DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to an amendment filed 5/12/2026.
Claims 50-60, 62-69, 74-76 and 80-85 are pending. Claims 74-76 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention (VEGF-C), there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 1/13/2026. Claims 50-60, 62-69 and 80-85
This application is a continuation of International Application No. PCT/US2025/014959, filed February 7, 2025, which claims the priority benefit of U.S. provisional application 63/551,418, filed February 8, 2024, and U.S. provisional application 63/707 ,055, filed October 14, 2024.
Information Disclosure Statement
An information disclosure statement filed 5/12/2026 has been identified and the documents considered. The corresponding signed and initialed PTO Form 1449 has been mailed with this action.
Response to Amendments
The amendments to the specification are sufficient to overcome the objections to the disclosure. As well as the claims. As well, the amendments to require the totality of SEQ ID NO:1 and 12 is sufficient to overcome the rejection under 35 USC 102 and non-statutory double patenting.
Claim Rejections - 35 USC § 112, 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.
Claims 50-56, 58-60, 62-69 and 81-85 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicants claim an amino acid sequence with 95% sequence identity to SEQ ID NO:1. This amount of changes between SEQ ID NO:1 and 95% is 37 amino acids. The specification discloses only 1-7 amino acid changes and these changes are integral to altering function. Given that the 7 changes are critical to new function, alteration of any other amino acids would be changes above and beyond what have been described.
The mutations that are claimed only amount to 7 modifications which is a relationship of 99% identity to SEQ ID NO:1. Comparing SEQ ID NO:12 and SEQ ID NO:1, the edit distance is 7.
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Hence, the disclosure does not teach capsid peptides or virus comprising thereof with less than 99% identity or more than 7 edit distance units.
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The structure of a capsid which in this case is an AAV capsid and the virus comprising thereof which is an AAV is intimately tied to its function. Modifications can alter structural integrity and therefore function. The disclosure defines this thus,
0029] Functional: As used herein in reference to a polypeptide component of a dependoparvovirus capsid (e.g., Cap (e.g., VP1, VP2, and/or VP3) or Rep), the term "functional" refers to a polypeptide which provides at least 50, 60, 70, 80, 90, or 100% of the activity of a naturally occurring version of that polypeptide component (e.g., when present in a host cell). For example, a functional VP1 polypeptide can stably fold and assemble into a dependoparvovirus capsid (e.g., that is competent for packaging and/or secretion). As used herein in reference to a dependoparvovirus capsid or particle, "functional" refers to a capsid or particle comprising one or more of the following production characteristics: comprises a desired payload, is fully folded and/or assembled, is competent to infect a target cell, or remains stable (e.g., folded/assembled and/or competent to infect a target cell) for at least a threshold time.
To that end, many mutations were made. However, only a few mutations were functional.
1625] A library of variants was created utilizing multiple sets of strategies of design and selection. The main objectives were to develop capsids capable of packaging into AAV particles efficiently, transducing central nervous system tissues effectively after intravenous administration, and detargeting the liver and other tissue types.
[1661] Capsid polypeptide Variant 1 (“V1”), having a VP1 polypeptide sequence as set forth in SEQ ID NO:12, resulted in viral particles with an improved CNS, cardiac, and skeletal muscle delivery profile, as well as improved liver detargeting, as compared to viral particles with wild type AAV9 capsid sequences having a VP1 capsid polypeptide as set forth in SEQ ID NO:1.
[1677] The V1 AAV capsid (having a VP1 polypeptide sequence as set forth in SEQ ID NO:12) demonstrated efficient transduction and biodistribution of cardiac and skeletal muscles as measured by payload expression (FIG. 5A) and viral genome quantification (FIG. 5B). Biodistribution to DRG and off-target peripheral organ samples was low (FIG. 5B).
