DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 29 December 2025 have been entered. Claims 1-4, 6, 8-9, 26, 29-32, 34, 45, 48, and 54-61 were previously pending in the application. Claims 1-4, 6, 8-9, 26, 29-32, 34, 45, 48, and 54-61 are currently pending in the application. Claims 1, 45, 54, 55, 56, 57, and 58 are independent claims. The election of the following species remains in effect in the instant application:
Fusion partner to a cell surface marker specific VHH: b) an adeno-associated virus (AAV) capsid protein.
Claims 2-4, 6, 8, and 26 remain withdrawn from consideration as being directed to a nonelected species. Claims 1, 9, 29-32, 34, 45, 48, and 54-61 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/EP2019/061295, filed 02 May 2019, which claims priority to EPO 18170659.9, filed 03 May 2018. Filing of a certified copy of the EPO 18170659.9, filed 03 May 2018 is acknowledged.
Thus, the earliest possible priority for the instant application is 03 May 2018.
37 CFR 1.821-1.825
In view of Applicant’s submission of a new sequence listing, Drawings replacement sheet for Figure 2, and amendments to the specification which correct the prior error(s), this application is now in compliance with the requirements of 37 CFR 1.821 through 1.825.
Specification
The objection to the specification of the disclosure for reciting trade names and/or marks without the accompanying generic terminology and/or proper symbol is withdrawn in view of the amendment to the specification.
Claim Objections
The objection to amended claim 1 for reciting the abbreviation “VHH” without first writing out the term for which “VHH” is an abbreviation, is withdrawn in view of the amendment to claim 1.
The objection to amended and previously presented claims 29, 32, 48, and 57-58 for reciting “VP1” and/or “VP2” without first writing out the non-abbreviated terms, is withdrawn in view of the amendment to claims 29, 32, 57, and 58.
Claim Rejections - 35 USC § 112(b)
The rejection of amended, original, and previously presented claims 29-32, 34, 45, 48, 56-58, and 60-61 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for indefinite language is maintained over amended claim 57 and withdrawn over amended, original, and previously presented claims 29-32, 34, 45, 48, 56, 58, and 60-61. Applicant’s amendments to the claims such that claims 29, 57, and 59 now recite language clarifying the insertion position numbering has overcome the issue of the claims being unclear which AAV serotype numbering “position 453-459 of VP1” is referring to and that the insertion is between any two amino acids corresponding to positions 453-459.
However, amended claim 57 was also rejected for reciting “improving transduction efficiency of a target cell”. Claim 57 was amended to recite “increasing transduction efficiency of a target cell”, which is still a relative term. The term “increasing” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The method recites “increasing transduction efficiency of a target cell” but does not provide any reference for which the “increasing” is increased by comparison. For example, the claimed method does not include any transduction step which would have an increased transduction efficiency, and so it is unclear both 1) what transduction efficiency is being increased and 2) what the transduction efficiency is being increased relative to. As such, the metes and bounds of the claim still cannot be determined.
Applicant provides no arguments beyond indicating the amendment to recite “increasing” instead. Therefore, Applicant’s arguments do not overcome a finding of indefiniteness for amended claim 57, and the rejection is maintained.
Claim Rejections - 35 USC § 103
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The rejection of amended, previously presented, and original claims 1, 9, 29-32, 34, 45, 48, and 54-61 under 35 U.S.C. 103 as being unpatentable over Judd et al. 2012, Molecular Therapy- Nucleic Acids, 1, e54, 1-10, IDS; Muik et al. 2017, Biomaterials, 144, 84-94; Kaliberov et al. 2014, Lab Invest., Vol. 94(8), 893-905, cited in a prior action; Benchimol et al. 1989, Cell, Vol. 57(2), 327-334, cited in a prior action; and Hefta et al. 1988, Proceedings of the National Academy of Science, Vol. 85(13), 4648-4652, cited in a prior action, is maintained. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant’s claim amendments address issues of formalities and indefiniteness but do not alter the scope to further limit the claims sufficiently to overcome the rejection of record.
