DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
The Amendments and Remarks filed 27 April 2026 in response to the Office Action 27 January 2026 are acknowledged and have been entered. Claims 1, 10, 11, 24, 25, 46, 75, 76, and 79-81 are amended. Claims 2-9, 12-13, 15-23, 26-32, 35, 38-44, 47-74, 77 are cancelled. Claim 89 is newly added. Claims 1, 10-11, 14, 24-25, 33-34, 36-37, 45-46 and 75-76, 78-89 are pending. Claims 46 and 85-86 are withdrawn as being drawn to a nonelected invention Claims 1, 10, 11, 14, 24-25, 33-34, 36-37, 45, 75-76, 78-84, and 87-89 are under examination on the merits.
Any objection or rejection not reiterated herein has been withdrawn in view of applicant’s claim amendments.
Priority
The instant application is a 371 PCT of application US2018/039878 filed 06/27/2018 which claims priority to application 62/525,708 filed 06/27/2017.
Response to Arguments
Applicants argue that notes that none of paragraphs [0019], [0230]-[0231], [0021], or [0229] as cited in paragraph 14 on page 5 of the Office Action appear in Mali P3. Accordingly, these paragraphs cannot be relied upon to form the basis of an obviousness rejection against the instant claims. Applicant's arguments have been fully considered but they are not persuasive. The provisional application for Mali filed 4/4/2017 (i.e., Mali P3) provides support on the teaching relied upon by Mali. These teachings are located in Mali P3 throughout the specification and are not labeled as the same paragraphs according to the PGPUB.
Information Disclosure Statement
The information disclosure statement filed 04/27/2026 has been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 89 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claim recites: “wherein the recombinant viral particle … exhibits a transduction efficiency that is at least 10% as compared to the transduction efficiency of a wild-type control viral particle…” The metes and bounds of the claim cannot be reasonably determined because the claim fails to specify the conditions under which the recited transduction efficiency is measured. Specifically, the claim does not define: the target cell type; the multiplicity of infection (MOI); the assay used to determine transduction; the time point at which transduction is measured; the animal model or in vitro system, if any; the identity of the encapsulated nucleotide of interest; the method used to quantify transduction efficiency. Transduction efficiency is known in the art to vary substantially depending upon these variables. Consequently, one of ordinary skill in the art could not determine with reasonable certainty whether a particular viral particle falls within or outside the scope of the claim. See MPEP §2173.05(b) and Nautilus, Inc. v. Biosig Instruments, Inc., 572 U.S. 898 (2014).
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 89 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Nature of the Invention
Claim 89 recites a recombinant viral particle comprising a nucleotide of interest encapsulated within a recombinant viral capsid, wherein the recombinant viral particle exhibits a transduction efficiency that is at least 10% as compared to a wild-type control viral particle of the same serotype lacking the first and second cognate members.
State of the Art
The prior art establishes that AAV capsid engineering and retargeting is highly empirical and requires extensive screening of large variant libraries to identify functional constructs. se Asokan (Asokan et al. Discov Med. 2010 May ; 9(48): 399–403). Michelfelder (Michelfelder and Trepel. Adv. Genet. 67:263-304 (2009)) teaches that that AAV capsid engineering and receptor retargeting are highly unpredictable by describing challenges associated with maintaining infectivity following capsid modification (see entire paper).
Breadth of the claims
The claim is defined primarily by a functional performance characteristic, namely achieving a specified transduction efficiency threshold, while encompassing a broad genus of recombinant viral particles. The scope of the claim encompasses numerous variables including, but not limited to: multiple viral serotypes; numerous possible insertion sites within viral capsid proteins; various first members and second cognate members of protein-protein binding pairs; numerous antibodies and antigen-binding fragments; different target cell types and tissues; different nucleotide cargoes; and different production and administration conditions.
Guidance of the Specification
The specification provides only a limited number of working examples. Specifically, the disclosure provides data for only two viral serotypes (AAV2 and AAV9), only two SpyTag/SpyCatcher configurations, and only approximately five antibody constructs. The specification therefore discloses only a small subset of the embodiments encompassed by the claims. The specification further fails to provide predictive structural guidance that would allow a person of ordinary skill in the art to determine, without substantial experimentation, which combinations of: serotype, insertion site, SpyTag/SpyCatcher configuration, targeting antibody, target cell population, and nucleotide cargo will achieve the claimed transduction threshold.
