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 .
Restriction/Election of Species
The previous Examiner required a restriction in the Office Action mailed out on 13 March 2026. The previous Examiner identified three Groups.
In their Response filed on 10 July 2026, Applicant elected Group I, claims 42-50, 52, and 53, without traverse.
The previous Examiner also required an election of species in the Office Action mailed out on 13 March 2026.
In their Response filed on 10 July 2026, Applicant elected the following species, without traverse: LVB30, as identified in Table 1 of the instant Specification, corresponding to SEQ ID NOs: 36, 85, 134, and 182.
Disposition of Claims
Claims 42-58 are pending.
Claims 51 and 54-58 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10 July 2026.
Claims 48 and 53 are also withdrawn from further consideration, even though they are part of the elected invention, Group I, because these claims do not read on the elected species.
Accordingly, Claims 42-47, 49-50, and 52 will be examined on their merits.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US 2024/0197918 A1, Published 20 June 2024. Applicant’s amended Specifications are presented on 10 September 2024 and 23 October 2023 are acknowledged and entered.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The information disclosure statements (IDSes) submitted on 25 September 2024 and 10 July 2026 have been considered by the examiner.
Drawings
The drawings are objected to because Figure 8 contains images which are too small and blurry to discern the details being displayed. Namely, the VHH, GP2, Cyclic peptide, and Knottin all contain images which do not allow for proper identification of the contents being disclosed. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. Specifically, Figure 8 comprises twelve (12) sequences without SEQ ID NOs being present in either the figure itself or in the figure legend within the Specification. These sequences have at least 4 specifically defined and enumerated amino acid residues and are therefore required to have SEQ ID NOs. If the sequences correspond to existing SEQ ID NOs in the Sequence Listing, then they must be identified by their corresponding SEQ ID NOs in either the figure itself or in the figure legend within the Specification, even if they are disclosed elsewhere in the disclosure. If the sequences do not correspond to existing SEQ ID NOs in the Sequence Listing, then each sequence must be assigned its own unique SEQ ID NO.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities: In Paragraph 0123 of the PGPub of the instant application, it says “Wild type AAV capsid proteins sequences are disclosed in table XXX”. It is unclear which table is being referenced. Also, it should say “protein[[s]] sequences” instead of “proteins sequences”.
Appropriate correction is required.
The disclosure is objected to because of the following informalities: At Paragraph 0046, sequences are described by reference to GenBank Accession Nos., which are subject to change, rather than to sequences set forth in the specification. This is an improper incorporation by reference, since the information required to describe and enable the required sequences is found in the NCBI database, extraneous to the application. Furthermore, since the NCBI sequences are not irrevocably fixed but are corrected and updated as additional sequence information becomes available, the NCBI accession numbers may refer to sequences which change after the application filing date. Thus, the disclosure is objected to for this improper incorporation by reference.
Furthermore, essential material such as that which provides written description or enablement, as here since the antigen is needed for functional antibody identification, should not come from NPLs. See 37 CFR 1.57d.
Appropriate correction is required.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims are only allowed to have one period, as stated in MPEP § 608.01(m). The claim which does not adhere to this rule is Claim 42. Regarding Claim 42, parts i and ii should utilize parentheses instead of periods to separate them from the claim language itself.
Claim Rejections - 35 USC § 112(b); Second Paragraph
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 45 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.
Claim recites the limitation "the peptide insertion" in Line 1. There is insufficient antecedent basis for this limitation in the claim as Claim 42, upon which Claim 45 depends, does not introduce the limitation of “a peptide insertion”. While Claim 42 does recite both “an acetylcholinesterase collagenic tail (ColQ) peptide sequence” and “an RGD-motif peptide sequence”, the word “insertion” is not actually recited anywhere in this claim. The only other claim which recites “insertion” other than Claim 45 is Claim 44. As such, it is unclear what peptide insertion is being referenced. It is suggested that either Claim 42 or 45 be amended to properly introduce the limitation of “a peptide insertion” or that Claim 45 be amended to be dependent on Claim 44, but Applicant is free to amend the claims as they deem necessary.
Claim 45 is also rendered indefinite because it is unclear which peptide insertion is being referenced as Claim 42 refers to both the ColQ peptide sequence and the RGD-motif peptide sequence or if it is meant to refer to both. It is suggested that Claim 45 be amended to clarify which peptide insertion is being reference or if the claim limitation is meant to refer to both the ColQ peptide sequence and the RGD-motif peptide sequence, but Applicant is free to amend the claim as they deem necessary.
