Ex Parte Fuertes-Lopez et al

Patent Trial and Appeal BoardSep 30, 2014

10816591 (P.T.A.B. Sep. 30, 2014)

UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte LAURA FUERTES-LOPEZ and MARCOS TIMON-JIMENEZ ____________ Appeal 2011-008678 Application 10/816,591 Technology Center 1600 ____________ Before LORA M. GREEN, JEFFREY N. FREDMAN, and ANNETTE R. REIMERS, Administrative Patent Judges. REIMERS, Administrative Patent Judge. DECISION ON APPEAL STATEMENT OF THE CASE1 Laura Fuertes-Lopez and Marcos Timon-Jimenez (Appellants)2 appeal under 35 U.S.C. § 134(a) from the Examiner’s decision to reject claim 24. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 Claims 1–23 have been canceled. 2 The real party in interest is MOLOGEN AG. Appeal 2011-008678 Application 10/816,591 2 CLAIMED SUBJECT MATTER The claimed subject matter “concerns a DNA expression construct for the treatment of infections with leishmania, and a corresponding vaccine” (Spec. 1). Claim 24, the sole claim, recites: 24. A vaccine for vaccinating a living being against infections by leishmania, the said vaccine comprising: a DNA expression construct comprising covalently-closed, linear deoxyribonucleotide molecules; said deoxyribonucleotide molecules each comprising a linear double-stranded region; said double-stranded region comprising single strands being linked by short, single- stranded loops of deoxyribonucleic acid nucleotides; said double strand-forming single strands comprising: a terminator sequence, and a coding sequence encoding at least the p36 LACK antigen under control of a promoter sequence and operable in the living being to be immunized; said DNA expression construct being covalently linked to at least one oligopeptide to increase transfection efficacy; said at least one oligopeptide consisting of the amino acid sequence of SEQ ID 3. Appeal 2011-008678 Application 10/816,591 3 THE REJECTION The following rejection is before us for review: Claim 24 stands rejected under 35 U.S.C. § 103(a) as unpatentable over Gurunathan,3 Wittig,4 and Makkerh5. ANALYSIS The Examiner finds that Gurunathan “teaches a DNA expression construct encoding the p36 LACK antigen from Leishmania major operatively linked to the CMV promoter and a polyA sequence and the use of the construct as a vaccine to generate protective immunity against Leishmania major in a mammal” (Ans. 4). The Examiner finds that Wittig teaches dumbbell shaped DNA expression constructs comprising covalently closed linear DNA that contains only a coding sequence operably linked to a promoter and polyA termination sequence where the linear ends are linked by short single stranded loops of DNA, and wherein the construct is further covalently linked to a peptide which directs transport of the construct across a cell’s endosome or into the nucleus (Id.). 3 Gurunathan et al., Vaccination with DNA Encoding the Immunodominant LACK Parasite Antigen Confers Protective Immunity to Mice Infected with Leishmania major, 186 J. EXPERIMENTAL MEDICINE 1137-1147 (1997). 4 Wittig et al., US 6,451,593 B1, issued Sept. 17, 2002. 5 Makkerh et al., Comparative mutagenesis of nuclear localization signals reveals the importance of neutral and acidic amino acids, 6 CURRENT BIOLOGY 1025-1027 (1996). Appeal 2011-008678 Application 10/816,591 4 The Examiner finds that Wittig “teaches the use of the nuclear localization sequence (NLS) from SV40, a sequence which inherently comprises PKKKRKV” (Id.). The Examiner finds that Makkerh “teaches that the sequence consisting of PKKKRKV is the defined nuclear localization sequence of SV40, which can be used to target heterologous molecules to the nucleus” (id. at 5). The Examiner finds it obvious to make a dumbbell DNA construct according to the teachings of Wittig et al. which encodes p36 LACK as taught by Gurunathan et al., and which is further linked to the defined NLS peptide PKKKRKV as taught by Makkerh et al. Further, based on the substantial guidance for making dumbbell constructs provided by Wittig et al., the skilled artisan would have had a reasonable expectation of success in making a dumbbell DNA expression construct capable of being used as a vaccine against Leishmania major which encodes the p36 LACK antigen and which is covalently linked to a peptide such as the NLS PKKKRKV peptide from SV40 (Id.) “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). “If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.” Id. at 417. Gurunathan teaches a method of eliciting an immune response in a living being “using LACK DNA . . . against progressive, nonhealing infections with L. major” (Gurunathan 1142, col. 2). Gurunathan teaches Appeal 2011-008678 Application 10/816,591 5 that the DNA vaccine, when administered subcutaneously, induces a Th1 response to leishmanial antigens (Gurunathan 1142, col. 2; 1144, col. 2). Wittig teaches a DNA vaccine where the DNA expression construct is composed