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 .
Claim(s) 98-117 are pending.
Preliminary Amendments
Applicant’s preliminary amendment filed on 04/11/2024 is acknowledged. Specification was amended to (a) add a “Sequence listing” statement and (b) amend the “cross reference to related applications” statement.
Applicant’s preliminary amendment filed on 05/09/2025 is acknowledged. The claim(s) were amended to cancel claims 1-97 and add claims 98-117.
Priority
Acknowledgement is made that this application is a 371 of PCT/US2022/078140 filed 10/14/2022 and claims priority based on provisional application(s) filed as 63/256,365 on 10/15/2021.
All claims are given the priority date of 10/15/2021.
Information Disclosure Statement
Receipt of the information disclosure statement(s) on 06/25/2024 and 06/01/2026 are acknowledged. The signed and initialed PTO-1449 form(s) has/have been mailed with this action.
Drawings
Figures 9A and 11 should be designated by a legend such as --Prior Art-- because only that which is old is illustrated. See MPEP § 608.02(g). Corrected drawings in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. The replacement sheet(s) should be labeled “Replacement Sheet” in the page header (as per 37 CFR 1.84(c)) so as not to obstruct any portion of the drawing figures. If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
Minor Informalities
The disclosure is objected to because of the following informalities:
On page 13, lines 11-12, the description of Figure 6C says “construct 9”, however, the drawings recite “construct 1”. It would be remedial to have consistency between the “brief description of the drawings” and the figure panel in the drawings.
Table 21 on page 184 is illegible.
Appropriate correction is required.
Trademarks and/or Tradenames
The use of the term following terms below, which is/are a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
MegaClear (p. 171, line 24);
Rneasy (p. 171, line 24);
CellTiter Glo (p.176, line 9 and 11);
VeritiPro (p.184, line 22);
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112(b) – indefiniteness
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.
Claim(s) 104 and 112 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 104 recites the broad recitation “second splice acceptor”, and the claim also recites “(reverse)” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Removal of the parenthetical “reverse” and the addition of “orientation” to recite, “The bidirectional nucleic acid construct of claim 103, wherein the construct comprises a first splice acceptor site upstream of the first segment and a second splice acceptor site in the reverse orientation downstream of the second segment.”, would obviate this rejection.
Claim 112 recites the limitation "the SERPINA1 gRNA" in ii). There is insufficient antecedent basis for this limitation in the claim. Claim 112 depends from claim 109 which provides antecedent basis for “albumin guide RNA (gRNA)” but not SERPINA1 gRNA.
One way to obviate this rejection is to amend the claim to depend from claim 110 and amend the claim to recite:
“The method of claim 110, wherein the RNA-guided DNA binding agent, the albumin gRNA, and/or a SERPINA1 gRNA are administered in a nucleic acid vector or a lipid nanoparticle.”
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 110 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 fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, Applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.
Claim 110 is drawn to a genus of SERPINA1 gene targeted nucleic acid agent for reducing expression of endogenous SERPINA1 without significantly reducing expression of the AAT polypeptide AND treating AATD in a subject. The rejected claims thus comprise a genus of SERPINA1 nucleic acid targeting agent and are defined as belonging to the broad class of nucleic acid agents and as having the function of reducing expression of endogenous SERPINA1 without significantly reducing expression of the AAT polypeptide AND treating AATD in a subject.
To satisfy the written description requirement, MPEP §2163 states, in part “… a patent
specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.” Moreover, the written description requirement for a genus may be satisfied through sufficient description of a representative number of species 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 functional and structure, or by a combination of such
identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.”
The specification envisions the SERPINA1 gene targeted nucleic acid agent as the following: “In some embodiments, the endogenous SERPINA1 gene targeted nucleic acid agent is an siRNA, a dsRNA, or a guide RNA. In certain embodiments, the endogenous SERPINAI gene targeted nucleic acid agent is selected from an RNAi agent targeted to nucleotides 957-977, 1403-1425, or 1410-1436 of SEQ ID NO: 703, and a guide RNA targeted the endogenous SERPINA1 gene at a position corresponding to nucleotides 412-431, 506-525, or 538-557 of SEQ ID NO: 703.”, (p.7 or 9, lines 22-27).
