, ATF2, Elkl, c-myc, or p53. Thus, JNK probably
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Application 14/035,450
acts by modifying the expression of genes that play an important role in
controlling cell death or survival." Id.
9. Liu discloses:
The present invention describes methods for identifying
compounds that inhibit JNK and MLK kinase activity as drugs
for treating a mammal susceptible to or having a neurological
condition. This invention also discloses methods for preventing
neuronal cell death and treating neurological conditions that
involve neuronal cell death, particularly neurodegenerative
diseases characterized by glutamine or kainate mediated
toxicity, such as Huntington's disease and Alzheimer's disease.
Liu Abstract.
10. Liu discloses
This invention relates to the discovery that inhibiting a JNK or
MLK within a hippocampal neuronal cell can protect the cell
from apoptosis. As such, JNK and MLK can be used as drug
targets to screen for therapeutic agents to prevent glutamate or
kainic acid mediated toxicity, to block excitotoxicity and to
prevent neuronal loss in a variety of neurological conditions,
such as Huntington's disease and Alzheimer's disease.
Liu i17.
11. Liu discloses:
The JNK kinases phosphorylate and activate the transcription
factor c-Jun which mediates apoptosis. Recent studies suggest
that c-Jun may serve as an important mediator for neuronal
apoptosis induced by a variety of environmental stresses. In
primary cultured sympathetic, hippocampal or cerebellar
granule neurons, deprivation of growth factor in these primary
cultures lead to persistent activation of JNKs and consequently
the phosphorylation of c-Jun. Ham, J., et al., Neuron, 14:927-
939 (1995); Xia, Z., et al., Science, 270:1326-1330 (1995).
Suppression of c-Jun expression by antisense-oligonucleotides,
or functional blockade by microinjection of antibodies or
expression of dominant negative c-Jun prevents neuronal
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Application 14/035,450
apoptosis; in contrast, over-expression of c-Jun induces
apoptosis in sympathetic neurons.
Id. ,I 34.
12. Liu discloses: "By inhibiting JNK's activity with an agent,
neuronal cell death can be avoided. The JNK activity to be targeted includes
JNKl, JNK2 and JNK3 .... This therapeutic approach can be used to
prevent and/or treat neurological conditions, as described above." Id. ,r 57.
13. Liu studied "the role of activation of the JNK activation in
Alzheimer diseases." Id. ,I,I88-90. Liu concluded that "the elevation of the
JNK activity is a common cause of neuronal cell death, regardless of the
cause" and that "inhibition of the JNK activity will prevent neuronal death in
these neurological conditions." Id. ,r 91.
ANALYSIS
Appellants argue claims 1, 3, 4, 13, 14, 16, 18, and 20-22 together.
We designate claim 1 as representative.
In finding claim 1 obvious, the Examiner found that Bonny disclosed
that JNKil is a JNK inhibitor that blocks c-Jun phosphorylation and protects
B-cells from apoptosis. Ans. 2-3. The Examiner further found that Bonny
disclosed the amino acid sequence of the L-enantiomer of JNKI 1 and taught
that the D-retro-inverso peptide of JNKil penetrated cells and inhibited c-
Jun phosphorylation as efficiently and effectively the L-enantiomer. Id. The
Examiner also found that the D-retro-inverso peptide of JNKil had an amino
acid sequence identical to SEQ ID N0:24 of claim 1. Id.
The Examiner acknowledged, however, that Bonny did not teach that
the D-retro-inverso peptide of JNKil "specifically treats or inhibits neuronal
cell death and Alzheimer's." Id. at 3. To address this deficiency, the
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Application 14/035,450
Examiner relied on Liu as teaching that "JNK inhibitors which target JNKl,
JNK2 and JNK3 can be used to prevent neuronal cell death and treat
diseases such as Alzheimer's." Id. Based on the combination of Bonny and
Liu, the Examiner concluded that it would have been obvious to "to have
taken the D-JNKI 1 of Bonny and administered it to a patient in order to treat
or prevent neuronal cell death and Alzheimer's disease." Id. The Examiner
explained that the ordinary artisan "would have been motivated to use the
JNK inhibitor of Bonny, D-JNKil, to inhibit neuronal cell death and treat or
prevent Alzheimer's because Liu teaches that JNKl inhibitors reduce
neuronal cell apoptosis, which treats Alzheimer's when administered to
subjects." Id.
We adopt the Examiner's findings of fact and reasoning regarding the
scope and content of the prior art (Final Act. 4 2-8; Ans. 2-11) and agree
with the Examiner that claim 1 would have been obvious over the
combination of Bonny and Liu. We address Appellant's arguments below.
Appellant argues that Bonny is "directed towards in vitro studies of B-
cell apoptosis" and is "silent regarding any in vitro or in vivo studies
regarding the inhibition of neuronal cell death or the treatment of a neuronal
disorder, such as Alzheimer's disease." App. Br. 4. We are not persuaded.
The Examiner relied upon Bonny for its teaching that D-JNKI 1
(which is identical to SEQ. ID N0:24 of claim 1) is a JNK inhibitor that
blocks c-Jun phosphorylation and protects B-cells from apoptosis. Ans. 2-3;
FF2-8. The Examiner did not rely upon Bonny as teaching treatment of a
neuronal disorder, such as Alzheimer's disease, instead relying on Liu for
this teaching. Appellant "cannot show non-obviousness by attacking
4 Office Action mailed May 2, 2016 ("Final Act.").
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Application 14/035,450
references individually where, as here, the rejections are based on
combinations of references." In re Keller, 642 F.2d 413,426 (CCPA 1981).