Since a skilled a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 45 is rejected on the grounds of being indefinite.
Claim 50 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.
Regarding Claim 50, it recites the limitation “wherein: the VP1 capsid protein is encoded by a nucleic acid sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 134-140, 142, 143, 145, 148, 149, 170, 172, or 173; and/or the VP2/VP3 capsid protein is encoded by a nucleic acid sequence at least 80%, 85%,90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 182-188, 190, 191, 193, 196, 197, 218, 220, or 221”. The claim language used conflicts with itself as the first part indicates that nucleic acid sequences will be recited, but then also refers to amino acid sequences and leads to the interpretation that the SEQ ID NOs actually correspond to amino acid sequences. The SEQ ID NOs actually being claimed, however, correspond to nucleic acid sequences. For instance, SEQ ID NOs: 134 and 182, at least, are nucleic acid sequences. As such, it is unclear if nucleic acid sequences or amino acid sequences were meant to be recited. This lack of clarity renders the claim indefinite. It is suggested that the claim be amended to recite “wherein: the VP1 capsid protein is encoded by a nucleic acid sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to any one of the nucleic acid sequences selected from the group consisting of SEQ ID NOs: 134-140, 142, 143, 145, 148, 149, 170, 172, or 173; and/or the VP2/VP3 capsid protein is encoded by a nucleic acid sequence at least 80%, 85%,90%, 95%, 96%, 97%, 98%, 99% or 100% identical to any one of the nucleic acid sequences selected from the group consisting of SEQ ID NOs: 182-188, 190, 191, 193, 196, 197, 218, 220, or 221” or similar language, assuming that nucleic acid sequences were meant to be recited, but Applicant is free to amend the claim as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 50 is rejected on the grounds of being indefinite.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim Rejections - 35 USC § 112(a); First Paragraph
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.
Claims 43, 49-50, and 52 are 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 an AAV capsid comprising a VP1 capsid protein comprising an acetylcholinesterase collagenic tail (ColQ) peptide sequence a VP2/VP3 capsid protein comprising an RGD-motif peptide sequence, wherein the ColQ peptide comprises an amino acid sequence with 100% sequence identity to SEQ ID NO: 302, the VP1 capsid protein comprises an amino acid sequence comprises a sequence with 100% sequence identity to SEQ ID NO: 36, wherein VP2/VP3 capsid protein comprises an amino acid sequence with 100% sequence identity to SEQ ID NO: 85, wherein the VP1 capsid protein is encoded by a nucleic acid sequence with 100% sequence identity to SEQ ID NO: 134, and wherein the VP2/VP3 capsid protein is encoded by a nucleic acid sequence with 100% sequence identity to SEQ ID NO: 182, does not reasonably provide enablement for an AAV capsid comprising a VP1 capsid protein comprising an acetylcholinesterase collagenic tail (ColQ) peptide sequence a VP2/VP3 capsid protein comprising an RGD-motif peptide sequence, wherein the ColQ peptide comprises an amino acid sequence with less than 100% sequence identity to SEQ ID NO: 302, the VP1 capsid protein comprises an amino acid sequence comprises a sequence with less than 100% sequence identity to SEQ ID NO: 36, wherein VP2/VP3 capsid protein comprises an amino acid sequence with less than 100% sequence identity to SEQ ID NO: 85, wherein the VP1 capsid protein is encoded by a nucleic acid sequence with less than 100% sequence identity to SEQ ID NO: 134, and wherein the VP2/VP3 capsid protein is encoded by a nucleic acid sequence with less than 100% sequence identity to SEQ ID NO: 182 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/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to an AAV capsid comprising: i) a VP1 capsid protein comprising an acetylcholinesterase collagenic tail (ColQ) peptide sequence; and ii) a VP2/VP3 capsid protein comprising an RGD-motif peptide sequence, wherein the ColQ peptide comprises an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence TPFYPVGYTVKQPGTCGDGVLQPGEECDDGNPDVSDGCIDCHRAYCGDGYRHQGVEDCDGSDFGYLTCETYLPGSYGDLRCTQYCSIDSTPCRYFT (SEQ ID NO: 302), wherein: the VP1 capsid protein comprises an amino acid sequence at least 80%, 85%, 90%, 95%,96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 36-42, 44, 45, 47, 50, 51, 72, 74, or 75; and/or the VP2/VP3 capsid protein comprises an amino acid sequence at least 80%, 85%, 90%,95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 85-91, 93, 94, 96, 99, 100, 121, 123, or 124, wherein: the VP1 capsid protein is encoded by a nucleic acid sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 134-140, 142, 143, 145, 148, 149, 170, 172, or 173; and/or the VP2/VP3 capsid protein is encoded by a nucleic acid sequence at least 80%, 85%,90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 182-188, 190, 191, 193, 196, 197, 218, 220, or 221, and wherein the capsid comprises: i) a VP1 capsid protein comprising an amino acid sequence at least 80%, 85%, 90%,95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 36; and ii) a VP2/VP3 capsid protein comprising an amino acid sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 85.
