DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/22/2025 has been entered.
Applicant’s arguments and amendments filed on July 22, 2025 have been received and entered. Claims 186 has been amended, while claims 1-185, 189, 191-194, 190, 195 have been canceled. 186-188, 190 and 195 are pending in the instant application.
Election/Restrictions
Applicant's election with traverse of claims 186-194 (group I) in the reply filed on July 25, 2023 was acknowledged. The traversal was on the grounds that method of group II should be rejoined with the elected composition of group I. This was not found persuasive because as stated in previous office action the product as claimed could be used in another method or the method as claimed could be practiced with another nucleic acid such as one disclosed in Fikes. The requirement was deemed proper and was therefore made FINAL.
Claim 195 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on July 25, 2023.
Claims 186-188 and 190 are under consideration.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No.12095730, filed on May 30, 2008.
Maintained-Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 186-188 and 190 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Sponaas et al (Gene therapy, 1999, 1826-1834, IDS) as evidence by Freisewinkel (PNAS, 1993, 90, 9703-9706) Claesson et al., (Proc. Nat. Acad. Sci. USA, 1983, 80, 7395-7399), and Fikes et al (WO9958658, dated 11/181999, IDS) in view of Cirillo (WO2005/071093, dated 8/4/2005).
With respect to claims 186-188, 190, Sponaas et al teach an expression vector comprising a promoter operably linked to a fusion gene encoding a major histocompatibility complex (MHC) targeting li sequence comprising CLIP region, and at least one antigen (HEL) (see figure 1, page 1830, col. 2, para. 4).
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It is noted that Sponaas et al teaches that Ii cDNA is obtained from Freisewinkel (see page 1830, col. 2, para. 4) that discloses cDNAs encodes the human p33 Ii as disclosed below having 100% sequence homology to SEQ ID NO: 2 as evidenced by Claesson et al., 1983 and Fikes (see figure 4, 216 amino acid and sequence search report) (limitation of claims 187-190). Sponaas et al teaches that the li directly linked with antigenic protein (see figure 1 above). Regarding use of adenoviral vector comprising said construct, Sponaas explicitly teaches Ii fusion proteins have been used to target antigens to the class II presentation pathway either by transfection of DNA or by infection with adenovirus constructs (see page 1826, col. 2, para. 3). Sponaas further discloses using an Ii–antigen fusion protein expressed by a nonreplicating adenovirus vector, wherein the recombinant antigen is detectable as long as 4 weeks after injection into mice (see page 1828. Col. 2, para. 3).
Sponaas et al teach a composition that appears to be structurally and functionally similar to one disclosed in the instant application, but differs from claimed invention by not disclosing that the (i) antigenic peptide is HCV and (ii) construct incorporated in an E1 and E3- deleted adenovirus derived from a simian source.
Fikes et al cure the deficiency by teaching a MHC targeting sequence that includes human li protein as set forth in figure 12 that has 100% sequence identity to SEQ ID NO: 2 and includes CLIP region (see figure 12 and sequence search report, page 40, lines 30-34)) meeting the limitation of the claims 187-189, wherein the antigen peptide include those derived from viruses such as HBV, HCV (see page 16, lines 18-28). Further, Fikes contemplated delivering the targeting sequence via adenoviral (see page 5, lines 26). It is further disclosed that the invariant chain is directly linked with antigenic protein as evident from the li-antigen fusion protein (see figure 2-9).
