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
Applicant’s election without traverse of Group I in the reply filed on 7/13/2026 is acknowledged.
Claims 22-39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/13/2026.
Species elections to SEQ ID NO:48 (claim 1), SEQ ID NO:1 (claim 18(a)); SEQ ID NO:9 (claims 18(c)); and SEQ ID NO:13 (claim 19(a)), made without traverse in the reply filed 7/13/2026, are acknowledged.
Claims 1-21 are under consideration.
Specification
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 Rejections - 35 USC § 112
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 1-21 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.
When determining if a recited genus has adequate written description for a genus:
(1) the broadest reasonable interpretation of the genus is determined;
(2) the disclosure is examined to determine if the specification has provided a representative number of species to describe the complete structure of the genus;
(3) the disclosure is examined to determine whether a representative number of species have been sufficiently described by other relevant characteristics, specified features and functional attributes that would distinguish different members of the claimed genus; and
(4) the state of the art is examined to the determine if it supports/supplement the genus description in the specification in a manner that would demonstrate the application was in possession of the claimed genus at the time of effectively filing.
Genus: Independent claim 1 recites, “a nucleic acids comprising about 1300 to about 2300 and at least 75% identity to any one of” and list a large number of SEQ ID NOS: or fragments of SEQ ID NOS. The elected SEQ ID NO under consideration is SEQ ID NO:48. As such, the discussion will be limited to SEQ ID NO:48. However, the written description would be applicable to all of the recited sequences.
Claim 4 recites “at least 80% identity”. Claim 5 recites, “at least 85% identity”. Claim 6 recites “at least 90% identity”. Claim 7 recites, “at least 95% identity”. Claim 8 recites, “at least 97%”.
Broadest Reasonable Interpretation (BRI) of the Genus:
The claimed genus is “a nucleic acid”, meaning DNA or RNA, having “about 1300 to about 2300 nucleotides in length”. The specification states “the term “about” means ± 20% of the indicated range. As such, 20% of the 1300 is 1040, thus extending the lower range to 1040 bp and 20% of 2300 is 2760. Thus the sequence can be the full length SEQ ID NO:48 or a large number of different fragment sequences that fall between the above designed range of length. As such, the genus further defines the nucleic acid as “having at least 75% identity to any of SEQ ID NOS…” As such, the sequences can have as many as 25% of the sequence having a different sequences. The sequences can of any 25% of the sequence deleted or substituted contiguously or non-contiguously. As such, the genus comprises an extremely large number of possible nucleic as sequence structure of divergent primary bp sequence. Thus the BRI of the claimed genus as applied to SEQ ID NO:48 is an extremely large number of sequences in the thousands of thousands of sequences. Again it is noted that the actual breadth of the genus is even larger because it recites large number of SEQ ID NOS or fragments thereof. As such, the genus recited is for claim 1 is unimaginably large.
As discussed above, dependent claims 4-9 further narrow the sequence identity as such each genus of claims 4-9 comprise smaller subsets of the genus of the independent claim that comprise thousands to hundreds of different sequences. As such, the claims overall encompass large groups of sequences defined by large ranges of length and primary sequence structure.
The claim describes the claim nucleic acid sequence genus as “vector stuffer sequences”. As such, the nucleic acids genus of the claims serves as a stuffer sequence.
Specification Description:
[0002] The size of the adeno-associated virus (AAV) vector genome is known to be constrained, with vector sizes of approximately the native size of 4.7 kb being packaged successfully but much larger vector genomes subject to reduced production of functional AAV vector (Wu et al., Molecular Therapy 2010 18(1): 80-86). On the other hand, vector genomes which are substantially smaller than the vector genome packaging limit can result in suboptimal packaging (Dong et al., Human gene therapy 1996 7:2101-2112). Also, if the cis plasmid has a ‘backbone’ sequence—such as typically encoding the elements of bacterial origins of resistance and antibiotic resistance, needed to propagate the plasmid in bacteria—that is close in size to the intended AAV vector genome, the amount of unintended ‘reverse packaged’ sequence can increase (Hauck et al., Molecular Therapy (2009) 17:144-152). For these reasons, it may be beneficial to include ‘stuffer sequences’ that on their own do not confer unfavorable properties to packaged AAV, as material in the plasmid backbone, and for use in situations where the intended AAV payload is considerably shorter than the native AAV packaging size. The importance of inert stuffer sequence has been highlighted by Keiser et al., Nature Medicine (2021) 27:1982-1989, whereby it was shown that a ‘payload-free’ AAV with stuffer sequence was capable of inducing substantial toxicity in non-human primates.
[0038] AAV preferentially packages a full-length genome, i.e., one that is approximately the same size as the native genome, and is not too big or too small. However, expression cassettes encoding inhibitory nucleic acid sequences are substantially smaller than AAV full-length genome. To avoid packaging of fragmented genomes, a stuffer sequence may be linked to an expression construct comprising a heterologous nucleic acid sequence and flanked by the 5′ ITR and 3′ ITR to expand the packagable genome, resulted in a genome whose size was near-normal in length between the ITRs. Generally, the packaging capacity of AAV is about 4.7 kb between the 5′ ITR and 3′ ITR. For self-complementary AAV (scAAV) vector, the packaging capacity is about 2.4 kb between the 5′ ITR and 3′ ITR.