The disclosure demonstrates only two SpyTag/SpyCatcher configurations. No evidence is provided that the claimed transduction threshold can be achieved across the full scope of all cognate binding pairs encompassed by the claims. Likewise, only five antibodies are tested, yet the claims encompass potentially thousands of antibodies and antigen-binding fragments having different sizes, valencies, epitopes, affinities, and steric properties. The specification does not provide a predictive rule allowing one of ordinary skill in the art to determine which antibodies will maintain capsid infectivity and satisfy the claimed transduction threshold. Consequently, the specification merely identifies a limited number of successful embodiments and leaves the skilled artisan to discover additional working species through substantial screening and experimentation.
Experimentation Required
In order to practice the claimed invention, an immense amount of experimentation would be required. A skilled artisan would be required to construct and test numerous candidate viral particles to determine which embodiments satisfy the claimed functional limitation. Accordingly, practicing the invention as broadly claimed would require a massive amount of highly unpredictable experimentation.
Applying the factors set forth in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), the Examiner finds: (1) the breadth of the claims is substantial; (2) the amount of guidance provided is limited; (3) the number of working examples is small relative to the scope claimed; (4) the quantity of experimentation necessary to identify additional operative embodiments would be extensive; (5) the art of viral capsid engineering and retargeting is unpredictable; and (6) success depends upon numerous interacting biological variables not adequately addressed by the specification. Accordingly, undue experimentation would be required to practice the full scope of the claimed invention.
Therefore, claim 89 is rejected under 35 U.S.C. §112(a) for lack of enablement.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1, 10-11, 14, 24-25, 33, 37, 75-76, 78-84, and 87-89 are rejected under 35 U.S.C. 103 as being unpatentable over Ried (Ried et al. (2002); J. Viral. 76(9):4559-4566) in view of Arnold (Arnold et al. Molecular Therapy Vol. 14, No. 1, July 2006, cited on the Information Disclosure Statement filed 11/20/2025), Boucas (Boucas et al. J Gene Med 2009; 11: 1103–1113, cited on the Information Disclosure Statement filed 11/20/2025), Mali (US 2020/0340012 A1; provisionally filed 4/4/2017), and Veggiani (Veggiani et al. Trends Biotechnol. 2014 October ; 32(10): 506–512).
Regarding claims 1, 11, 14, 24-25, and 33 Ried teaches a versatile recombinant adeno-associated virus (rAAV) vector targeting system which would allow one to redirect rAAV binding to specific cell surface receptors by simple coupling of different ligands to its capsid [abstract]. Ried teaches the insertion of an immunoglobulin G (IgG) binding domain of protein A, Z34C, into the adeno-associated virus type 2 (AAV2) capsid protein at amino acid position 587 (i.e., heterologous amino acid sequence comprising a first member of a protein:protein binding pair) [abstract; Fig. 1]. Ried teaches that the rAAV2-Z34C vectors can be coupled to antibodies against CD29 (β1-integrin), CD117 (c-kit receptor), and CXCR4 (i.e., targeting ligand, antibody) specifically and allowed the vectors to transduce distinct human hematopoietic cell lines, thereby retargeting the rAAV vectors to specific cell surface receptors. [abstract].
Although Reid teaches insertion of Z34C in to the AAV2 capsid at amino acid position 587, Reid do not teach that this position is an exposed variable loop. Ried do not teach that the immunoglobulin G (IgG) binding domain of protein A, Z34C is a peptide tag and that the viral capsid protein further comprises a second cognate member of the protein:protein binding pair, wherein the first member and the second cognate member are bound by an isopeptide bond.
Arnold teaches the development of multiple targeted AAV vectors utilizing a single capsid modification via straightforward avidin–biotin ligand coupling [abstract]. Arnold teaches that there are sites within the AAV2 capsid gene known to permit the addition of exogenous sequences, of which two are within the VP1/VP2 unique region and three are located within the VP3 region of the AAV2 Cap ORF [pg. 98, col. 2, para 2]. Arnold teaches the selection of sites in serotype 1, 3, 4, and 5 Cap ORFs based on structural similarity to the surface-exposed loop region of the AAV2 capsid protein defined by amino acids 584–590 [pg. 98, col. 2, para 2]. Thereby Arnold teaches that amino acid 587 of AAV2 capsid is in the surface-exposed loop.