“In certain embodiments, the SERPINA1 gene targeted nucleic acid agent is a
SERPINAI guide RNA that is at least partially complementary to a target sequence present in
exon 2, 3, 4, or 5 of the endogenous human SERPINAI gene and that targets neither the first
AAT polypeptide coding sequence nor the second AAT polypeptide coding sequences. In some embodiments, the SERPINA1 gene targeted nucleic acid agent is a SERPINA1 guide
RNA that is at least partially complementary to a target sequence within the endogenous
SERPINA1 gene at a position corresponding to nucleotides 412-431, 506-525, or 538-557 of
SEQ ID NO: 703. In some embodiments, the SERPINAI guide RNA comprises: a guide
sequence selected from SEQ ID NOs: 1129-1131; a guide sequence that is at least 95%
10 identical to SEQ ID NOs: 1129-1131; or 17, 18, 19, or 20 consecutive nucleotides of a
sequence chosen from SEQ ID NOs: 1129-1131.”, (p.10, lines 1-11).
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims regarding structure and function, the examples are only representative of siRNA, a dsRNA, or a guide RNA used for reducing expression of endogenous SERPINA1 without significantly reducing expression of the AAT polypeptide AND treating AATD in a subject. These results are not necessarily predictive of all “SERPINA1 gene targeted nucleic acid agents” capable of reducing expression of endogenous SERPINA1 without significantly reducing expression of the AAT polypeptide AND treating AATD in a subject. Thus, it is impossible for one to extrapolate from the three subgenera of gene targeted nucleic acid agent described herein that the genus would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of “SERPINA1 gene targeted nucleic acid agent” capable of reducing expression of endogenous SERPINA1 without significantly reducing expression of the AAT polypeptide AND treating AATD in a subject.
Zhuo et al (Recent Advances in SELEX Technology and Aptamer Applications in Biomedicine, Int J Mol Sci, vol 18, issue 2142, pates 1-19, published October 14th, 2017) teaches: “Aptamers are short DNA/RNA oligonucleotides capable of binding to target molecules with high affinity and specificity. The process of selecting an aptamer is called Systematic Evolution of Ligands by Exponential Enrichment (SELEX).”, (abstract).
Moreover, Zhuo et al teaches, “The conventional SELEX method mainly consists of the following three steps: selection, partitioning and amplification (Figure 1). Before the selection, a library of oligonucleotides is synthesized, which generally contains up to 1015 different unique sequences [1]. Each unique sequence contains random bases (20–50 nt) flanked by two conserved primer binding sites, which are used for PCR amplification by annealing primers. In the selection step, the library is incubated with target molecules for the indicated time. After incubation, the unbound sequences are separated from those that bound by different methods. The target-bound sequences are amplified by PCR(DNASELEX)or reverse transcription PCR (RNA SELEX). The PCR products, being a new sub-pool, are utilized for the next round of selection. After several selection rounds, the enriched sequences are sequenced, and their binding abilities are further evaluated. Generally, it takes from weeks to months to obtain specific aptamer candidates, and the hit rates are low. Thus, the obtainment of high quality aptamers against relevant targets still remains a bottleneck.”, (page 2, para 5).
The instant specification is silent on SELEX and/or the process of making aptamers to target the SERPINA1 gene, which is under the umbrella of the broad recitation of “nucleic acid agent”.
Therefore, the art does not appear to offset the deficiencies of the specification. Merely describing a “SERPINA1 gene targeted nucleic acid agent” capable of reducing expression of endogenous SERPINA1 without significantly reducing expression of the AAT polypeptide AND treating AATD in a subject without sufficient detail relating to the genus of nucleic acid agent in reducing expression of endogenous SERPINA1 without significantly reducing expression of the AAT polypeptide AND treating AATD in a subject does not allow the skilled artesian to reasonably conclude that the Applicants were in possession of the claimed invention in claim 110.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim(s) 116-117 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Claims 116-17 do not explicitly recite “human organism”, however the instant specification discloses, “In some embodiments, the cell may be a prokaryotic cell, such as, e.g., a bacterial cell. In some embodiments, the cell may be a eukaryotic cell, such as, e.g., a yeast, plant, insect, or mammalian cell. In some embodiments, the eukaryotic cell may be a mammalian cell. In some embodiments, the eukaryotic cell may be a rodent cell. In some embodiments, the eukaryotic cell may be a human cell.”, (p.95, lines 5-9). Moreover, “In some embodiments, the administration is in vitro. In some embodiments, the administration is in vivo. In some embodiments, the host cell is a liver cell.”, (p.107, lines 23-24).
Therefore, claim 116 and 117 encompasses a human cell that can be modified ex vivo and reintroduced into a human, which encompasses cells in vivo in a human (i.e., a human organism), which is excluded from the scope of patentable subject matter.
Limiting claim 116 and 117 to “an isolated cell” would obviate the rejection.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 98-117 are rejected under 35 U.S.C. 103 as being unpatentable over Finn et al (US 2020/0270618 A1, published August 27th, 2020; filing date of October 18th, 2018) in view of Wang et al (Adeno-associated virus vector as a platform for gene therapy delivery, Nature Reviews Drug Discovery, Vol 18, pages 358-378, published February 1st, 2019).