Query Match 100.0%; Score 1142; DB 1; Length 232;
Best Local Similarity 100.0%;
Matches 216; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MDDQRDLISNNEQLPMLGRRPGAPESKCSRGALYTGFSILVTLLLAGQATTAYFLYQQQG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 17 MDDQRDLISNNEQLPMLGRRPGAPESKCSRGALYTGFSILVTLLLAGQATTAYFLYQQQG 76
Qy 61 RLDKLTVTSQNLQLENLRMKLPKPPKPVSKMRMATPLLMQALPMGALPQGPMQNATKYGN 120 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 77 RLDKLTVTSQNLQLENLRMKLPKPPKPVSKMRMATPLLMQALPMGALPQGPMQNATKYGN 136
Qy 121 MTEDHVMHLLQNADPLKVYPPLKGSFPENLRHLKNTMETIDWKVFESWMHHWLLFEMSRH 180 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 137 MTEDHVMHLLQNADPLKVYPPLKGSFPENLRHLKNTMETIDWKVFESWMHHWLLFEMSRH 196
Qy 181 SLEQKPTDAPPKESLELEDPSSGLGVTKQDLGPVPM 216
||||||||||||||||||||||||||||||||||||
Db 197 SLEQKPTDAPPKESLELEDPSSGLGVTKQDLGPVPM 232
The combination of reference differs from claimed invention by disclosing construct incorporated in an E1 and E3 deleted adenovirus derived from a simian source.
Cirillo cures the deficiency by disclosing limitation of using adenoviral vector derived from viruses that naturally infect and replicate in humans as carrier for vaccine delivery (see page 2, lines 18-33). Cirillo discloses chimpanzee adenoviruses vectors as vaccine carriers for the administration of vaccines comprising transgenes encoding immunogens derived from an infectious agent (See page 3, lines 14-15). Cirillo teaches CV33DEl-E3 a plasmid construct that comprises a CV33 chimpanzee adenoviral genome, deleted of the El and E3 regions, which is replaced by an immunogen expression cassette comprising HCV non-structural genes under the control a human CMV promoter followed by a bovine growth hormone polyadenylation signal (see page 11, lines 26-30). It is further disclosed that the function of E3 is not necessary 20 for the production of a recombinant adenoviral particle it is not necessary to replace this gene product in order to produce a recombinant that is capable of packaging a virus useful in the invention (see page 17, 19-21). Table 4 provides data summarizing the percentage of gag-specific CD3+ T cells that were either gag-specific CD8+ or CD4+ T cells (see page 46 o, lines 20-25). Cirillo teaches immunization potential of CV32DE1E3 vector (example 7).
In view of the foregoing, it would have been obvious to one of ordinary skill in the art at the time the invention to combine the teaching of prior art by substituting the antigenic HEL peptide in the construct of Sponaas with antigenic peptide from a virus such as HCV as disclosed in Fikes, in order to stimulate MHC response, said modification amounting to combining prior art elements according to known methods to yield predictable results. It would be further obvious for one of ordinary skill in the art to incorporate the construct in a replication defective E1 and E3 deleted adenoviral vector derived from chimpanzee as disclosed in Cirillo, in order to circumvent reduction of the efficacy of adenovirus (Ad) vector-based vaccines by neutralizing antibody in human subject, said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so in order to overcome the limitation of using of adenoviral vectors as vaccine carrier because of presence of neutralizing antibody elicited by previous natural infections or vaccinations significantly affects their efficacy (see above). One who would practice the invention would have had reasonable expectation of success because (i) Sponaas had already disclosed a composition comprising construct comprising at least one operatively linked protein fragment and at least one antigenic protein that stimulates MHC response, while Fikes teach antigenic peptide fragment is from virus (such as HCV) could be used to stimulate MHC- response and (ii) Cirillo had already disclosed E1E3- deleted adenoviral vaccine carriers derived from simian serotypes could circumvent the reduction of the efficacy of adenoviral vector by neutralizing Abs to the vaccine carrier. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Response to arguments
Applicant re-iterates prior arguments on pages that are substantially the same as discussed in previous office action mailed on 04/09/2025. The arguments are substantially the same as those addressed in the prior office actions mailed on 04/09/2025 and incorporated herein. To the extent that Applicants’ arguments are pertinent to new arguments, they are addressed as follows:
Applicant disagrees and believes that the working examples in the specification demonstrate that the claimed subject matter does possess surprising properties, which would not have been predicted with a reasonable expectation of success based on the cited prior art. Even if arguendo a prima facie case of obviousness has been established based on the cited prior art, the invention has bene demonstrated to achieve unexpected, improved results, which in no way could have been predicted. As such, it must be appreciated that the claimed subject matter is surprisingly efficacious in the elicitation of immune responses, beyond that which would have been predicted from the cited art.