State of the prior art/Predictability of the art. The art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess et al., J of Cell Bio. 111:2129-2138, 1990). In transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar et al. Molecular and Cellular Biology 8:1247-1252, 1988). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e. inhibit or activate). Ju (Proceedings of the National Academy of Sciences, U.S.A., Vol. 88, Pg. 2658-2662, 1991) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide.
This substitution need not be at a position where said residue would contact the target protein. Baker (Immunity, Vol. 13, Pg. 475-484, 2000) teaches that Tax-peptide is an agonist of the of T cell activity (Abstract). However, mutation of proline at position 6 of this peptide to alanine creates a T cell antagonist (Abstract). Importantly, this residue does not contact the T cell receptor (Abstract).
In another case, Huang (The Journal of Biological Chemistry, Vol. 272, No. 43, Pg. 27155-27159, 1997) teaches that conjugation of peptides to other proteins can change their biological properties. They teach that multiple conjugation of the peptide TGFβ1 (residues 41-65) to carrier proteins enhances its antagonist activity but also confers partial agonist activity as well (Abstract). Thus, the chemical context of a biologically active peptide is also important.
Truncation of proteins can also lead to adverse effects on protein structure and thus protein function. Martindale (Nature Genetics, Vol. 18, Pg. 150-154, 1998) teaches that truncation of huntingtin leads to aggregate development which compromises cell viability (Abstract). Nonaka (Human Molecular Genetics, Vol. 18, No. 18, Pg. 3353-3364, 2009) teaches that truncation of TDP-43 to its C-terminal fragments causes abnormally phosphorylated and ubiquitinated inclusions of the protein (Abstract). Taken together, not just any truncation of a protein will yield a soluble, functional, protein fragment.
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. For example, agonist and antagonist peptides can be interconverted through conjugation or mutagenesis. Importantly, binding can still occur after mutation or conjugation in the literature examples provided above, illustrating that a simple show of binding is not predictive of the nature of a peptide’s biological activity. This point is underlined by Montrose-Rafizadeh (The Journal of Biological Chemistry, Vol. 272, Pg. 21201-21206, 1997) who teaches that receptor binding does not predict agonist or antagonist activity (Pg. 21205, Column 2, Paragraph, first full, Sentence, first).
With respect to the use of peptides in the treatment of a disease such as cancer, the state of the art at the time of filing was such that it was unpredictable whether or not a peptide would function therapeutically. Their functionality depends, in part, on whether or not they reach their intended target in a sufficient quantity as to cause a therapeutic effect. Mendoza (Arch. Immunol. Ther. Exp., Vol. 53, Pg. 47-60, 2005) teaches that peptides derived from larger molecules that are important modulators of apoptosis are frequently becoming leads for the development of anticancer therapeutics (Pg. 48, Column 2, Paragraph, first partial). However, they also state that natural peptides have low bioavailability and short half-life in the mammalian circulation system, while synthetic peptides have potential cytotoxicities (Pg. 57, Column 1, Paragraph, last full). Due to these characteristics, systematic testing in in vivo as well as in vitro settings must be done rigorously to verify peptide applications in the clinic (Pg. 57, Column 1, Paragraph, last full). Taken together, barring experimental evidence, no peptide can merely be assumed to function in the treatment of a disease, for example cancer, in vivo just because it functions as an inhibitor in vitro.
Working examples. No working examples of the claimed variants are disclosed in the specification. Examples 1-4 disclose various AAV vectors with modified capsids, such as LBV30, LBV31, LBV55, LBV91, and LBV92, which presumably all have sequences that are 100% identical to their constituent sequences, in particular LBV30, the elected species, which presumably has sequences which are 100% identical to instant SEQ ID NOs: 302, 303, 36, 85, 134, and 182 (see Paragraphs 0186-0195; Tables 2-3).
