Ex Parte Bonny

Patent Trials and Appeals BoardApr 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. Â§ 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. Â§ 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 Appeal 2017-009011 Application 14/035,450 The Examiner rejected claims 1, 3, 4, 13, 14, 16, 18, and 20-22 under 35 U .S.C Â§ 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. 3 Appeal 2017-009011 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 Âµmol/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 Âµmol/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 4 Appeal 2017-009011 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 5 Appeal 2017-009011 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 6 Appeal 2017-009011 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."). 7 Appeal 2017-009011 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 8 Appeal 2017-009011 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. Â§ 1.132, executed December 21, 2015 ("Hugon Deel."). 9 Appeal 2017-009011 Application 14/035,450 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. 10 Appeal 2017-009011 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. Â§ 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. Â§ l.I36(a)(l). AFFIRMED 11