Applicant argues that:
Muik explicitly teaches not to insert an scFv or VHH into a VP capsid protein of AAV, and itself teaching a coupling of a preformed AAV particle with an scFv for targeting;
It was unexpected that the insertion approach can be successfully applied with VHH and AAV capsid proteins since Judd explicitly selected mCherry protein due to its proximity of its N- and C-termini, which is in contrast to VHH which have N- and C-termini at opposite sides of the protein and would therefore have unpredictability of proper folding upon insertion into a loop of the VP protein.
However, this is not agreed.
In response to applicant’s arguments against the references individually, it is noted that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In addition, it must be recognized that 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 the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Specifically, regarding Applicant’s argument 1), note that Muik was cited for teaching the motivation to attach an antibody-derived domain onto the surface of an AAV capsid to target the AAV vector to distinct cell types [prior action page 8 ¶ 3]. Muik was not relied on to specifically teach the genetic incorporation of the antibody domain into the capsid protein coding region.
Kaliberov was cited for teaching that camelid heavy-chain-only antibodies (hcAbs) contain characteristics ideal for viral vector retargeting strategies: 1) cytosolic stability allowing functional incorporation into the viral capsid and 2) compatibility with phage biopanning selection to allow target cell specificity [column 3 ¶ 3]. Kaliberov also teaches that hcAbs contain a single variable domain (VHH) linked to two constant domains; that cloned and isolated single domain antibodies have shown a remarkable stability profile compared with conventional Igs and scFVs; and that engineered single domain antibody (sdAb) fusion proteins have demonstrated effective targeting in model systems [column 3 ¶ 3]. Kaliberov also teaches the validation of targeted gene delivery using adenovirus vector with capsid incorporated with VHH [column 4 ¶ 1]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use a single variable antibody-derived VHH domain for incorporation into a viral capsid protein for targeting the capsid protein to a specific target cell type.
Kaliberov further teaches that camelid heavy-chain-only Abs (hcAbs) specifically address the issues that scFV have for cytoplasmic biosynthesis of capsid proteins and nuclear assembly of viral particles, in that they have a stability profile compatible with the cytosolic biosynthesis of capsid proteins and subsequent nuclear assembly of viral particles [column c ¶ 2-3].
Regarding Applicant’s argument 2), that genetic incorporation into a capsid protein of a VHH domain would not be expected to fold properly due to Judd’s choice of mCherry being informed by proximal N- and C-termini, note that Kaliberov teaches the successful selective cellular targeting via incorporation of VHH domains into capsid proteins, and as such, Kaliberov provides predictability that such domains are capable of folding properly when inserted into a capsid protein [abstract, column 4 ¶ 1]. As such, an ordinarily skilled artisan would have a reasonable expectation of success in incorporating a VHH domain into an AAV capsid protein.
Additionally, to the extent that Applicant is claiming the unexpected nature of such folding to indicate that their invention amounts to unexpected results. Note that Applicant has not provided any data in support of a finding of unexpected results, and such arguments amount to arguments of counsel. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP § 716.01(c) for examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration. Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. MPEP 716.01(c). Attorney argument is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and § 2144.03 for a discussion of admissions as prior art.
It is also noted that any evidence of unexpected results must be commensurate in scope with the claimed invention, and that a greater, or greater than additive, effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected MPEP 716.02 (a) and (d). 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). Again note that Applicant has not provided any evidence of unexpected results, and therefore such arguments are not commensurate in scope with the claimed invention.
Therefore, Applicant’s arguments do not overcome a finding of obviousness under 35 U.S.C. 103 over Judd, Muik, Kaliberov, Benchimol, and Heft, and the rejection is maintained.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. KATIE L PENNINGTON whose telephone number is (703)756-4622. The examiner can normally be reached M-Th 8:30 am - 5:30 pm, Friday 8:30 am - 12:30 pm CT.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634