Guidance in the specification. The specification provides guidance towards various modifications, as noted in Paragraph 0101, which states that modifications “to AAV capsid protein sequences can be any protein modification known in the art including amino acid deletions, mutations, insertions, or re-arrangements”, while Paragraph 0103 states that AAV capsid proteins of the disclosure can be both chimeric and contain at least one of an amino acid deletion, mutation, insertion, or re-arrangement”. The instant Specification discloses substitutions with similar amino acids (i.e., conservative amino acid substitutions) (see Paragraph 0120), but does not disclose which regions of the claimed sequences can tolerate such changes. This also applies to the insertion and deletion mutations and the rearrangements or swaps recited in the Specification. Paragraph 0123 states that “modified AAV capsid proteins of the disclosure comprise insertions and/or deletions or variable regions swaps that may alter the length of the capsid protein sequence”. Despite this information, the instant Specification fails to identify the essential or critical residues or bases of the claimed amino acid sequence and nucleotide sequences, respectively.
Amount of experimentation necessary. Since the art teaches that it is unpredictable whether or not peptide variants and nucleotide variants of known sequences will function as expected, and the specification does nothing to ameliorate these concerns, one would be burdened with undue experimentation to use the products of instant claims as broadly as they are currently claimed.
Claims 43, 49-50, and 52 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant application attempts to tie function to sequence identity in the context of an AAV capsid comprising: i) a VP1 capsid protein comprising an acetylcholinesterase collagenic tail (ColQ) peptide sequence; and ii) a VP2/VP3 capsid protein comprising an RGD-motif peptide sequence, wherein the ColQ peptide comprises an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence TPFYPVGYTVKQPGTCGDGVLQPGEECDDGNPDVSDGCIDCHRAYCGDGYRHQGVEDCDGSDFGYLTCETYLPGSYGDLRCTQYCSIDSTPCRYFT (SEQ ID NO: 302), wherein: the VP1 capsid protein comprises an amino acid sequence at least 80%, 85%, 90%, 95%,96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 36-42, 44, 45, 47, 50, 51, 72, 74, or 75; and/or the VP2/VP3 capsid protein comprises an amino acid sequence at least 80%, 85%, 90%,95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 85-91, 93, 94, 96, 99, 100, 121, 123, or 124, wherein: the VP1 capsid protein is encoded by a nucleic acid sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 134-140, 142, 143, 145, 148, 149, 170, 172, or 173; and/or the VP2/VP3 capsid protein is encoded by a nucleic acid sequence at least 80%, 85%,90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 182-188, 190, 191, 193, 196, 197, 218, 220, or 221, and wherein the capsid comprises: i) a VP1 capsid protein comprising an amino acid sequence at least 80%, 85%, 90%,95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 36; and ii) a VP2/VP3 capsid protein comprising an amino acid sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 85.
As noted above in the Scope of Enablement rejection, no working examples of the claimed variants are disclosed in the specification. Examples 1-4 disclose various AAV vectors with modified capsids, such as LBV30, LBV31, LBV55, LBV91, and LBV92, which presumably all have sequences that are 100% identical to their constituent sequences, in particular LBV30, the elected species, which presumably has sequences which are 100% identical to instant SEQ ID NOs: 302, 303, 36, 85, 134, and 182 (see Paragraphs 0186-0195; Tables 2-3). The specification provides guidance towards various modifications, as noted in Paragraph 0101, which states that modifications “to AAV capsid protein sequences can be any protein modification known in the art including amino acid deletions, mutations, insertions, or re-arrangements”, while Paragraph 0103 states that AAV capsid proteins of the disclosure can be both chimeric and contain at least one of an amino acid deletion, mutation, insertion, or re-arrangement”. The instant Specification discloses substitutions with similar amino acids (i.e., conservative amino acid substitutions) (see Paragraph 0120), but does not disclose which regions of the claimed sequences can tolerate such changes. This also applies to the insertion and deletion mutations and the rearrangements or swaps recited in the Specification. Paragraph 0123 states that “modified AAV capsid proteins of the disclosure comprise insertions and/or deletions or variable regions swaps that may alter the length of the capsid protein sequence”. Despite this information and the presence of percent identity cutoffs in the claims, the instant Specification fails to identify the essential or critical residues or bases of the claimed amino acid sequence and nucleotide sequences, respectively.