As an initial matter, applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (efficacious in the elicitation of immune responses or a response that included both CD4+ and CD8+ T-cell responses or sustained protection for 360 days as compared to Ad-GP as previously argued ) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
As stated in previous office action, claims are broad and require at least one invariant chain that covers all naturally occurring or artificially generated full length invariant chain that is at least 85% identical to human invariant chain as set forth in SEQ ID NO: 2. Thus, the BRI of phrase at least one invariant chain used in the adenoviral vector encompass a broad genus of full-length invariant chain sequence derived from any vertebrate species subsequently limiting to any mammalian species that may include mouse, human, chicken, cow, dog, mouse and rat (see page 10, line 11), wherein the full-length invariant chain is at least 85% identical to SEQ ID NO: 2 (human invariant chain).
As stated in previous office action, Applicant’s argument of Ad-liGP exhibits unexpected superior results as compared to Ad-GP is not found persuasive because unexpected results have to be commensurate with the scope of the invention. "Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)." Examples 1-4, 8-10 of instant specification all use E1 and E3 deleted adenovirus-expressing, antigen fused to invariant chain, wherein full-length invariant and full-length LCMV glycoprotein (antigen). There is no evidence on record that simian derived adenoviral vector comprising at least one invariant chain with derived from any other vertebrate species would exhibit the same unexpected superior result as argued by the applicant. This is evident form the applicant’s declaration filed in parent application no 12095730 disclosing unexpected technical advantage of using the human invariant chain as set forth in SEQ ID NO: 2 instead of the murine invariant chain as set forth in SEQ ID NO: 4 of present application (see exhibit B of the declaration filed on 8/16/2011 in 12095730). The resulting effects clearly show species specific effect of Adli-GP and there is no evidence on record that unexpected effect observed with adenovirus-expressing, antigen fused to invariant chain, wherein full-length human invariant chain as set forth in SEQ ID NO: 2 could be extended to other species as broadly encompassed by at least one full length invariant chain that is at least 85% identical to SEQ ID NO: 2.
Applicant has not provided evidence and/or rebutted the use of simian derived adenoviral vector as required by the claim. The examples do not specify the source of adenoviral vector used in example 1-4, 8 nor do specification provide any evidence of any advantage and/or surprising finding with use of simian derived E1 and E3 deleted adenoviral vector as vaccine carrier as required by the claims. It is further unclear from the specification if the invariant chain and the host organisms or receivers of the treatment that are from different species would exhibit the unexpected surprising results as exemplified with mouse invariant chain in a mouse host (example) (emphasis added).
