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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12, 2026 has been entered.
Claim Status
Claims 1-5, 8, 20-23, 25-28, 39, 43, 46, 48-52, 58-60, 63, 65-66 and 75-77 are currently pending in this application.
Election/Restrictions
Upon further consideration, the restriction of product from processes of making or using the product is restored because the product as claimed is not deemed allowable. Applicant’s election with traverse of Group I, claims 1-13, 15-18, 20-28, 34, and 38 in the reply filed on June 24, 2024 is acknowledged. Also, Applicant’s election of (e) wherein the peptide insertion comprises a sequence selected from SEQ ID NOs: 84-104, and Applicant’s election of (a) any species of nuclear localization signal (NLS) sequence, (b) species of peptide insertion in an AAV VP1 capsid protein, and (c) species of heterologous nucleic acid encoding Factor VIII. Claims 2-5, 8, 20-23, 25-28, 39, 43, 46, 48-52, 58-60, 63, 65-66, and 75-77 are withdrawn for being directed to non-elected subject matter.
Benefit of Priority Claim
Acknowledgement is made of applicant’s claim for the benefit of the prior-filed applications US 62/663,963 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c). Entitlement to priority to April 27, 2018 based on US 62/663,963 does not apply to the subject matter of a peptide insertion in one or more of AAV VP1, VP2 or VP3 capsid proteins of AAV2 having an amino acid sequence of SEQ ID NO: 122, therefore the earliest effective filing date of claim 1 is April 26, 2019 based on PCT/US2019/029487.
Claim Rejections - 35 USC § 112(a), Written Description
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, 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 claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of.
In the instant case, the claim is directed to a protein comprising an insertion of a nuclear localization signal (NLS), wherein the protein is an adeno-associated virus (AAV) capsid protein, such as wherein the capsid protein is modified from a parental AAV capsid protein consisting of SEQ ID NO: 1, 59, or 22 and wherein the insertion is at a specific position selected from 33, 35, 37, 139, 140, or 163.
Claim 1 recites the limitation “wherein said peptide insertion comprises an NLS sequence selected from SEQ ID NOs:84-104” which is broadly worded with the open-ended “comprising” and the lack of any formal definition for the term “peptide.” While the structure of the inserted peptide is partially defined by what it must comprise, the inserted peptide is unlimited in what other structures it may also comprise. It is noted that the instant application explains the peptide insertion may comprise 50-100 or more amino acid residues ([0088]). Thus, the length of the peptide insertion is not expressly limited.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described. In the instant case, the specification fails to provide any clear description of a representative number of species for the broad genus of possible insertion sequences as detailed below.
Insertions Comprising Any Sequence Unlimited in Size/Length
Claim 1 is broadly directed to a genus of modified AAV capsid proteins comprising an insertion of a “peptide” comprising a recited NLS and unlimited additional structure in the form of any peptide/polypeptide sequence (e.g., 50-100 or more residues or greater).
It must be emphasized that the scope the claim encompasses insertions with no limitation in sequence nor length/size so long as the insertion comprises at least one of SEQ ID NOs: 84-104 and so long as the AAV capsid protein possesses at least one known AAV VP1, VP2, or VP3 capsid protein functionality. For example, claim 1 encompasses the AAV VP1 protein based on instant SEQ ID NO: 1 modified to have an insertion of any combination of SEQ ID NOs: 84-104 consecutively in a row and still additional structure beyond that.
A peptide insert having a length of 163 residues encompasses virtually an infinite number of peptide species (over 9 x 10202 based on 20^157. Even for peptide inserts limited to 100 amino acid residues, the genus of peptides of claim 1 encompasses over 5.6 x 1063 to 9.9 x 10120 structurally and functionally undisclosed peptides just for peptides required to comprise SEQ ID NO: 95 or 104 respectively (20^49 or 20^93). However, the instant application only describes a small genus of peptide inserts consisting of 7 to 51 amino acid residues (Tables 2 and 4, SEQ ID NO: 84-104). Still, for peptide inserts limited in length to 51 amino acid residues, the genus of peptides of claim 1 encompasses over 1.7 x 1057 structurally and functionally undisclosed peptides comprising SEQ ID NO: 95 (20^44). The species disclosed (SEQ ID NOs: 84-104 and combination thereof) do not adequately represent the enormously vast genus of peptides encompassed by the claims that upon insertion into said parental AAV capsid protein will necessarily and predictably yield a functional AAV capsid protein.
