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 .
Election/Restrictions
The full genus of SEQ ID NO: 1 was search and found to be free of the prior art. The election of species requirement mailed November 19, 2025, is withdrawn.
Requirement for Information
Applicant and the assignee of this application are required under 37 CFR 1.105 to provide the following information that the examiner has determined is reasonably necessary to the examination of this application.
Avitide, the assignee of this application, discloses AVIPure® - AAV8 (avitide.com/resource-library/avipure-aav8-development-webinar/, accessed June 6, 2026) as having:
Extremely high capacity: DBC10 > 1.0 x 1015 vp/mLRESIN
Ability to process at fast flow rates enabling high volumetric processing capability
The ability to clean with 0.5 M NaOH for repetitive purification cycles
High purity of eluted product in a single step from lysate feed streams
Large diameter agarose bead enables high flow rates and excellent resistance to fouling
The website states: “The order of magnitude improvement in resin lifetime promises to dramatically decrease resin costs for AAV programs requiring annual production of very large amounts of capsids. The affinity ligand is a novel protein with exquisite specificity for rAAV8, binding the virus with picomolar affinity. Overall, AVIPure® – AAV8 resin provides excellent yield, purity and throughput for single-step purification of rAAV8 and enables the use of sodium hydroxide as a cleaning agent for greater than 20 cycles without losing capacity or purification performance.”
In response to this requirement, please provide answers to each of the following interrogatories eliciting factual information:
1) What is the structure of the affinity ligand with “exquisite specificity for rAAV8” in AVIPure® - AAV8, sold by the assignee of this application? What is the amino acid sequence of this ligand?
2) What is the earliest date that this product, sold by the assignee of this application, was described in a printed publication, or in public use, on sale, or otherwise available to the public?
This information is necessary to determine if a claimed affinity ligand was 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.
The applicant is reminded that the reply to this requirement must be made with candor and good faith under 37 CFR 1.56. Where the applicant does not have or cannot readily obtain an item of required information, a statement that the item is unknown or cannot be readily obtained may be accepted as a complete reply to the requirement for that item.
This requirement is an attachment of the enclosed Office action. A complete reply to the enclosed Office action must include a complete reply to this requirement. The time period for reply to this requirement coincides with the time period for reply to the enclosed Office action.
Claim Interpretation
BRI of “specifically interactions” is according to paragraph [0042] of the specification and further exemplified in paragraphs [0054]-[0058].
Claim Objections
Claim 1 is objected to because of the following informalities: in part (s) “is comprises” is an error. Appropriate correction is required.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications, Application No. PCT/US21/54870 and 63/091,207, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The applications fail to provide adequate support and enablement for the same reasons as presented in the rejections under 35 U.S.C. 112 below. In addition, Application 63/091,207 fails to explicitly disclose instant SEQ ID NO: 1. Therefore, the earliest effective filing date of instant claims 1-8, 10, 12, and 14-24 is April 13, 2023.
Claim Rejections - 35 USC § 112(a)
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 1-8, 10, 12, and 14-24 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.
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 the applicant was in possession of the claimed genus.
The invention is in the technical field of affinity ligands useful for specifically interacting with adeno-associated virus serotype 8 (AAV8). The affinity ligands can be used to isolate and purify AAV8-based products, which in turn are useful in the field of gene therapy.
The claims are drawn to a broad genus of amino acid sequences purported to be useful for specifically interacting with AAV8. Owing to the variable positions X1 to X17, instant SEQ ID NO: 1 comprises a core sequence (the sequence internal to [A] and [B]) of over 1.88 x108 unique amino acid sequences. Although with the aid of a computer it may be possible to generate all of the amino acid sequences that meet the structural requirements of the genus, it is not readily apparent from the specification, claims, nor prior art which of these sequences possess the ability to specifically interact with AAV8. Even claim 8, the narrowest claim, recites 79 different sequences.
The specification discloses the actual reduction to practice of SEQ ID NO: 53 (Figures 3 and 4). This species is not representative of the full scope of the claimed genus because it is only one of over 1.88 x108 unique amino acid sequences in the genus.
Therefore, the instant specification has failed to meet the written description requirement by actual reduction to practice of a representative number of species alone.
The prior art pertaining to peptide structure and function is highly unpredictable. Although it is generally recognized that the function of a peptide is related to its amino acid sequence, the ability to predict the effect of changes to sequence on function requires empirical determination.
In the instant case, Figure 2 of the specification shows that peptides with different sequences within the claimed genus exhibit different stability in the presence of 0.5 M NaOH. Although the sequences are in the genus, they have different functional properties.