Boucas teaches that most reported targeting approaches are based on insertion of small peptide ligands within the cap open reading frame (ORF) [pg. 1104, col. 1, para 2]. Boucas teaches that this ORF codes for three structural proteins [(VP1 (90 kDa), VP2 (72 kDa) and VP3 (60 kDa)] that share most of their amino acid sequence and that build up the capsid in a 1 : 1 : 10 ratio [pg. 1104, col. 1, para 2]. Boucas teaches that preferred sites for peptide insertion in AAV serotype 2 capsids are amino acid positions 587 and 588 (according to VP1 numbering), which are located in a region common to all three capsid proteins [pg. 1104, col. 1, para 2].
Mali teaches an AAV capsid engineered to comprise SpyTag or a KTag [0019] in order to selectively deliver Cas9 to cells that express KTag or SpyTag, respectively, on its surface [230-231]. Mali teaches that SpyTag or KTag is incorporated at amino acid residue R447, S578, N587 or S662 of VP1 [0021]. Mali teaches that when a SpyTag is incorporated onto the capsid pseudotyping can be achieved through click chemistry which involves the conjugation of a KTag to the moiety to be pseudotyped [0229]. Thereby Mali teaches the ability to use the SpyTag/ KTag protein:protein binding pairs in order to change viral tropism.
Veggiani teach that an ideal interaction between proteins would be covalent, specific, require addition of only a peptide tag to the protein of interest, and form under a wide range of conditions [abstract]. Veggiani teach that a direct isopeptide bond formation between the irreversible peptide-peptide interaction of SpyTag and KTag or SpyCatcher and SpyTag can be used to direct affibodies or antibodies to the surfaces of cells [pg. 4, para 2; pg. 5, para 1; Fig. 2, 3, 4; abstract]
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to try to genetically fuse the SpyTag of Mali to the AAV2 capsid of Ried, instead of Z34C, at amino acid position 587, which is within an exposed variable loop, and conjugate the CD29, CD117, and CXCR4 antibodies to SpyCatcher or KTag which are capable forming an irreversible isopeptide bond with a SpyTag. One of ordinary skill would be motivated to make the modification given the teachings of Arnold and Boucas that the preferred sites for peptide insertion in AAV serotype 2 capsids are amino acid positions in the exposed variable loop. One of ordinary skill would also be motivated to make the modification to SpyCatcher or KTag since the substitution and rearrangement of parts will achieve the same result of retargeting the AAV vector of Reid to a tissue or cell type of interest and the use of the peptide tags would create an ideal covalent interaction that is irreversible as taught by Veggiani. The combination of prior art elements according to known methods to yield predictable results supports can support a conclusion of obviousness. See MPEP 2143(I). One of ordinary skill in the art would have a reasonable expectation of success since both Ried, Arnold Boucas, and Mali all teach genetically altering AAV2 surface proteins to display proteins of interest for the purpose of retargeting AAV2 virus particles to specified cells.
Regarding claim 10, Ried teaches that a AAV2-Z34C mutant that additionally contains a
deletion of 9 aa [pg. 4561, col. 2, para 1-2].
Regarding claim 37 and 81, Ried teaches the production of AAV2 particles that contained GFP as a transgene [pg. 4561, col. 1, para 3; pg. 4563, col. 1, para 1] and the delivery of the GFP transgene to targeted cells [pg. 4563, col.1, para 2].
Regarding claim 75, Ried teaches that the natural tropism of the AAV2-Z34C mutants was reduced [pg. 4562, col. 1, para 2]. Therefore, it would be obvious that the recombinant viral capsid protein as taught and suggested as discussed above would also have reduced natural tropism.
Regarding claim 76, Ried teaches the retargeting (redirection) of mutant rAAVGFP587Z34C [pg. 4563, col. 1, para 2]. Therefore, it would be obvious that the recombinant viral capsid protein as taught and suggested as discussed above would also have redirected tropism.
Regarding claims 78-80, Ried do not teach that the targeting ligand specifically binds the cell surface molecules claimed or bind molecules repressed on a neuronal or muscle cell. Ried teaches that that rAAV vectors can be targeted to specific cell surface receptors by use of a universal targeting approach [pg. 4565, col. 1, para 4]. Therefore, it would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention that the rAAV vectors as taught and suggested as discussed above could be designed to target any cell, including a neuronal or muscle cell, or bind any cell surface marker based on which cell surface receptor the immunoglobulin binding domains of the capsid protein is targeting.