Regarding claim(s) 98-99 and 103-106, Finn et al teaches, “Also provided are donor constructs (e.g., bidirectional constructs), comprising a sequence encoding AAT, for use in targeted insertion into a human safe harbor site, such as intron 1 of an albumin safe harbor site.”, (para [0007]). See figure 15 below.
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More specifically, “In some embodiments, the donor construct comprises a heterologous AAT gene that encodes a functional AAT protein. In some embodiments, the functional AAT protein is a human wild-type AAT protein sequence according to SEQ ID NO: 700. In some embodiments, the functional AAT protein is a human wild-type AAT protein sequence according to SEQ ID NO: 702.”, (para [0141]).
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When instant SEQ ID NOs: 781 and 782 are translated, they are 100% identical to SEQ ID NOs: 700 and 702 of Finn et al (see below).
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Lastly, Finn et al teaches, “For example, coding sequence (1) and/or coding sequence (2) that encodes for heterologous AAT can be codon optimized, such that coding sequence (1) and the reverse complement of coding sequence (2) possess less than 100% complementarity. In some embodiments, the coding sequence of the second segment encodes heterologous AAT using one or more alternative codons for one or more amino acids of the same (i.e., same amino acid sequence) heterologous AAT encoded by the coding sequence in the first segment. An “alternative codon” as used herein refers to variations in codon usage for a given amino acid, and may or may not be a preferred or optimized codon (codon optimized) for a given expression system. Preferred codon usage, or codons that are well-tolerated in a given system of expression is known in the art.”, (para [0146]).
Regarding claim 100, Finn et al teaches, “In some embodiments, the bidirectional nucleic acid construct disclosed herein does not comprise a homology arm.”, (para [0143]).
Regarding claim 101, Finn et al teaches, “In some embodiments, the bidirectional nucleic acid construct is linear. For example, the first and second segments are joined in a linear manner through a linker sequence.”, (para [0152]).
Regarding claim 102, Finn et al teaches, “In some embodiments, the construct may comprise any one or more of a polyadenylation tail sequence, a polyadenylation signal sequence, splice acceptor site, or selectable marker. In some embodiments, the polyadenylation tail sequence is encoded, e.g., as a “poly-A” stretch, at the 3′ end of the coding sequence. Methods of designing a suitable polyadenylation tail sequence and/or polyadenylation signal sequence are well known in the art.”, (para [0137]).
Regarding claim 107, Finn et al teaches, “In some embodiments, the constructs disclosed herein comprise one, two, or three ITRs.”, (para [0157]).
Regarding claim 108 and 109, Finn et al teaches, “In some embodiments, the present disclosure provides a method of treating alpha-1 antitrypsin deficiency (AATD) in a subject in need of AAT protein, comprising administering: i) a nucleic acid construct comprising a heterologous AAT protein coding sequence; ii) a RNA-guided DNA binding agent; and iii) an albumin guide RNA (gRNA) comprising a sequence chosen from: a) a sequence that is at least 95%, 90%, 85%, 80%, or 75% identical to a sequence selected from the group consisting of SEQ ID Nos: 2, 8, 13, 19, 28, 29, 31, 32, 33; . . .; d) a sequence that is at least 95%, 90%, 85%, 80%, or 75% identical to a sequence selected from the group consisting of SEQ ID NOs: 2-33; e) at least 17, 18, 19, or 20 contiguous nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 2-33. . , thereby treating AATD in the subject.”, (para [0010]).
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Finn et al teaches all SEQ ID NOs: 2-33 with 100% match, see the alignment below of instant SEQ ID NOs: 2 and 33, and SEQ ID NO:2 and 33 of Finn et al.
Regarding claim 110, Finn et al teaches, “In some embodiments, the combination therapy comprises any one or more of the gRNAs comprising any one or more of the guide sequences disclosed in Table 1 or Table 2, together with a siRNA that targets ATT or mutant ATT. In some embodiments, the siRNA is any siRNA capable of further reducing or eliminating the expression of wild type or mutant AAT.”, (para [0269]).
Regarding claim(s) 111 and 112, Finn et al teaches, “In some embodiments, any of the guide RNAs described herein, RNA-guided DNA binding agents described herein, and/or donor construct (e.g., bidirectional construct) disclosed herein, alone or in combination, whether naked or as part of a vector, is formulated in or administered via a lipid nanoparticle;”, (para [0210]).
Wherein Finn et al teaches SERPINA1 gRNA at para [0084], table 2, and Figure 4.
