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 .
DETAILED ACTION
The text of those sections of Title 35, U.S. Code not included in this action can be found
in a prior Office action.
This Action is in response to the papers filed on June 4, 2026 for a Request for Continued Examination. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 June 4, 2026 has been entered.
Pursuant to the amendment filed on June 4, 2026, claims 1, 15, 28, 35, 108-110, 123, 126, 131-133, 164-167 and 169-210 are currently pending of which claims 1, 35, 176, 177, 182, 196, 197, 207, and 210 have been amended, and claims 20 and 168 have been cancelled. No claims have been added.
The Restriction Requirement set forth in the Office Action of December 6, 2024 was withdrawn between Groups I-V based on the amendments to the claims as stated in the Nonfinal Rejection; however, the Restriction Requirement was maintained for Groups VI-X, and specifically for pending claims 123, 126, and 132-133 despite the amendments to these claims. Furthermore, in view of the amendment filed on November 10, 2025, claims 198-207, which are dependent on claim 123, have been withdrawn since these claims are dependent upon withdrawn claims that are directed to a method of producing the recombinant AAV particle which were restricted to Group IX. The Restriction Requirement between Groups I-V and VI-X was previously made FINAL.
Therefore, claims 1, 15, 28, 35, 108-110, 131, 164-167, 169-197 and 208-210 are currently under examination to which the following grounds of rejection are applicable.
Priority
The present application is a 35 U.S.C. 371 national stage filing of the International Application No. PCT/US2020/034328, filed May 22, 2020. Applicant’s claim for the benefit of a prior-filed parent provisional application 62/852,791 filed on May 24, 2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is May 24, 2019.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on June 4, 2026 and June 18, 2026 were filed. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Response to Arguments
Withdrawn Objections/Rejections in response to Applicants’ arguments or amendments:
Claim Rejections - 35 USC § 112
In view of Applicants’ amendment to the claims dated June 4, 2026, the rejection of claims 35, 176, 177, 182 and 197 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, are withdrawn.
Claim Rejections - 35 USC § 103
In view of Applicants’ amendment to the claims dated June 4, 2026, wherein claims 1, 35, 176, 177, 182, 196, 197, 207, and 210 have been amended, and claims 20 and 168 have been cancelled, the rejection to claims 1, 108, 109, 110, 131, 164-166, 168-170,176, 182-197, and 208-210 rejected under 35 U.S.C. 103 as being obvious over Li et al (US Publication No. 2018/0371496 A1, publication date December 27, 2018; of record IDS filed September 22, 2022(Cite No. A44)) in view of Bossis et al. (Journal of virology 77.12 (2003): 6799-6810;of record IDS filed September 22, 2022 (Cite No. C15), are withdrawn.
In view of Applicants’ amendment to the claims dated June 4, 2026, wherein claims 1, 35, 176, 177, 182, 196, 197, 207, and 210 have been amended, and claims 20 and 168 have been cancelled, the rejection to claims 1, 15 rejected under 35 U.S.C. 103 as being obvious over Li et al (US Publication No. 2018/0371496 A1, publication date December 27, 2018; of record IDS filed September 22, 2022(Cite No. A44)) in view of Bossis et al. (Journal of virology 77.12 (2003): 6799-6810;of record IDS filed September 22, 2022 (Cite No. C15)), as applied to claim 1, and in further view of Penzes et al. (Journal of General Virology 96.9 (2015): 2769-2779; of record IDS filed September 22, 2022 (Cite No. C120)) , are withdrawn.
In view of Applicants’ amendment to the claims dated June 4, 2026, wherein claims 1, 35, 176, 177, 182, 196, 197, 207, and 210 have been amended, and claims 20 and 168 have been cancelled, the rejection to claims 1, 20, 28, 167, 171-175, 178 and 179 rejected under 35 U.S.C. 103 as being obvious over Li et al (US Publication No. 2018/0371496 A1, publication date December 27, 2018; of record IDS filed September 22, 2022(Cite No. A44)) in view of Bossis et al. (Journal of virology 77.12 (2003): 6799-6810;of record IDS filed September 22, 2022 (Cite No. C15)), as applied to claim 1, and in further view of Byrne et al. (US Publication No. 2020/0407751 A1), are withdrawn.
In view of Applicants’ amendment to the claims dated June 4, 2026, wherein claims 1, 35, 176, 177, 182, 196, 197, 207, and 210 have been amended, and claims 20 and 168 have been cancelled, the rejection to claims 1, 178, 180-181 rejected under 35 U.S.C. 103 as being obvious over Li et al (US Publication No. 2018/0371496 A1, publication date December 27, 2018; of record IDS filed September 22, 2022(Cite No. A44)) in view of Bossis et al. (Journal of virology 77.12 (2003): 6799-6810;of record IDS filed September 22, 2022 (Cite No. C15)), as applied to claim 1, and in further view of Byrne et al. (US Publication No. 2020/0407751 A1), and as applied to claim 178, and in further view of Alam et al. (ChemBioChem 18.22 (2017): 2217-2221), are withdrawn.