Further, Applicant’s argument with respect to unexpected surprising result is not found persuasive because any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Sponaas explicitly teaches Ii fusion proteins can be used to target antigens to the class II presentation pathway either by transfection of DNA or by infection with adenovirus constructs, with li fusion proteins as evidenced from the teaching of Sponaas.. The recombinant nature of these immunogens permits the use of virus or tumor antigens that otherwise would not be available for vaccination” (see page 1826, col. 2, para. 3). In view of foregoing, it is apparent that Sponaas explicitly contemplated several different ways to use li fusion protein to target an antigen including using adenovirus constructs (emphasis added). A variety of viral vectors including adenoviral and replication deficient adenoviral vector are known to be suitable for this purpose and are well-known in the art as suggested in Sponaas (see page 1828. Col. 2, para. 3). Cirillo teaches using adenoviral vector derived from viruses that naturally infect and replicate in humans as carrier for vaccine delivery (see page 2, lines 18-33). Cirillo discloses chimpanzee adenoviruses vectors as vaccine carriers for the administration of vaccines comprising transgenes encoding immunogens derived from an infectious agent (See page 3, lines 14-15) including E1-E3 deleted adenoviral vector (see page 11, lines 26-30). The results shows that the percentage of gag-specific CD3+ T cells were either gag-specific CD8+ or CD4+ T cells (see page 46 , lines 20-25). Thus, prior art suggests incorporating nucleic acid construct in E1, E3 deleted adenovirus derived from simian overcomes pre-existing immunity to common human serotype of adenovirus to strongly induce transgene product-specific CD8+ T cell responses, thus the relevance of Applicants' arguments with respect using adenoviral vector to express the nucleic acid encoding li-antigen fusion protein is not apparent. Therefore, the fact that E1, E3 deleted adenovirus derived from simian encoding li-immunogen may elicit a strong immune response as compared to virus encoding immunogen is an expected result, and is the goal behind using simian derived E1and E3 deleted adenovirus encoding li-immunogen. As indicated in MPEP 716.02(c), Where the unexpected properties of a claimed invention are not shown to have a significance equal to or greater than the expected properties, the evidence of unexpected properties may not be sufficient to rebut the evidence of obviousness. In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977). “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.” In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967).
Applicant fails to provide any evidence or argument as why one of ordinary skill in the art would not expect a superior T-cell responses with Ad-li-immunogen as compared to Ad encoding immunogen particularly since prior art explicitly reported replication defective adenovirus encoding Ii–antigen fusion protein expressed by a nonreplicating adenovirus vector shows detection of antigen as long as 4 weeks after injection into mice (see Nakano et al Science, 1997; 275: 678–683, art of record cited in Sponaas, page 1228, col. 2, para. 3).
Therefore, in view of the fact patterns of the instant case, and the ground of rejection outlined by the examiner, applicants’ arguments are not compelling and do not overcome the rejection of record.
Examiner’s note: Should applicant provide the earlier filed evidence from the parent application and amend the base claim to limit the scope commensurate with the unexpected superior results , wherein said adenoviral vector encoding the invariant chain comprising the amino acid sequence as set forth in SEQ ID NO: 2 operably directly linked to a HCV, wherein said adenoviral vector is capable of mounting a CD8+ T-cell stimulatory effect that is independent of CD4+ T-cells, instant obviousness rejection may be overcome.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Nakano et al (Science, 1997; 275: 678–683, IDS)
Rooke et al (Methods in Molecular Biology, 2000, Vol. 134, 69-79, IDS).
Rowe et al (Molecular Therapy, 2006 13(2), 310-319, available Nov. 2005, IDS), teaches that the Ii-OVA vector is most potent inducer of IFN-g-secreting CD8+ T cells (see abstract, see page 316, col. 2, para. 2).
Pinto (J Immunol (2003) 171 (12): 6774–6779, art of record) teaches use of adenoviral vaccine carriers derived from a simian serotype in order to circumvent reduction of the efficacy of adenovirus (Ad) vector-based vaccines by neutralizing Abs to the vaccine carrier (see abstract). Pinto teaches AdC68 vector, that an E1-deleted AdC6 vector induces a potent transgene product-specific CD8+ T cell response that can be increased substantially by using a heterologous E1-deleted Ad recombinant expressing the transgene product for booster immunization (see page 6775, col. 1, para. 3).
Xiang et al (VIROLOGY 219, 220–227 (1996)) teaches construct lacking E3 expression is not essential which encodes a protein that by down-regulating expression of major histocompatibility complex (MHC) antigens protects infected cells from T-cell-mediated destruction. Xiang teaches E1 and E3 deleted adenoviral recombinant expressing the rabies virus glycoprotein (G protein) under the control of the cytomegalovirus early promoter was tested for induction of a rabies virus-specific immune response.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114.
Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632