Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claim Status
Claims 21-27, 38-42, 53-57 and 60 are currently pending in this application.
Election/Restrictions
Election was made without traverse of Group III, claims 21-27, 38-42, and 54-56, in the reply filed on Jul. 15, 2026 and of the species consisting of SEQ ID NO: 7 (“T614V”) or SEQ ID NO: 15 (encoding “T614V”). Claims 53, 57 and 60 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected subject matter, there being no allowable generic or linking claim. Claims 21-27, 38-42, and 54-56 have been considered on the merits.
Claim Objections
Claims 21 and 54 each recites a group consisting of a list of indented members, which is clear enough due to the indentation, would still have improved clarity if semicolons were used between members to better differentiate from the multiple point mutations of the same members separated by commas as commas and the conjunction ‘and’ are used both between members and the limitation language per some individual group. Appropriate correction is requested for clearer readability.
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.
Claims 22, 25, 38, and 40-41 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 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 applicant’s 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.
Claim 22, 25 and 40-41 each recites one of the terms “a modified variant” of “AAV5 capsid protein,” “a modified AAV5 capsid protein” or “a modified capsid protein “from adeno-associated virus serotype 5,” regarding either VP2 or VP3, which encompasses a broad range of variants in view of no limiting definition in the claims or instant specification. Thus, the terms “modified” and “modified variant” takes its ordinary meaning in the art. Furthermore, the instant specification also teaches of randomizing capsid protein sequences in libraries (Example 1, FIG. 1, 3-4), thus the term modified or variant seems to encompass mutations at any position(s).
For the elected VP1 species T614V (SEQ ID NO: 7), there are at least 20 × (724-1) sequence variations (14,460) having a single point substitution, based on 20 multiplied by total protein length minus one, which excludes non-standard amino acids, insertions, deletions, and recombinant fusions. For AAV5 VP3, there are at least 20 × 532 sequence variations (10,640) having just single point mutations and, as the number of substitutions increases, the number of sequence variants increases by 20N (e.g., 400, 8000, 160,000, etc.), meaning there are over 179,000 variants (10,640+400+8000+160,000) having just 4 substitutions and no other modification. For AAV5 VP2, based NCBI database query showing at least three different protein lengths, there are at least 39,000 single point mutation variants (20 × 515) + (20 × 723) + (20 × 725) and, for 4 substitutions increases the number of sequence variants increases to over 200,000 variants just using standard amino acids and excluding other mutation types like insertions and deletions.
The prior art teaches numerous mutations for making VP2 and VP3 variants, such as Y to F substitutions, internal insertions of 7-9 amino acid residues, variable loop serotype swaps, heparin-binding motif mutations, and C-terminal mutants (see e.g., Wang et al., Nat Rev Drug Discov 18: 358-78 (2019) at pg. 361-364, Fig. 3; Ling et al., Hum Gene Ther Methods 27: 143-9 (2016) at abstract; Figure 1, pg. 147, last para., to pg. 148; US 20160289275; Markusic et al., J Transl Med 15: 94 (2017); Buning et al., Mol Ther Methods Clin Dev 12: 248-65 (2019)). The prior art also teaches mutations, deletions, and truncations causing loss of function (Naumer et al., J Virol 86: 13038-48 (2012) at pg. 13046; abstract; Ogden et al. 2019 (IDS ref. of record) at Fig. 1D).
Thus, one of ordinary skill in the art would understand the modifications and variants to include residue substitutions and insertions having various functional impacts, many of which lack any known nexus between them as both their differing structures can provide significantly different functions, such as altering tropism, retrograde transport, heparin sulfate binding, phosphorylation and/or proteasomal degradation (id.).
In analyzing whether the written description requirement is met for a genus in a claim, it is first determined whether a representative number of species have been described by their structure. In the instant case, the variants of VP2 described are limited to four structures G90V, G90V/T575S, T478V, and T478V/T575S related specifically to instant SEQ ID NO: 17, and the variants of VP3 described are limited to G34V, G34V/T519S, T422A, T422A/T519S, T422V, and T422V/T519S.
Nowhere does the instant specification describe any other modifications or variants, leaving the skilled artisan unguided to investigate the prior art for such species and their suitability for combining with the features of the instantly claimed capsid. Furthermore, the specification fails to provide guidance as to how to determine whether a given VP2 or VP3 variant (e.g., out of 100,000 possibilities) can be made part of the claimed capsid and retain function, such as in combination with VP1 G226V, S2A/G226V/T711S, T164A, T164V, S2A/T164A/T711S, or S2A/T614V/T711S; VP2 G90V, G90V/T575S, T478V, or T478V/T575S; and/or VP3 G34V, G34V/T519S, T422A, T422A/T519S, T422V, or T422V/T519S.
In view of the art, this is an unpredictable art when combining multiple VP mutations together and multiple mutated VP protein subunits together into the same AAV capsid and predict successful capsid formation (see e.g., Naumer et al., at pg. 13046 reporting point mutation that abolishes capsid assembly). Furthermore, the scope of variants is vast with over 100,000 variants per VP protein depending on the number of substitutions alone (e.g., 4 or more).
Regarding claim 25, while the position of each substitution is defined, the “altered” VP3 protein (ii) encompasses any variation or modifications as discussed above.
Regarding claim 38, in view of dependent claim 39, claim 38 encompasses a wild-type AAV5 capsid protein which does not have the amino acid sequence of SEQ ID NO: 33; however, neither the instant application nor the prior art discloses any other wild-type AAV5 VP3 protein besides instant SEQ ID NO: 33.
Thus, this limited descriptive information is not deemed sufficient to reasonably convey to one skilled in the art that applicant is in possession of the genus of modified variants of AAV5 VP2 or VP3, especially produced via random mutagenesis potentially resulting in 100,000s of varaints with the possibility of loss of capsid protein functionalities. The skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of the entire scope of the claimed isolated capsid over the entire genus of VP2 or VP3 proteins encompassed by claims 22, 25, and 40-41.
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 21-27, 38-42, and 54-56 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 pre-AIA the applicant regards as the invention.
Claim 21 and 54 is each rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claim 21 or 54 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: no single structural/functional mutation(s) is shared among all members, not all mutations/combinations of mutations have a common structure and the uses differs in that G226V and S2A/G226V/T711S provide improved capsid packaging efficiencies while T164A, T164V, S2A/T164A/T711S, S2A/T614V/T711S provides improved AAV5 transduction in addition to improved packaging efficiencies, so the mutations map to unshared uses despite a general shared use in recombinant AAV5 infection/production. Furthermore, the S2A/G226V/T711S combination attenuates transduction making it less desirable for such uses.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use. Claims 22-27 and 38-42 are included in this rejection for depending from indefinite claim 21. Claims 55-56 are included in this rejection for depending from indefinite claim 24.
Claim 54 recites “the modified capsid protein VP1,” “the product encoded by the heterologous nucleic acid” and “the target cells,” each of which lack sufficient antecedent basis in claim 54. Claims 55-56 are included in this rejection for depending from indefinite claim 54.
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.
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/ERIC J ROGERS/
Examiner, Art Unit 1638
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