Furthermore, the prior art teaches that insertions of peptides having 6 and/or 8-10 amino acids (HIS, AU, FLAG, HA, or Ser) into AAV2 capsid proteins at various positions inhibited virion production or produced defective virions (e.g., at position 39) (Wu et al., J Virol 2000 Sep;74: pg. 8635-47, at Fig. 1, Table 1). For example, these insertions resulted in “noninfectious” virions having an infectivity 5-logs lower compared to wild-type due to being unable to make capsids or failing to make stable capsids (class 4b) or being defective in a host cell binding, internalization, and/or uncoating step(s) (class 4a or 4d) (Wu at Table 2; Fig. 3). Thus, even insertions of “small” peptides can unpredictably destroy AAV capsid protein function. Regardless, the prior art teaches several regions on the AAV particle surface that do tolerate the insertion of foreign sequences (e.g., at position 139), despite unpredictable changes from small changes in insert size, sequence, and/or position generally, with previous insert sizes restricted to no more than about 30 amino acids at such permissive sites (Warrington et al., J Virol 78: 6595-609 (2004) at pg. 6596). Notably, Warrington teaches an insert of 76 amino acids (FKN) or as much as 150 amino acids (LEP+4 from cloning site) at position 139 of VP2 sometimes failed to produce functional VP2 and AAV particle structures (pg. 6598, left col., Fig. 1-2, Table 2), but the same inserts in VP1 or VP2 at position 139 could produce AAV particles depending on the context of other capsid protein coexpressed therewith during assembly (Fig. 6-7, Table 2).
Thus, not any sized peptide insert in an AAV capsid protein has a predictable effect and can be tolerated even at positions tolerating smaller inserts. In particular, the insertion of 150 amino acids (LEP) in VP2 at position 139 (pIM45-LEP138) significantly reduced expression indicative of protein misfolding (Warrington at Fig. 1A). As the prior art does not teach any predictable pattern for permissive insertion sites and larger inserts, these aspects must be described to a reasonable extent so that one of the ordinary skills in the art would recognize that Applicant was in possession of the full genus of inserts encompassed by claim 1 at the effective filing date of the claimed invention.
Although the instant specification describes permitted insertions in SEQ ID NO: 1, 59, and/or 122 at various positions, the instant application only shows empirical data for insertions having a length of 51 residues or less. The instant application describes putative examples of species of such proteins related to a parental protein having the sequence of SEQ ID NOs: 1, 59, or 122 wherein the insertions have various lengths (Tables 2 and 4), such as shown in some of the proteins having a sequence of SEQ ID NOs: 2-58, 60-83, and 105-121 (Tables 1 and 3; [0223]; [0009]-[0010]). Furthermore, not all of these proteins have been verified to retain a partial (e.g., minimal) AAV capsid protein activity of the parental protein (e.g., a VP1 capsid protein function), such as using a method taught by the prior art (WO2013170078A1, IDS ref.; at FIG. 14-17). Moreover, the instant specification specifically describes insertions of three or more tandem repeats of such insertion sequences ([0030]) with an increased length due to as many as 5 additional intervening residues ([0032]). Thus, the application prophetically describes species of such proteins comprising insertions of lengths of over 163 amino acid residues with no upper limit, e.g., 6, 7, or 8 tandem repeats, etc.