Furthermore, while it is not explicitly stated, it is assumed that the constructs used in the instant Specification have sequences which are 100% identical to the claimed sequences. Even if that is not the case, the data provided do not explicitly include any claimed variants having as little as 80% sequence identity, or even 81-99% sequence identity, relative to the claimed sequences, raising questions about how effective these claimed variants would be in the data provided. Thus, it is not clear what was tested, it does not appear that any claimed variants were tested, and the essential characteristics of the genera being claimed by Applicant have not been identified or disclosed.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contributions to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle and Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient details that one skilled in the art can reasonably conclude that the invention had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which the peptide or nucleotide variants can have any sequences which vary from instant SEQ ID NOs: 36, 85, 134, 182, and 302 by as much as 20%, one must describe a sufficient variety of species to reflect the variation within the genus. However, one of skill in this art cannot envision the structure of any peptide or nucleotide variants with the required sequence identity other than the few species provided by Applicant and the prior art. Therefore, since only a few species are provided to represent the genera, the claims encompassing the same clearly fail the written description requirement.
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014).
Overall, at the time the invention was made, the level of skill for preparing peptide and nucleotide variants and then selecting those peptides and nucleic acids which meet the desired percent identity cutoff was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identity peptide and nucleotide variants with the recited percent identity cutoff, the written description provision of 35 U.S.C. 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010). Absent the conserved structure provided by a core peptide or nucleotide sequence, the skilled artisan would not be able to visualize or otherwise predict, a priori, what any peptide or nucleotide which meets the recited percent identity cutoff would look like structurally.
While applicant has described a few species within the genera recited, and the art may provide more, each genus is very large and would encompass peptide and nucleotide structures that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the peptide or nucleotide structures encompassed by the claimed/recited genera only defined by sequence identity. Any future peptide and nucleotide variants may or may not be encompassed, as if they are, they would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the entire recited genera of peptide and nucleotide variants. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Therefore, the claims are rejected here.
As such, it does not appear Applicant was in possession of the full scope of the claimed invention at the time of filing and thus Claims 43, 49-50, and 52 do not meet the written description requirement.
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.
Claims 42-47, 49-50, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Wörner et al. (Wörner, T. P., Bennett, A., Habka, S., Snijder, J., Friese, O., Powers, T., Agbandje-McKenna, M., & Heck, A. J. R. (2021). Adeno-associated virus capsid assembly is divergent and stochastic. Nature Communications, 12(1), Article 1642.) (cited in the previous Office Action), Weinmann et al. (Weinmann, J., Weis, S., Sippel, J., Tulalamba, W., Remes, A., El Andari, J., Herrmann, A.-K., Pham, Q. H., Borowski, C., Hille, S., Schönberger, T., Frey, N., Lenter, M., VandenDriessche, T., Müller, O. J., Chuah, M. K., Lamla, T., & Grimm, D. (2020). Identification of a myotropic AAV by massively parallel in vivo evaluation of barcoded capsid variants. Nature Communications, 11(1), Article 5432.) (cited in the previous Office Action and on the IDS filed by Applicant on 25 September 2024), Rotundo et al. (Rotundo, R. L., Rossi, S. G., Kimbell, L. M., Ruiz, C., & Marrero, E. (2005). Targeting acetylcholinesterase to the neuromuscular synapse. Chemico-Biological Interactions, 157(C (Special Issue)), 15–21.) (cited in the previous Office Action) (Rotundo 1), Vandenberghe et al. (US 2009/0197338 A1, Published 06 August 2009), Mendell et al. (US 2014/0323956 A1, Published 30 October 2014), Grimm et al. (WO 2019/207132 A1, Published 31 October 2019) (cited on IDS filed by Applicant on 10 July 2026), and Rotundo et al. (WO 2006/076024 A2, Published 20 July 2006) (Rotundo 2).
Wörner et al. teach that adeno-associated viruses (AAVs) express three distinct viral proteins: VP1, VP2, and VP3 (see Abstract; Page 2, Left Column, Paragraphs 1-2; Figure 1). Wörner et al. also teach that AAVs are increasingly used as gene therapy vectors, wherein recombinant AAVs that package a gene of interest for delivery to tissues or cells to treat a disease (see Abstract; Page 2, Left Column, Paragraph 1).
Wörner et al. does not teach AAV comprising modified capsid proteins with peptide insertions.
Weinmann et al. teach that RGD-motifs, which are known binding partners for integrins, inserted in AAV9 increase mouse muscle transduction (see Page 8, Right Column, Paragraphs 1-2).
Rotundo 1 teach that specific binding sites exist at the neuromuscular junction (NJM) that can retain the collagenic tail (ColQ) of acetylcholinesterase (AChE) and helps with localization of the enzyme to the site of nerve-muscle contact (see Page 17, Left Column, Paragraphs 1-2).