Regarding claim 82, Ried teaches the transduction of human hematopoietic cells [abstract].
Regarding claims 83-84, the teachings of Reid are discussed above as applied to claims 78-79 and 81-82.
Regarding claim 87, Ried teaches the production of AAV2-based vectors with a recombinant capsid [pg. 4560, col. 2, para 3].
Regarding claim 88, Ried teaches a AAV cap gene encoding the rAAV capsid protein [Fig. 1].
Regarding claim 89, “at least 10% transduction efficiency” is merely a quantitative expression of an inherent property of the resulting viral particle. Optimization of transduction efficiency through routine selection of: insertion sites, targeting ligands, antibody formats, and production conditions, would have been within the ordinary skill in the art. Therefore, discovering an optimum or workable value of a result-effective variable is ordinarily obvious.
Claims 34 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Ried (Ried et al. (2002); J. Viral. 76(9):4559-4566) in view of Arnold (Arnold et al. Molecular Therapy Vol. 14, No. 1, July 2006, cited on the Information Disclosure Statement filed 11/20/2025), Boucas (Boucas et al. J Gene Med 2009; 11: 1103–1113, cited on the Information Disclosure Statement filed 11/20/2025), Mali (US 2020/0340012 A1; provisionally filed 4/4/2017) and Veggiani (Veggiani et al. Trends Biotechnol. 2014 October ; 32(10): 506–512) as applied to claims 1 and 33, and further in view of Choi (Choi et al. Curr Gene Ther. 2005 June ; 5(3): 299–310.).
The teachings of Ried, Arnold, Boucas, Mali, and Veggiani are discussed above as applied to claims 1 and 33 and similarly apply to claim 34 and 36.
Ried, Arnold, Boucas, Mali, and Veggiani do not teach a recombinant viral capsid protein comprising the recombinant viral capsid protein and the reference viral capsid protein lacking any member of the specific protein:protein binding pair at a ratio between 1: 1 and 1: 15.
Choi teaches the engineering of adeno-associated virus (AAV) capsid, in order to increase efficiency in targeting specific cell types that are nonpermissive to wild type (wt) viruses and to improve efficacy in infecting only the cell type of interest [abstract]. Choi teaches the generation of capsid mutants, or hybrid serotypes, by various methods and strategies [abstract]. Choi teaches the generation of mosaic capsid by packaging a mixture of capsid proteins from two different serotypes by using different ratios of input plasmids encoding different serotype capsid sequences [see section 2.3].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to generate a recombinant viral capsid as taught and suggested by Ried, Arnold, Boucas, Mali, and Veggiani, where the recombinant viral capsid protein and the reference viral capsid protein has a ratio between 1: 1 by using a 1:1 ratio of plasmid encoding the recombinant viral capsid protein to plasmid encoding the reference viral capsid protein as taught by Choi. The combination of prior art elements according to known methods to yield predictable results supports can support a conclusion of obviousness. See MPEP 2143(I). One of ordinary skill in the art would have a reasonable expectation of success since both Ried, Arnold, Boucas, Mali and Choi teach engineering of adeno-associated virus (AAV) capsid, in order to increase efficiency in targeting specific cell types.
Claim 45 is rejected under 35 U.S.C. 103 as being unpatentable over Ried (Ried et al. (2002); J. Viral. 76(9):4559-4566) in view of Arnold (Arnold et al. Molecular Therapy Vol. 14, No. 1, July 2006, cited on the Information Disclosure Statement filed 11/20/2025), Boucas (Boucas et al. J Gene Med 2009; 11: 1103–1113, cited on the Information Disclosure Statement filed 11/20/2025), Mali (US 2020/0340012 A1; provisionally filed 4/4/2017) and Veggiani (Veggiani et al. Trends Biotechnol. 2014 October ; 32(10): 506–512) as applied to claims 1, 33, and 37, and further in view of Wang (US 8,273,344 B2, 9/25/2012).
The teachings of Ried, Arnold, Boucas, Mali, and Veggiani are discussed above as applied to claims 1, 33, and 37 and similarly apply to claim 45.