of a dumbbell shaped DNA with coding sequences under the control of a promoter (Wittig, col. 5, ll. 4–10, 54–63; col. 6, ll. 53–57; col. 8, ll. 24–26) where “peptides needed for the nuclear localization of the expression constructs can be linked to the construct in such a way, that after entering the cytosol of a cell said construct is transported by the translocation apparatus of the cell into nuclear compartments where it can be transcribed” (Wittig, col. 6, ll. 58–62). Wittig teaches the use of the SV-40 nuclear localization signal (Wittig, col. 5, ll. 4–10) as the peptide and Makkerh teaches that the “NLS [nuclear localization signal] of the simian virus 40 large T-antigen (SV40 T- ag) is a single cluster of basic amino acids . . . PKKKRKV132” (Makkerh 1025, abstract). Applying the KSR standard of obviousness to the findings of fact, we conclude that the person of ordinary skill would have reasonably modified the subcutaneously administered leishmanial DNA vaccine of Gurunathan to follow the DNA vaccine design of Wittig, including the localization peptide, since Wittig’s “constructs have none of the disadvantages of plasmid constructs, including their size, which inhibits fast transport into the cell’s nucleus, and the presence of unwanted background sequences, including bacterial sequences, which can lead to unintended immune responses” (Ans. 4–5; Wittig, col. 5, ll. 25–28). Such a combination is merely a “predictable use of prior art elements according to their established functions.” KSR, 550 U.S. at 417. Appeal 2011-008678 Application 10/816,591 6 Appellants contend that Gurunathan suggests that immunostimulatory bacterial sequences (CpG sequences) present in the plasmid encoding LACK contribute to the generation of IL-12 and IFN-γ and that a skilled artisan would not have been motivated to use the MIDGE vector, as taught by Wittig, which lacks the majority of these sequences to express p36 LACK (App. Br. 4–7, 12–13; Reply Br. 2–5). We are not persuaded. A teaching away requires a reference to actually criticize, discredit, or otherwise discourage the claimed solution. See In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004) (“The prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed”). Appellants do not identify any specific teaching in Gurunathan that teaches away from the use of Wittig’s vector, or even teaches away from the use of an expression vector that is reduced in size, such as Wittig’s vector. Further, Gurunathan does not teach that CpG sequences are either required or necessary (see Gurunathan 1137, col. 1), nor do Appellants identify any teaching in Wittig that CpG sequences should be avoided. Appellants’ claim does not exclude the inclusion of CpG sequences, nor does the claim exclude the use of any desired sequence whatsoever, where the discussion of the expression construct in claim 24 uses the open transitional phrase “comprising.” See Georgia-Pacific Corp. v. U.S. Gypsum Co., 195 F.3d 1322, 1327 (Fed. Cir. 1999) (The transitional term “comprising” is “inclusive or open-ended and does not exclude additional, unrecited elements or method steps”). Appeal 2011-008678 Application 10/816,591 7 Appellants contend that the combined teachings of Gurunathan, Wittig, and Makkerh do not provide a basis for a reasonable expectation for success (Appeal Br. 9–13). Specifically, Appellants contend that [i]n considering . . . the obviousness rejection, it is irrelevant whether or not the exact NLS peptide sequence was already known (Makkerh). The crucial selective step for the skilled practitioner is to decide from the 3 variants proposed in Wittig, a choice that only leads to uncertainty due to the insufficient disclosure in regards to likely success, and the sequence details of the various peptides (App. Br. 10). Appellants further contend that the Examiner has used impermissible hindsight (Reply Br. 3–4). We are not persuaded. Wittig teaches that “[p]eptide-nucleic acid- linkages with localization sequences are known for short DNA oligomers. Morris . . . describe the coupling of oligomers 18–36 base pairs in length, with a 27 amino acid residues containing peptide, which contains the nuclear localization sequence from SV40” (Wittig, col. 5, ll. 4–10). Makkerh teaches that the “NLS [nuclear localization signal] of the simian virus 40 large T-antigen (SV40 T-ag) is a single cluster of basic amino acids . . . PKKKRKV132” (Makkerh 1025, abstract). Appellants provide no evidence that the sequence would be insufficient to direct a target to the nucleus of a cell, while Wittig teaches the use of the SV-40 nuclear localization signal as the peptide (Wittig, col. 5, ll. 4–10) and Makkerh directly teaches that this sequence is the element required for such nuclear localization (Makkerh 1025, abstract). In O’Farrell, the court found that [t]he admonition that “obvious to try” is not the standard under § 103 has been directed