The specification does not describe a general correlation between structure and function for the claimed genus. The role of the seventeen variable amino acids and positions [A] and [B] of SEQ ID NO: 1 in the AAV8 binding site, binding site formation, binding site environment and overall fold, stability and dynamics of the peptide are not described. Although several peptides were examined for AAV8 binding, this data was not presented in terms of a structure-function analysis. Therefore, it is not possible to determine how changes at positions X1 to X17, [A], and [B] will affect the claimed function of interacting with AAV8.
Solid state peptide synthesis and the cloning, recombinant expression and purification of proteins is well-known in the art. It is not disputed that one of ordinary skill in the art could isolate, albeit with route experimentation and optimization, a peptide of a given sequence provided that the sequence is known. Where the specification fails to provide description is in the structure of the peptide to make. For all of the reasons presented above, one of ordinary skill in the art would not know which of the countless peptides that meet the structural requirements of the claims would also be able to interact specifically with AAV8. The specification does not make clear which peptides are in the genus and which are not because it does not describe the physical basis for the claimed activity. In other words, the specification does not describe which peptides to make.
For these reasons, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention.
In conclusion, only SEQ ID NO: 53 satisfies the written description requirements of 35 U.S.C. 112.
Claims 1-8, 10, 12, and 14-24 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 using SEQ ID NO: 53, does not reasonably provide enablement for using all affinity ligands of SEQ ID NO: 1 to specifically interaction with AAV8. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To comply with the enablement requirements of 35 U.S.C. §112, first paragraph, a specification must adequately teach how to make and how to use a claimed invention throughout its scope, without undue experimentation. Plant Genetic Systems N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003). There are a variety of factors which may be considered in determining whether a disclosure would require undue experimentation. These factors include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The Nature of the Invention
The invention is in the technical field of affinity ligands useful for specifically interacting with adeno-associated virus serotype 8 (AAV8). The affinity ligands can be used to isolate and purify AAV8-based products, which in turn are useful in the field of gene therapy.
The breadth of the claims
The claims are drawn to a broad genus of amino acid sequences purported to be useful for specifically interacting with AAV8. Owing to the variable positions X1 to X17, instant SEQ ID NO: 1 comprises a core sequence (the sequence internal to [A] and [B]) of over 1.88 x108 unique amino acid sequences. Although with the aid of a computer it may be possible to generate all of the amino acid sequences that meet the structural requirements of the genus, it is not readily apparent from the specification, claims, nor prior art which of these sequences possess the ability to specifically interact with AAV8. Even claim 8, the narrowest claim, recites 79 different sequences.
The State of the Prior Art
The Examiner is not aware of prior art disclosing peptide of the formula in instant claim 1 (SEQ ID NO: 1).
Pulicherla et al. (Peptide affinity reagents for AAV capsid recognition and purification. Gene Ther 18, 1020–1024 (2011)) report the discovery of AAV capsid-binding peptides identified through phage panning (Figure 1). The heptapeptide motif GYVSRHP selectively recognized AAV serotype 8 capsids and blocked transduction in vitro (p. 1020, col 2). Recombinant AAV8 vectors were purified directly from crude cell lysate and supernatant through sequential application of peptide affinity and anion exchange chromatography (Figures 2-3). Peptide affinity reagents may serve as useful alternatives to monoclonal antibodies in AAV capsid recognition, and offer readily scalable solutions for purification of clinical grade AAV vectors (p. 1021, col 2).
Luginbuhl et al. (US 2023/0348863 A1) teach purification matrices comprising AAV-binding polypeptides and methods of using the same (para [0006]). The AAV-binding polypeptides were isolated from a library based on the AAVR ectodomain sequence (Example 1). Luginbuhl et al. teach that the purification matrix can capture AAV8 particles from cell lysate (Examples 6, 9, 10).
Toueille (Development of purification steps for several AAV serotypes using POROSTM CaptureSelectTM AAVX affinity chromatography. Cell Gene Therapy Insights 2018; 4(7), 637-645) teaches affinity purification tools for AAV. The ligands comprise the variable domains of camelid heavy-chain-only antibodies (page 1). Toueille teaches that the purification matrix can capture AAV8 particles (Figures 1-5).
Although each of these references disclose AAV8 affinity peptides, none of them disclose a peptide of instant SEQ ID NO: 1.
The Predictability or Unpredictability of the Art
The prior art pertaining to peptide structure and function is highly unpredictable. Although it is generally recognized that the function of a peptide is related to its amino acid sequence, the ability to predict the effect of changes to sequence on function requires empirical determination.
In the instant case, Figure 2 of the specification shows that peptides with different sequences within the claimed genus exhibit different stability in the presence of 0.5 M NaOH. Although the sequences are in the genus, they have different functional properties.