Appellant acknowledges that Liu discloses "methods for preventing
neuronal cell death and treating neurological conditions that involve
neuronal cell death" but argues that "[t]he Liu reference ... fails to disclose
any evidence or data to support such methods." App. Br. 4. More
specifically, Appellant argues that "Liu does not demonstrate that JNK was
actually inhibited in any of the experiments" and that "Liu does not provide
any in vivo results related to the inhibition of neuronal cell death." Id. We
are not persuaded.
There is no requirement for in vivo data or clinical testing to support a
finding of obviousness; all that is required is that the prior art suggest
carrying out the claimed method and provide a reasonable expectation that it
would work. In re Dow Chemical Co., 837 F.2d 469,473 (Fed. Cir. 1988)
("The consistent criterion for determination of obviousness is whether the
prior art would have suggested to one of ordinary skill in the art that this
process should be carried out and would have a reasonable likelihood of
success, viewed in the light of the prior art."). Here, Liu suggests using a
JNK inhibitor to treat Alzheimer's disease and prevent neuronal death (FF9-
13) and Bonny identifies a JNK inhibitor that has been shown to prevent !L-
IB-induced apoptosis. FF2-8. The combined teachings of Liu and Bonny
provide a reasonable expectation that carrying out the claimed method
would be successful. See e.g., FFI3 ("[I]nhibition of the JNK activity will
prevent neuronal death in these neurological conditions.").
Appellant argues that "there is nothing of record, other than hindsight
analysis, to suggest that one of skill would have been motivated to employ a
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Application 14/035,450
JNK inhibitor in inhibiting neuronal cell damage or treating Alzheimer's
disease." App. Br. 5. We are not persuaded.
As our reviewing court's predecessor stated in In re McLaughlin, 443
F.2d 1392, 1395 (CCPA 1971):
Any judgment on obviousness is in a sense necessarily a
reconstruction based upon hindsight reasoning, but so long as it
takes into account only knowledge which was within the level
of ordinary skill at the time the claimed invention was made
and does not include knowledge gleaned only from applicant's
disclosure, such a reconstruction is proper.
Here, we find no evidence that the Examiner gleaned anything from
Appellant's disclosure in reaching the conclusion that claim 1 would have
been obvious. It is clear from the Examiner's discussion of the references
that the Examiner relied only on what was known to one skilled in the art
prior to the time the invention was made.
Appellant contends that Liu fails to provide motivation to use the JNK
inhibitor of Bonny for inhibiting neuronal cell death in a subject suffering
from or being at risk for developing Alzheimer's disease because Liu's
statements on treating Alzheimers "are not supported by sound evidence or
data." Id. at 6. As evidence, Appellant relies on the testimony of Dr.
Jacques Hugon. 5 Dr. Hugon testifies that the ordinary artisan would not rely
upon Liu because it lacks confirmatory experimental data (Hugon Deel.
,r,r 9-11, and 20), because any inhibition of cell death "could theoretically
result from inhibition of p38, rather than JNK" (id. ,r 12), because Dr. Hugon
could not determine the "precise identity of the inhibitor used in Liu" (id.
5 Declaration of Dr. Jacques Hugon under 37 C.F.R. § 1.132, executed
December 21, 2015 ("Hugon Deel.").
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n 13-18), and because Liu is "not a peer-reviewed publication." Id. ,r 19.
We are not persuaded.
As an initial matter, we do not accept Appellant's premise that it
requires a high degree of scientific certainty to render it obvious to extend
Bonny's teaching of using a JNK inhibitor to prevent pancreatic B-cell death
to using a JNK inhibitor to prevent the death of another type of cell. All that
is required to establish obviousness is a reasonable expectation of success.
See, In re O'Farrell, 853 F.2d 894, 903---04 (Fed. Cir. 1988) ("Obviousness
does not require absolute predictability of success .... For obviousness
under section 103, all that is required is a reasonable expectation of
success.").
Here, Liu' s teaching that inhibition of JNK prevents neuronal cell
death (FF 10, FF 12, and FF 13) by suppressing expression of c-Jun (FF 11) is
consistent with Bonny's teaching that inhibition of JNK prevents pancreatic
B-cell death by blocking activation of the transcription factor c-Jun. FF2,
FF7, and FF8. Liu and Bonny thus both teach that JNK inhibitors prevent
cell death by the same mechanism of action - by suppressing c-Jun. This
creates a reasonable expectation that that Bonny's JNK inhibitors would be
successful if used as taught in Liu. While we disagree with Appellant that
Liu is unreliable, and in fact agree with the Examiner that Liu is reliable for
the reasons set forth in the Examiner's Answer (see Ans. 7-11), we find that
the consistency in Bonny and Liu's teachings, particularly with respect to
mechanism of action, would assuage any concerns an ordinary artisan might
have had about that Liu's reliability. 6
6 Neither Appellant nor Dr. Hugon questions the reliability of Bonny's
teachings.
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Application 14/035,450
With respect to Dr. Hugon's inability to determine the "precise
identity of the inhibitor used in Liu," we note that the Examiner relies on the
inhibitor disclosed in Bonny, not the inhibitor disclosed in Liu. Moreover,
we find that Dr. Hugon' s inability to identify the inhibitor used in Liu does
not render Liu unreliable. To the contrary, we find Liu reliable for the
reasons discussed above and for the reasons discussed in the Examiner's
Answer.
Accordingly, we affirm the Examiner's rejection of claim 1 as
obvious over the combination of Bonny and Liu. Because they were not
argued separately, claims 3, 4, 13, 14, 16, 18, and 20-22 fall with claim 1.
SUMMARY
For these reasons and those set forth in the Examiner's Answer and Final
Office Action, we affirm the Examiner's rejection of claims 1, 3, 4, 13, 14, 16,
18, and 20-22 under 35 U.S.C. § I03(a) as obvious over the combination of
Bonny and Liu.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § l.I36(a)(l).
AFFIRMED
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