[0039] Preferably, the starting sequence for obtaining a vector stuffer sequence is of mammalian origin, such as human origin. The length of the stuffer sequence may be adjusted such that the vector genome is at or close to the (natural) packaging limit of AAV capsid. Furthermore, a vector stuffer sequence can be designed to minimize adverse effects in the context of in vivo gene therapy. For example, regions of the human genome may be identified as a source for vector stuffer sequences by identifying sequences with minimal impact if integration in the genome occurs and minimal risk of initiating unexpected transcription. Therefore, regions of the genome may be examined in which i) deletions and duplications were common in the population and not associated with disease-relevant phenotypes (no evidence of evolutionary pressure) and/or ii) RNA expression across human tissues was low or undetectable (lack strong intrinsic enhancers/promoter elements). Furthermore, vector stuffer sequences can be designed to have reduced, minimized, removed, or to lack one or more elements to make the vector sequence inert or safe. In some embodiments, the vector stuffer sequence is modified to: reduce or remove expressed regions (e.g., exons+10 bp on either side, human ESTs); reduce or remove regulatory elements (e.g., promoter sequences, enhancer sequences, repressor sequences, splicing donors or acceptors, or other cis-acting elements found in the human genome that could potentially affect transcription of the transgene); reduce or remove repetitive elements (e.g., microsatellite repeats, dinucleotides repeats, trinucleotide repeats); reduce, remove, or modify ATG codons to reduce or eliminate the possibility of peptides being generated from the filler or stuffer sequence due to latent start codons; reduce or remove CpG dinucleotides to lower likelihood of unmethylated CpG dinucleotides (from cis-plasmids generated in bacteria) inducing an innate immune response; or any combination thereof. The present disclosure provides vector stuffer sequences possessing one or more of the aforementioned features, with further advantages of one or more of: high titer; low toxicity; and reduced truncations in miRNA and/or stuffer sequence.
As such, the specification generically describes nucleotide sequences that serve as space retainer for expression vector comprising expression cassettes that are smaller than AAV or plasmid genomes. They also describe the sequence structure generically as not being one that will encode anything or interfere with the genome or expression cassette expression and will not impart adverse effects to the vector as its use for gene therapy, transcription and/or translation. The specification also describes a large number of SEQ ID NOS and fragments thereof that encode sequences that can serve as stuffer sequences. Regarding SEQ ID NO:48, the specification only discloses SEQ ID NO:48 that is 1697 bp in length. The specification does not describe any other sequences species other than the full length sequence of SEQ ID NO:48. The specification does not describe any particular substitutions, deletions or additions that can be made to SEQ ID NO:48. As such, the specification fails to describe any other members of the genus.
State of the Prior Art:
A search of the prior art found no matching sequences to SEQ ID NO:48, other than an identical sequence in application 17/796,563 that is also filed by Applicant and has the same inventors and the same effective filing date as the instant claims. Further, the specification describes the state of the prior art for vector stuffer sequences in [0002]. “It was shown that a ‘payload-free’ AAV with stuffer sequence was capable of inducing substantial toxicity in non-human primates.” (Keiser et al., Nature Medicine (2021) 27:1982-1989l of record in IDS 3/5/2026). As such, while means of making fragment and sequences of altered sequence identity, the specification and prior art teach that such sequences do not predictable serve their use as a space maker that does not interfere with or impact the overall function of a vector.
In conclusion, the breadth of the claimed nucleic acid sequence genus structurally defined by sequence length and sequence identity of at least 75% to SEQ ID NO lack adequate written description. While the specification contemplates a large number of divergent nucleotide sequences, it only describes one full length sequence for a SEQ ID NO, presently under consideration SEQ ID NO:48. The specification generically describes what the sequences cannot be because of possible interferences with its function as a stuffer sequence. However it does not describe any specific types of fragmentations or changes in identity to the sequences of the genus. As such, the specification fails to disclose a representative number of species that describe the complete structure of the genus. Further, the prior art does not teach any sequences with the claimed length and identity that successfully serve as stuffer sequences and the prior art and specification teaches that not all sequences predictably serve as stuffer sequences and can impart adverse effects to overall vector. Thus, from the state of the art and the application description, one of ordinary skill would not be able to envision the all the species of the claimed genus of which the application possesses. Therefore, the claimed genus lack adequate written description.
Claim Rejections - 35 USC § 112
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 1-21 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.
Claims 1-21 are 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 nucleic acid sequences 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: Claims 1 and 9 recites a large number of different SEQ ID NOS and fragments thereof. The primary sequences of all the listed sequences are physically different. As such, they do not share “a single structural similarity”. It is evidence by the fact that SEQ ID NO:48 one of the claimed sequences were not found to be identical to any of the other claimed sequences when the art was searched.
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.
All claims are included in this rejection because all depend upon claim 1.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARCIA STEPHENS NOBLE whose telephone number is (571)272-5545. The examiner can normally be reached M-F 9-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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MARCIA S. NOBLE
Primary Examiner
Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632
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