The Level of Guidance in the Specification
The specification does not describe a general correlation between structure and function for the claimed genus. The role of the seventeen variable amino acids and positions [A] and [B] of SEQ ID NO: 1 in the AAV8 binding site, binding site formation, binding site environment and overall fold, stability and dynamics of the peptide are not described. Although several peptides were examined for AAV8 binding, this data was not presented in terms of a structure-function analysis. Therefore, it is not possible to determine how changes at positions X1 to X17, [A], and [B] will affect the claimed function of interacting with AAV8.
The Presence or Absence of Working Examples
The specification discloses the actual reduction to practice of SEQ ID NO: 53 (Figures 3 and 4). This species is not representative of the full scope of the claimed genus because it is only one of over 1.88 x108 unique amino acid sequences in the genus.
The Quantity of Experimentation Necessary
Considering the factors above, the skilled artisan would be burdened with undue experimentation in determining if one of the claimed amino acid sequences would be effective at specifically interacting with AAV8. When the above factors are weighed, it is the examiner's position that one skilled in the art could not practice the invention without undue experimentation.
Therefore, in view of the Wands factors, the claims appear to require undue experimentation to use the full scope of the claimed invention.
Claim Rejections - 35 USC § 112(b)
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.
Claims 1-7, 10, 12, and 14-24 are 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 1, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The use of the word preferably to define each variable X1-X17 renders the amino acid sequence of the affinity ligand indefinite. The dependent claims fail to remedy this issue and are likewise rejected.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4, 7, 10, 12, 14, and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 17 of copending Application No. 18/031,808 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Reference claim 17 recites a polypeptide comprising an affinity ligand comprising an amino acid sequence represented by the formula, from N-terminus to C-terminus,
[A]-X1QRRX2FIX3X4LRX5DPS-[X6]n-SAX7LLAX8AX9X10X11NDX12QAPX13-[B] (SEQ ID NO. 1), wherein (a) [A] comprises an a-helix-forming peptide domain;
(b) each of X1, X2, X3, X4, X5, X6, X7, X8, X10,X11, and X12 is independently any amino acid;
(c) n represents the number of X6 residues present and is an integer from one to ten,
(d) each of X9 and X13 is independently A, K or R; and
(e) [B] is absent, is VD, or is a peptide domain comprising an amino acid sequence of VDGQAGQGGGSGLNDIFEAQKIEWHEHHHHHH (SEQ ID NO.9 ),GQAGQGGGSGLNDIFEAQKIEWHEHHHHHH (SEQ ID NO. 10), VDGLNDIFEAQKIEWHEHHHHHH (SEQ ID NO. 11) or GLNDIFEAQKIEWHEHHHHHH (SEQ ID NO. 12).
This genus overlaps with the genus of instant claim 1.
Reference claims 1-9 recite nucleic acid libraries that encode these polypeptides, including a phage display library.
Reference claim 16 recites a method of identifying one or more affinity ligands that specifically binds AAV8 which comprises:(a) contacting said target molecule with a phage display library of Claim 9; (b) separating phage that specifically bind with said AAV8 from those that do not selectively interact with said target molecule to produce an enriched phage library; (c) repeating steps a) and b) with said enriched phage library to produce a further enriched phage library; (d) repeating step c) until said further enriched phage library is enriched from at least about 10- to about 106-fold or more relative to the original phage library; and (e) plating said further enriched phage library and isolating and characterizing individual clones therefrom and thereby identifying one or more affinity ligands that specifically bind to AAV8.
It would have been obvious to practice the method of identify affinity ligands of AAV8 of reference claim 16. In doing so, one of ordinary skill in the art would isolate affinity ligands of instant claim 1 because the reference claimed polypeptides overlap with the instantly claimed polypeptides.
Regarding claims 2-3, the reference claim 3 recites SEQ ID NO: 2, which is the same as instant SEQ ID NO: 4, and SEQ ID NO: 6, which is the same as instant SEQ ID NO: 5, as options for [A].
Regarding claim 4, reference claim 4 requires that the N-terminus of [A] is preceded by M or MAQGT.
Regarding claim 7, reference claim 6 requires that the ligand comprises a C-terminal lysine or cysteine.
Regarding claim 10, reference claim 9 requires that the affinity ligand further comprises a nucleic acid in the form of a phage display library.
Regarding claim 12, the phage display library of reference claim 9 would comprise a multimer of affinity ligands on each phage particle.
Regarding claims 14 and 24, the phage display library of reference claim 9 would comprise a nucleic acid encoding the affinity ligands.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 7 am - 3 pm.
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, Lianko G Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654
Prosecution Insights