The withdrawn rejections are in view of the Remarks filed on June 4, 2026 pointing to the Bossis et al teaching a recombinant AAV vector as being incapable of infecting primate animal cells as depicted in Bossis Table 1. Therefore, in view of the amended claim 1 which now recites the limitation “wherein the recombinant AAV particle is capable of infecting primate animal cells” the rejections have been withdrawn accordingly.
New Grounds of Rejection:
Claim Rejections - 35 USC § 112
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 1 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the recombinant adeno-associated virus (AAV) particle comprising: a VP1 amino acid sequence of the VP1-u region of AAV2 operably linked with the VP1/VP2 common region of the AAAV capsid protein, the sea lion AAV capsid protein, or the squamate AAV capsid protein, and both the AAV VP2 and VP3 amino acid sequences of the AAAV capsid protein, the sea lion AAV capsid protein, or the squamate AAV capsid protein; and wherein the first binding pair is located in the VP3 amino acid sequence, does not reasonably provide enablement for the full scope of claim 1 wherein the VP1 and VP2 are not specified, in addition to the site of the first binding pair. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the prior art; (4) The level of one of ordinary skill; (5) The level of predictability in the art; (6) The amount of direction provided by the inventor; (7) The existence of working examples; and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
The breadth of the claims. The invention encompasses a recombinant adeno-associated virus (AAV) particle comprising: (i) an AAV capsid comprising an AAV capsid protein, wherein the AAV capsid protein comprises at least an AAV VP3 amino acid sequence of an avian AAV (AAAV) capsid protein, a sea lion AAV capsid protein, or a squamate AAV capsid protein, and (ii) packaged within the AAV capsid, a viral genome, wherein the AAV capsid is modified to comprise at least a first member of a protein:protein binding pair ("first member"), wherein the recombinant AAV particle is capable of infecting primate animal cells. The AAV particle is not limited to any capsid protein, except the VP3 amino acid sequences derived from avian, sea lion, or squamate AAVs, in addition to the site of the first member in the AAV capsid. Claim 35 further limits the scope of claim 1 by claiming the full AAV particle amino acid sequences that are described in the Examples.
The nature of invention. The invention is directed to a recombinant AAV particles that are capable of infecting primate animal cells wherein they employ non-primate AAV capsid proteins for infection to bypass host immunity responses, in particular avian, seal lion, or squamate AAV capsid proteins.
State of the prior art. The art describes different approaches to design recombinant AAVs to bypass host immune responses while enhancing overall transduction in select cell lines, wherein methods involve combining different AAV serotypes capsid proteins. This approach is described by Li et al. (US 2018/0371496 A1) in which capsids from different AAV serotypes (AAV1 to AAV5) were compatible to assemble AAV virions in which transduction can be enhanced while escaping neutralization by neutralizing antibodies that form against select serotypes (par 0008, 10, 726; Example 1). In relation to avian, sea lion, and squamate AAVs, there is a lack of prior art regarding these viruses, and their respective sequences. Bossis et al. (Journal of virology 77.12 (2003): 6799-6810) teaches a recombinant avian AAV (AAAV); however the AAV is different from the claimed AAV in that it comprises AAAV rep and cap genes as opposed to only maintaining AAAV VP2 and VP3 sequences, and the VP1 and Rep sequences deriving from a primate AAV. The prior art appears to not teach outcomes wherein the recombinant AAV is combined with capsid sequences from both primate and non-primate AAV capsid sequences, and more specifically avian, sea lion, or squamate AAV sequences. Therefore, the outcomes of the claimed recombinant AAV comprising a VP2 that is not derived from the same AAV as the VP3, are not clear based on the lack of prior art, and the entirety of the instant Examples using both VP2 and VP3 from the same AAV serotype. It cannot be ascertained that the full scope of claim 1 AAVs are all capable of infecting primate animal cells.
Chai et al. (Viruses. 2019 Dec 9;11(12):1138) determined AAV transduction efficiencies can be enhanced by utilizing the VP1/VP2 of one serotype and VP3 of another compatible serotype, i.e. VP1/VP2 from serotypes 8 or 9, and VP3 from AAV2 (abstract). However, Chai’s results are based on results obtained with human AAV serotypes that are highly similar as opposed to the instant recombinant AAVs that employ more dissimilar AAVs, and respective capsid sequences to be combined.
