Ex Parte BonnyDownload PDFPatent Trial and Appeal BoardJul 25, 201713244582 (P.T.A.B. Jul. 25, 2017) Copy Citation 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 2 Appeal 2015-008223 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). 3 Appeal 2015-008223 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 4 Appeal 2015-008223 Application 13/244,582 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 5 Appeal 2015-008223 Application 13/244,582 “[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 6 Appeal 2015-008223 Application 13/244,582 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 7 Appeal 2015-008223 Application 13/244,582 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; 8 Appeal 2015-008223 Application 13/244,582 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). 9 Appeal 2015-008223 Application 13/244,582 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). 10 Appeal 2015-008223 Application 13/244,582 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 11 Copy with citationCopy as parenthetical citation