Vandenberghe et al. teach methods for increasing the gene transfer efficiency of AAV (see Abstract), as well as an AAV comprising prior art SEQ ID NO: 9, which is 95.2% identical to instant SEQ ID NO: 182 (see Sequence Listing).
Mendell et al. teach recombinant AAV (rAAV) as vectors for gene therapy, with a serotype of rh74 (see Abstract; Paragraphs 0012, 0058; Figure 4), as well as an AAV comprising prior art SEQ ID NO: 2, which is 82.9% identical to instant SEQ ID NO: 36 and 97.6% identical to instant SEQ ID NO: 85 (see Sequence Listing).
Grimm et al. teach the use of AAV comprising an RGD-motif peptide insertion in the AAV capsid (See Abstract), wherein said RGD motif comprises or consists of RGDLGLS, prior art SEQ ID NO: 2, which is 100% identical to instant SEQ ID NO: 303 (see Sequence Listing).
Rotundo 2 teach SEQ ID NO: 4 (AEJ35017), which corresponds to a fusion protein comprising a truncated trimeric COLQ tail and comprises a sequence that is 100% identical to instant SEQ ID NO: 302 (see Sequence Listing).
A person having ordinary skill in the art would have been motivated to modify the teachings of Wörner et al with those of Weinmann et al., Rotundo 1, Vandenberghe et al., Mendell et al., Grimm et al., and Rotundo 2 in order to generate an AAV capsid with a particular tropism. The RGD-motifs taught by Grimm et al. and Weinmann et al. and the ColQ taught by Rotundo 1 and 2 would have enabled the retargeting of the AAV of Wörner et al. comprising the sequences of the AAV of Vandenberghe et al. and Mendell et al. to make it more effective at transducing certain cell types, tissues, and/or organs, while reducing targeting of the liver. VP1 could carry ColQ and VP2 or VP3 could carry the RGD motif as one of few embodiments of this obvious modification. It would have been obvious to try the finite number of combinations for the peptide insertions in the AAV capsid, given that there are only a few possible rearrangements. The claimed invention in Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 82 USPQ2d 1321 (Fed. Cir. 2007), was directed to the amlodipine besylate drug product, which was sold in tablet form in the United States under the trademark Norvasc®. Amlodipine and the use of besylate anions were both known at the time of the invention. Amlodipine was known to have the same therapeutic properties as were being claimed for the amlodipine besylate, but Pfizer discovered that the besylate form had better manufacturing properties (e.g., reduced "stickiness").
Pfizer argued that the results of forming amlodipine besylate would have been unpredictable and therefore nonobvious. The court rejected the notion that unpredictability could be equated with nonobviousness here, because there were only a finite number (53) of pharmaceutically acceptable salts to be tested for improved properties.
The court found that one of ordinary skill in the art having problems with the machinability of amlodipine would have looked to forming a salt of the compound and would have been able to narrow the group of potential salt-formers to a group of 53 anions known to form pharmaceutically acceptable salts, which would be an acceptable number to form "a reasonable expectation of success."
The obvious molecules here would have linkers joining one or both inserted peptides to the rest of the chimeric protein(s) as is standard practice in this art.
As noted by Grimm et al., one problem of retargeting AAV is that substantial targeting of the liver is often unaltered, which can lead to side effects and delivery of therapeutic genes to the wrong organ. The combination of these teachings would lead to a safer and more effective vector for gene therapy and also render the instant claims obvious, as the prior art AAV would be safely retargeted to muscle or neuromuscular cells as both the RGD motifs and ColQ are both taught in the art to direct targets to muscle cells.
Such modifications, combining prior art elements according to known methods in order to yield predictable results, would have had a reasonable expectation of success and arrived at the claimed invention prior to the effective filing date of the instant application. For at least these reasons, instant Claims 42-47, 49-50, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over the prior art.
Conclusion
No claims are allowed.
The prior art made of record, but not relied upon, and considered pertinent to applicant's disclosure is listed below:
Gray (U.S. Patent No. 12,296,026 B2)
Gray teaches regulatory elements as well as vectors containing the same that may be used to stimulate transcription of a gene of interest in certain tissue types, wherein said vectors can be AAV vectors comprising mutant capsid that target particular cell types more effectively than wild-type capsids. This reference has not been utilized, as rejection would have been redundant to those set forth above.
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/CAREY ALEXANDER STUART/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671
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