Ried, Arnold, Boucas, Mali, and Veggiani do not teach a recombinant viral particle comprising a pharmaceutically acceptable carrier.
Wang teaches pharmaceutical application of the recombinant adeno-associated virus comprising a nucleotide of interest [col. 1, lines 8-18]. Wang teaches a pharmaceutical composition comprising the rAAV and a pharmaceutically acceptable carrier or excipient [col. 3, lines 42-45].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to include a pharmaceutically acceptable carrier as taught by Wang with the recombinant viral particle comprising a nucleotide of interest encapsulated by the recombinant viral capsid as taught and suggested by Ried, Arnold, Boucas, Mali, and Veggiani for the advantage of using it in a pharmaceutical application. The combination of prior art elements according to known methods to yield predictable results supports can support a conclusion of obviousness. See MPEP 2143(I). One of ordinary skill in the art would have a reasonable expectation of success since both Ried, Mali, and Wang teach delivery of virus particles.
Response to Arguments
Applicant’s arguments, see pgs. 12-20, filed 27 April 2027, with respect to the rejection of claims 1, 10-11, 14, 24-25, 33, 37, 75-76, 78-84, and 87-88 under 35 U.S.C. § 103 have been fully considered and is found not persuasive.
I. Applicant Improperly Focuses on Individual References Rather Than the Combined Teachings
Applicant repeatedly argues that Ried, Mali P3, Arnold, Boucas, Veggiani, Choi, and Wang individually fail to teach a recombinant viral capsid protein covalently attached to an antibody via an isopeptide bond and individually fail to demonstrate overcoming reductions in transduction efficiency. However, the rejection is not based upon any single reference. The rejection relies upon the combined teachings of the cited references. Nonobviousness cannot be established by attacking references individually where the rejection is based upon a combination of references. See In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). The issue is not whether any individual reference discloses every claimed feature, but whether the combined teachings would have suggested the claimed invention to a person of ordinary skill in the art with a reasonable expectation of success.
II. Applicant Mischaracterizes Ried
Applicant’s principal argument relies on Table 2 of Ried and the assertion that antibody-mediated targeting resulted in approximately 5% transduction relative to a particular wild-type comparator. The argument is not persuasive. Ried nevertheless demonstrates: successful insertion of a foreign binding domain into the AAV2 capsid; successful assembly of infectious viral particles; successful antibody-mediated targeting; and successful receptor-directed transduction. Accordingly, Ried demonstrates that AAV capsids can tolerate insertion of foreign binding domains and can be retargeted through antibody-mediated interactions. The cited data do not establish failure of the system. Rather, they demonstrate that targeted transduction was achieved. The relevant inquiry under §103 is not whether a reference discloses the optimum level of performance or commercial utility, but whether it provides a reasonable expectation that the proposed modification would function for its intended purpose. See In re O’Farrell, 853 F.2d 894 (Fed. Cir. 1988). Ried clearly demonstrates that such systems function.
III. Applicant Applies an Incorrect Legal Standard for Reasonable Expectation of Success
Applicant repeatedly argues that because Ried allegedly exhibits reduced transduction relative to wild-type AAV, a skilled artisan would lack a reasonable expectation of success. This argument is based upon an incorrect legal standard. Reasonable expectation of success does not require: certainty of success; optimal performance; superiority to all prior systems; or achievement of Applicant’s particular results. Instead, obviousness requires only a reasonable expectation that the proposed modification would work for its intended purpose. See: In re O’Farrell, 853 F.2d 894 (Fed. Cir. 1988) and Pfizer v. Apotex, 480 F.3d 1348 (Fed. Cir. 2007)
The prior art demonstrates exactly that. Ried teaches successful AAV retargeting. Mali teaches incorporation of SpyTag-based binding systems into AAV capsid proteins. Veggiani teaches SpyTag/SpyCatcher as a robust, irreversible protein-coupling platform. Together these references provide a reasonable expectation that replacing Ried’s non-covalent adaptor system with Mali/Veggiani’s covalent binding system would yield a functional targeted viral particle.
IV. Applicant’s Reliance Upon the Claimed Results Is Not Persuasive
Applicant argues that Figures 2, 3, and 9 of the present application demonstrate transduction efficiencies that are comparable to or greater than wild-type controls. These arguments are not persuasive for several reasons.