mainly Appeal 2011-008678 Application 10/816,591 8 at two kinds of error. In some cases, what would have been “obvious to try” would have been to vary all parameters or try each of numerous possible choices until one possibly arrived at a successful result, where the prior art gave either no indication of which parameters were critical or no direction as to which of many possible choices is likely to be successful. ... In others, what was “obvious to try” was 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. In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988). This is not a case where the prior art gave no direction or indication of the critical parameters. To the contrary, Wittig provides the specific type of nuclear localization signal required by claim 24 (Wittig, col. 5, ll. 4–10) and Makkerh provides the function SV-40 large T antigen NLS sequence necessary for nuclear localization (Makkerh 1025, abstract). This is also not a situation where only general guidance was provided, since Gurunathan, Wittig, and Makkerh provide specific details and a detailed enabling methodology for making DNA vaccines which result in a Th1 response to leishmanial antigens (Gurunathan 1142, col. 2; 1144, col. 2), dumbbell shaped DNA vaccine expression vectors (Wittig, col. 5, ll. 54–63; col. 8, ll. 24–26) linked to NLS peptides (Wittig, col. 5, ll. 4–10) and the SV-40 large T antigen nuclear localization signal (Wittig, col. 5, ll. 4–10; Makkerh 1025, abstract). Contrary to Appellants’ assertion, the Examiner’s rejection does not include knowledge gleaned only from the Appellants’ disclosure. Rather, for the reasons discussed above, the rejection takes into account the teachings of Gurunathan, Wittig, and Makkerh, i.e., knowledge that was Appeal 2011-008678 Application 10/816,591 9 within the level of ordinary skill at the time the claimed invention was made. See In re McLaughlin, 443 F.2d 1392, 1395 (CCPA 1971). Appellants contend that (1) “the functional unit or the basic peptide of the NLS sequence as applied in the present application [PKKKRKV] is identical to that as referred to by Dr. Timon-Jimenez in the declaration [PKKKRKVEDPYC]” (Appeal Br. 11–12; Jimenez Declaration, para. 3, 7 (citing the Lopez-Fuertes reference, see 248, col. 2 (“[t]he NLS peptide[]PKKKRKVEDPYC”))6,7; (2) “[t]his simply constitutes the SV40 NLS with a non-functional additional linker sequence, namely EDPYC” (Id. at 11); (3) “the claim requires a PKKKRKV sequence. A nonfunctional additional portion of EDPYC therefore does not change the scope of the claim” (Reply Br. 5); and (4) the use of a MIDGE vector produced an unexpected result (Appeal Br. 12–13; Jimenez Declaration, para. 7). We are not persuaded. Although we recognize that the Jimenez Declaration discusses improvement in producing a protective effect against L. major through a pharmaceutical composition, “consisting on [sic] a MIDGE vector coding for the LACK antigen and modified with the NLS peptide” (see Jimenez Declaration, para. 7), claim 24 does not call for the discussed NLS peptide. Appellants’ Specification describes “the sequence PKKKRKV (proline - lysine - lysine - lysine - arginine - lysine - valine = Seq ID 3) comprising a nuclear localization signal (NLS) from the simian virus SV40” (Spec. 6). This is also consistent with claim 24, which calls for “[the] at least one oligopeptide consisting of the amino acid sequence of 6 Declaration of Marcos Timon-Jimenez, filed April 9, 2008. 7 Lopez-Fuertes et al., DNA vaccination with linear minimalistic (MIDGE) vectors confers protection against Leishmania major infection in mice, 21 Vaccine 247–257 (2002). Appeal 2011-008678 Application 10/816,591 10 SEQ ID 3” (Appeal Br., Clms. App. (emphasis added)). Further, Appellants have not directed us to any portion of the Specification, the Jimenez Declaration, or the Lopez-Fuertes reference that discloses that “it is known that the EDYP extension [of the NLS sequence discussed in the Lopez- Fuertes reference] does not have a functional significance” (Reply Br. 5; See also Appeal Br. 11–12). Consequently, claim 24 is not commensurate in scope with the unexpected result since consistent with the Specification and claim 24 “there is no evidence of record to suggest that the longer oligopeptide in [Lopez-Fuertes] is identical in function to the smaller PKKKRKV sequence [of claim 24]” (Ans. 13). See In re Tiffin, 448 F.2d 791, 792 (CCPA 1971) (“objective evidence of non-obviousness must be commensurate in scope with the claims which the evidence is offered to support”). Accordingly, for the foregoing reasons, the Examiner’s rejection of claim 24 as unpatentable over Gurunathan, Wittig, and Makkerh is sustained. DECISION We AFFIRM the decision of the Examiner to reject claim 24 under 35 U.S.C. § 103(a) as unpatentable over Gurunathan, Wittig, and Makkerh. 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 Klh