Buning et al. (Molecular Therapy Methods & Clinical Development, 2019; 12, 248-265) teaches AAV capsid proteins expression being controlled by a single promoter, and furthermore, “AAV VPs share most of their amino acids. Specifically, the entire VP3 sequence is also contained within VP2 and VP1 (“common VP3 region”), and also VP2 and VP1 share approximately 65 amino acids (“common VP1/VP2 region”). Only VP1 contains a unique sequence at its N terminus (approximately 138 amino acids, VP1 unique).” (p 1, col 2; Fig. 1). Buning then describes modification of VP3 for peptide insertions wherein select modifications were determined to be suitable for peptide display, and only one, I-587, was suitable for target receptor-mediated cell transduction (p 3, col 2; Fig. 2; Table 1). Other sites have been determined, but such sites are rather limited. Additionally, the homologous residues of other serotypes also seem to be well suited for capsid engineering accordingly with slight variations (Table 3, 4). As a whole the prior art teaches the particular site of the location of a ligand in a capsid AAV appear to occur in the VP3 capsid, and moreover such sites are limited and differ slightly across serotypes.
The level of one of ordinary skill. There is a high level of skill required as seen in requiring a molecular engineering skills and knowledge in addition to experience with sequencing technologies and molecular cloning viral vectors.
The level of predictability in the art. The art is unpredictable. As described above, the prior art is lacking in chimeric recombinant AAVs wherein the capsid proteins are from different serotypes that include non-human AAVs. The prior art does teach the combination of serotypes has occurred in which the best outcomes were observed with VP1/VP2 from one serotype and VP3 from a different serotype, however this is dependent on the specific serotype combination, and was limited to human AAVs. Furthermore, the prior art teaches that the first member site or peptide insertion site is in the VP3 amino acid sequence, and that the site is highly specific to maintain the characteristics of the AAV vector. In view of the claimed recombinant AAV comprising capsids from avian, sea lion, or squamate AAVs, there is much uncertainty regarding the overall structure of the recombinant AAV in addition to its functionality wherein it is capable of infecting primate animal cells.
The amount of direction provided by the inventor; (7) The existence of working examples. The Specification includes 13 examples. Example 1 provide the structure of the recombinant AAV plasmid vectors wherein they each comprise the rep gene of AAV2, and a chimeric cap gene encoding a chimeric VP1 capsid protein comprising the VP1-u region of AAV2 operably linked with the VP1/VP2 common region, an AAAV VP2 capsid protein, and an AAAV VP3 capsid protein all from non-human AAVs, e.g. avian, sea lion, and squamates (par 732).The remaining examples are directed to peptide insertion sites in these VP3 amino acid sequences for binding purposes. Examples 2-4 describe these outcomes for each of the non-human AAVs wherein select sites were observed to not work as seen in Example 3 (par 754). The remaining examples further explore the sites that were functional/tolerated and use of different ligands while targeting different cell types, e.g. liver, lung, ear. In summary, the working examples only use AAV2 VP1 in addition to the VP2 and VP3 being from the same non-human animal AAV. Furthermore, the first member is located in the VP3 sequence, and is highly limited to particular amino acid sites.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure. There would be extensive experimentation required to determine the combinations of VP proteins are tolerated by the recombinant AAV wherein they are capable of infecting primate animal cells as claimed. Furthermore, the instant Specification investigated sites for peptide insertions in the VP3 sequences for each of the non-human AAVs, yet the work did not extend to the full sequences and the remaining VP proteins. Therefore, there remains much work to be done in view of the full scope of claim 1.
Conclusion: The claims are enabled for the full sequences recited in claim 35 that all employ the VP2 from the same AAV serotype as the VP3 while including the VP1 from AAV2; and moreover include the particular vectors used in the examples, and as such include the particular VP3 peptide modifications for the first member. It is not clear that the claimed VP3 would lead to similar outcome observed in the Examples with other VP1 and VP2 sequences than what is presented, and furthermore, the site of the first member should be described due to some sites leading to poor outcomes as observed in Example 3 and described in the prior art by Buning et al.
Claims 1, 15, 28, 108-110, 131, 164-167, 169-197 and 208-210 are rejected by dependency to claim 1, and for not absolving the scope of enablement issues for which the claim is rejected.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 108-110 are rejected under 35 U.S.C. 102(a)(1)(2) as being anticipated by Li et al. (US 2018/0371496 A1; provided in previous Office Action).
Claim 108 is directed to a packaging cell for producing the recombinant AAV particle of claim 1, comprising a nucleic acid molecule comprising an AAV cap gene encoding the AAV capsid protein.
Based on the claim not being limited to the composition of claim 1, but rather recites an intended usage of producing the composition in a packaging cell, the claim is anticipated by Li et al wherein packaging cell lines are taught that comprise nucleic acid molecules comprising an AAV cap gene encoding the AAV capsid protein (par 768).
Claims 109 and 110 are anticipated by Li et al based on teaching the cell lines as comprising a nucleic acid molecule comprising a rep gene encoding one or more AAV Rep proteins, wherein said rep gene is operably linked to a promoter (par 343-348,768; Fig. 17-20).
Conclusion
Claims 1, 15, 28, 35, 108-110, 131, 164-167, 169-197 and 208-210 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL A RIGA whose telephone number is (571)270-0984. The examiner can normally be reached Monday-Friday (8AM-6PM).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/TERESA E KNIGHT/Primary Examiner, Art Unit 1634
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