Unexpected Results Must Be Commensurate in Scope: The pending claims encompass broad genera including: numerous antibodies; antigen-binding fragments; multiple viral serotypes; multiple insertion positions; multiple cognate binding pairs; multiple target cell types. Applicant’s evidence is limited to a comparatively small subset of embodiments. Evidence limited to a small number of embodiments is insufficient to establish unexpected results across the full scope of the claims. See: In re Grasselli, 713 F.2d 731 (Fed. Cir. 1983) and In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003)
Applicant Has Not Demonstrated That The Results Would Have Been Unexpected Relative To The Closest Prior Art: Applicant compares certain embodiments against wild-type controls. However, the closest prior art is not wild-type AAV. The closest prior art includes: Ried’s antibody-targeted AAV vectors; Mali’s SpyTag-modified AAV vectors; Veggiani’s SpyTag/SpyCatcher conjugation systems. Unexpected results must be demonstrated relative to the closest prior art. Applicant has not provided comparative evidence showing that the claimed isopeptide-linked constructs unexpectedly outperform the systems taught by the cited references.
V. Arnold and Boucas Were Not Relied Upon For Antibody Conjugation
Applicant argues that Arnold and Boucas do not teach covalent attachment of antibodies. This argument is not responsive to the rejection. Arnold and Boucas were cited for their teachings that exposed AAV surface loops, including the region surrounding amino acid position 587, constitute suitable insertion locations for heterologous peptides and targeting moieties. The references were not cited as teaching antibody conjugation. he rejection relies upon Arnold and Boucas for their teachings regarding: capsid engineering; insertion-site permissibility; surface accessibility of inserted peptides. Thus, Applicant’s argument attacks teachings not relied upon in the rejection.
VI. Veggiani Supplies The Missing Covalent Coupling Feature
Applicant argues that Veggiani does not disclose viral vectors. This argument is not persuasive. A reference need not teach the entire invention to be properly combinable under §103.
Veggiani teaches: SpyTag; SpyCatcher; spontaneous isopeptide bond formation; irreversible protein conjugation. These are precisely the teachings for which Veggiani was cited. The rejection does not rely upon Veggiani to teach viral capsids. Instead, Veggiani supplies the known covalent binding system that would have been predictably substituted for the non-covalent adaptor system of Ried.
VII. Claim 89
Applicant argues that the prior art would not provide a reasonable expectation of achieving:
“a transduction efficiency that is at least 10% as compared to the transduction efficiency of a wild-type control viral particle.” The argument is not persuasive. The cited prior art establishes:
functional AAV retargeting (Ried); permissible insertion sites (Arnold, Boucas); SpyTag incorporation into AAV capsids (Mali); irreversible conjugation chemistry (Veggiani). The claimed threshold represents a performance characteristic of the resulting construct.
Optimization of transduction efficiency through routine selection of insertion sites, targeting ligands, antibody formats, and production conditions would have constituted no more than routine experimentation. Furthermore, Applicant has not established that the recited 10% threshold is critical. Absent evidence of criticality, a claimed numerical performance limitation that overlaps or approaches values obtainable through routine optimization does not render the claim nonobvious. See In re Aller, 220 F.2d 454 (CCPA 1955).
VIII. Choi and Wang
Applicant argues that Choi and Wang do not remedy the alleged deficiencies of the base combination. The argument is not persuasive because Choi and Wang were cited only for the additional limitations recited in dependent claims. Specifically: Choi was cited for mosaic capsid technology. Wang was cited for pharmaceutical compositions comprising recombinant AAV vectors and pharmaceutically acceptable carriers. Neither reference was relied upon to establish antibody conjugation or SpyTag/SpyCatcher technology. Accordingly, the arguments directed to Choi and Wang do not overcome the rejection of the dependent claims.
Applicant has not persuasively shown: 1. That the cited references teach away from the proposed combination; 2. That a person of ordinary skill would have lacked a reasonable expectation of success; 3. That the asserted transduction efficiencies constitute unexpected results commensurate with the full claim scope; or 4. That the Examiner’s articulated rationale for combining the references is deficient. Therefore, the rejection of claims 1, 10-11, 14, 24-25, 33, 34, 36, 37, 45, 75-76, 78-84, and 87-89 under 35 U.S.C. §103 is maintained.
Conclusion
No claims allowed.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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