The particular sequence of SEQ ID NO:1 encodes an AAV9 capsid. The disclosure states that single modifications were analyzed but no results were provided. Hence, the disclosure teaches a single specific structure and no other to embody the genus of molecules claimed. By claiming peptides with 95% identity, peptides with at most 37 mutations are claimed. Even considering those with 98% identity, almost 15 mutations are claimed. However, the disclosure only teaches a capsid peptide with at least 99% sequence identity to SEQ ID NO:1 which is SEQ ID NO:12 or VP2 or VP3 comprising. This characterization is not generic but specific with functional properties that cannot be assured especially in light of the results provided. Given the large size and diversity of the recited sequences, and the single embodiment: undue experimentation would be required to practice the claimed methods with reasonable expectation of success, absent a specific and detailed description in the specification.
Response to Arguments
Applicants argue that the office action incorrectly alleges that only a few mutations were functional. Applicants traverse this stating that there is nothing in the application to suggest any variant is non-functional. To this end, there is nothing that states any variant other than the identified variant of SEQ ID NO:12 or the one claimed in claim 50 is functional to meet the functional properties required of the invention (improved CNS, cardiac and skeletal muscle delivery and liver detargeting, ¶0301).
Applicants argue that this V(1) variant is only one particular member. On one hand, applicants argue the claims are directed to a specific combination of 7 amino acid substitutions and on the other that that that V(1) retaining those substitutions would allow additional variations. This is the difference between possession. The specification directs one to the single species of substitutions wherein the capsid defined by SEQ ID NO:1 tolerates 7 amino acid substitutions to render a capsid to direct AAV to CNS and cardiac and skeletal muscle while detargeting from liver. This is the extent of the possession. That other substitutions may be allowed does not define or describe or lead to possession of those additional substitutions. The Court indicated that while applicants are not required to disclose every species encompassed by a genus, the description of a genus is achieved by the recitation of a precise definition of a representative number of members of the genus, such as by reciting the structure. Structural features that could distinguish the compounds of the claimed genus from others not encompassed by the genus are missing from the disclosure. In this case, there are specific elements referenced but the claims reference these structures with broad generic functional terms that represent a large and diverse genus of elements. By providing a single variant, applicants have not done so. They have invited the practitioner to identify variants. What is required is a structural functional correlation. Without such a correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. In this latter case, disclosure of function alone is little more than a wish for possession; it does not satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing "a result that one might achieve if one made that invention"); In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming a rejection for lack of written description because the specification does "little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate"). Compare Fonar, 107 F.3d at 1549, 41 USPQ2d at 1805 (disclosure of software function adequate in that art).
Applicants argue that the structure of AAV is known via crystallographic structure and hence the structure is well known. This is not the issue. The issue is the structure-function relationship known such that one can make new variants and know how they will function. That the disclosure has a single variant meeting their function (improved CNS, cardiac and skeletal muscle delivery and liver detargeting, ¶0301) does not meet the description requirement.
As to assertions one could provide additional substitutions in the art given the state of the art, this misrepresents the state of the art. Specifically, it is known in the art, (Nisanov et al, Molecular Therapy Vol. 33 No 5 May 2025, pages 1937-1945).
Most protein mutations are deleterious to function, and accordingly it was found that the majority of AAV peptide insertion variants have lower packaging fitness than the parental wild type. 5
It is noted that successes noted in this article are not generic in nature but actually specific similar to that taught and claimed in the instant application. Single substitutions up to 4 were identified in specific variants to work in contrast to 37 modifications randomly made when considering 95% identity to the claimed variant. At issue is modifying the capsid this process can result in disruption of packaging fitness, stoichiometry of viral particles, functionality of capsids and VP homogeneity all reviewed by Dogbey and Barth (Molecular Biotechnology (2026) 68:62–70). Hence, there is also little predictability when altering the capsid of AAV. This is complicated as structural features that could distinguish the compounds of the claimed genus from others not encompassed by the genus are missing from the disclosure. In this case, there are specific elements referenced but the claims reference these structures with broad generic functional terms that represent a large and diverse genus of elements.
Conclusion
Claim 57 and 80 are free of the art and is objected to as dependent on a rejected claim bit would otherwise be considered allowable if redrafted in independent form.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIA MARVICH whose telephone number is (571)272-0774. The examiner can normally be reached 8 am - 5 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria 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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/MARIA MARVICH/Primary Examiner, Art Unit 1634
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