The instant specification lacks a written description for sufficient number of representative species for insertions of larger peptides (e.g., > 51 residues) at any position in a VP1, VP2, or VP3 AAV capsid protein, including wherein the parental protein is SEQ ID NO: 1, 59, and/or 122. Due to the unpredictability shown in the prior art, unlimited insertion size and wide range of insertion sites, more empirical evidence of untested insertion sizes greater than 51 residues is needed to show that Applicant was in possession of the full scope claimed. The skilled artisan cannot envision the variety of possible peptide insertions being permitted as broadly claimed to provide at least partial capsid function when the disclosure is silent of evidence beyond evidence for insertions of 51 residues or less. The prophetically described species having insert sizes of 163 residues or more are merely prophetically described without any working example or supporting evidence, such as retention of a minimal capsid protein function.
It is too unpredictable for a functional protein (AAV VP1, VP2, or VP3 capsid protein) to tolerate insertions of unlimited size. As mentioned already above, the prior art teaches that insertions of peptides as small as 6 and/or 8-10 amino acids into AAV2 capsid proteins at various positions can destroy protein function (Wu at Table 2; Fig. 3). Further, it is unpredictable specifically for an AAV capsid protein to tolerate even at known permissive insertion sites an insertion with 5 or more tandem NLS repeats even (e.g., > 150 amino acids) just based on evidence that the insertion site was already shown to tolerate a smaller peptide insertion, e.g., of 7-22 amino acids.
Furthermore, the allowance for additional sequences beyond the NLS motif(s) means the claims encompass untested sequences in addition to empirically tested ones. As the prior art notes, only one or a few amino acid mutations can significantly change the phenotype of the AAV capsid and that the correlation between a given mutation and the resulting phenotype is highly unpredictable, e.g., for random hexapeptides (WO2013170078A1 at [0115]).
Thus, the genus of insertions comprising any sequence with no upper limit is not sufficiently described by a representative number of species. Protein function is too unpredictable in general and in particular the functioning of AAV capsid protein in particular is too easily perturbed as taught by the art. Therefore in the instant case, empirical evidence is needed to show possession for inserts larger than about 51 amino acid residues, such as ones of 163 residues or more regardless of the position as well as ones comprising sequences in addition to SEQ ID NO: 84-104 of six or more residues (i.e., hexapeptides or larger).
As explained by the Federal Circuit, “(1) examples are not necessary to support the adequacy of a written description; (2) the written description standard may be met … even where actual reduction to practice of an invention is absent; and (3) there is no per se rule that an adequate written description of an invention that involves a biological macromolecule must contain a recitation of known structure. However, the claimed invention itself must be adequately described in the written disclosure and/or the drawings, such as using identifying structural characteristics (e.g., structural motifs or consensus sequences) or combinations of characteristics (e.g., a motif and overall hydrophobicity, polarity or charged side chains or a structural motif conferring an importin receptor binding activity) (see MPEP 2163).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed” (pg 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (pg 1116). As discussed above, the skilled artisan cannot envision the structure(s) of the genus of insertions regarding both sequence and length which allow for preservation of at least partial AAV capsid protein function based on the information provided in the instant application, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to potential and generic ways of modifying an AAV capsid protein via insertion of undefined amino acid sequences. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
There is a lack of evidence in the instant specification as filed that the inventors were in possession of any insertion merely comprising a recited NLs sequence(s) but otherwise without limit such that the capsid protein predictably retains at least a partial capsid protein function. The written description requirement may be satisfied through 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 structure and function, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed invention. In the instant case, examples of identifying characteristics may include a protein sequence, conserved structure-function, capsid monomer binding affinity/specificity, AAV packaging, or AAV replication/infection/transduction assay using the claimed protein to show retention of a partial (minimal) AAV capsid function. The instant application fails to provide sufficient descriptive information across the breadth of the claims.
Response to arguments
Applicant previously argued in the response filed 10/2/25 (pg. 10) that claim 1 was amended to wherein the insertion is less than 50 amino acids in length; however, instant claim 1 encompasses inserts of any length so long as they comprise at least one NLS selected from at least one of SEQ ID NOs: 84-103. Thus at further consideration and consideration of the newly cited references, the allowance has been withdrawn for the reasons above.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore, can be reached on 571-272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ERIC J ROGERS/Examiner, Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
Prosecution Insights