Figure 14A demonstrates use of LNP dose repose and the amount of hA1AT.
Regarding claim(s) 113 and 114, Figure 15 (see above) depicts two ssAAV8 vectors containing bidirectional nucleic acid constructs.
Regarding claim 115, Figure 14A demonstrates a LNP comprising a bidirectional nucleic acid construct.
Regarding claim(s) 116 and 117, Finn et al teaches, “In some embodiments, provided herein is a host cell, described above, that comprises the bidirectional construct disclosed herein. In some embodiments the host cell expresses the transgene polypeptide encoded by the bidirectional construct disclosed herein.”, (para [0065]).
Finn et al does not teach the nucleotide sequence of SEQ ID NO: 781 or SEQ ID NO:782.
Wang et al teaches, “. . . For gene expression in human cells, even wild-type human-derived gene sequences are not necessarily optimized to yield robust protein expression. This is in part because a natural sequence may not fully utilize the most preferred codon for an amino acid residue. In addition, elements of the transgene sequence itself, such as GC content, cryptic splice sites, transcription termination signals, motifs that affect RNA stability and nucleic acid secondary structures, can impact on expression. Therefore, codon optimization is widely used in rAAV gene therapy aiming to enhance gene expression. . .”, (see page 365, col 1, line 11-21).
Therefore, it would have been obvious to try one of ordinary skill in the art before the effective filing date of the claimed invention to modify the sequences of AAT1 (SEQ ID NOs: 700 and/or 702) as taught by Finn et al through codon-optimized as taught by Wang et al. SEQ ID NOs: 781 and 782 of the instant application are 100% identical to the translated sequence of SEQ ID NOs: 700 and 702 of Finn et al. Wang et al teaches that even wild-type human-derived gene sequences are not necessarily optimized to yield robust protein expression, and that codon optimization is widely used in rAAV gene therapy. Given that these sequences (SEQ ID NOs: 700 and 702 of Finn et al and the translation of instant SEQ ID NOs: 781 and 782) are 100% identical, there are finite positions within the coding sequence to optimize and still yield a protein sequence that is at least 100% identical. One of skill in the art could have codon optimized the nucleotide sequence corresponding to SEQ ID NOs: 700 and/or 702 of Finn et al, to predictably yield instant SEQ ID NOs: 781 and 782. One would have been motivated to do so to enhance gene expression of an rAAV, as taught by Wang et al.
Accordingly, claims 98-117 are unpatentable over Finn et al in view of Wang et al.
Claim(s) 98-117 are rejected under 35 U.S.C. 103 as being unpatentable over ‘690 (US 2026/0125690 A1, published May 7th, 2026; filing date of October 18th, 2018) in view of Wang et al (supra).
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Regarding claim(s) 98-99 and 103-106, ‘690 teaches, “Also provided are donor constructs (e.g., bidirectional constructs), comprising a sequence encoding AAT, for use in targeted insertion into a human safe harbor site, such as intron 1 of an albumin safe harbor site.”, (para [0007]). See figure 15 below.
More specifically, “In some embodiments, the donor construct comprises a heterologous AAT gene that encodes a functional AAT protein. In some embodiments, the functional AAT protein is a human wild-type AAT protein sequence according to SEQ ID NO: 700. In some embodiments, the functional AAT protein is a human wild-type AAT protein sequence according to SEQ ID NO: 702.”, (para [0140]).
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When instant SEQ ID NOs: 781 and 782 are translated, they are 100% identical to SEQ ID NOs: 700 and 702 of ‘690 (see below).
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Lastly, ‘690 teaches, “For example, coding sequence (1) and/or coding sequence (2) that encodes for heterologous AAT can be codon optimized, such that coding sequence (1) and the reverse complement of coding sequence (2) possess less than 100% complementarity. In some embodiments, the coding sequence of the second segment encodes heterologous AAT using one or more alternative codons for one or more amino acids of the same (i.e., same amino acid sequence) heterologous AAT encoded by the coding sequence in the first segment. An “alternative codon” as used herein refers to variations in codon usage for a given amino acid, and may or may not be a preferred or optimized codon (codon optimized) for a given expression system. Preferred codon usage, or codons that are well-tolerated in a given system of expression is known in the art.”, (para [0145]).
Regarding claim 100, ‘690 teaches, “In some embodiments, the bidirectional nucleic acid construct disclosed herein does not comprise a homology arm.”, (para [0142]).
Regarding claim 101, ‘690 teaches, “In some embodiments, the bidirectional nucleic acid construct is linear. For example, the first and second segments are joined in a linear manner through a linker sequence.”, (para [0151]).
Regarding claim 102, ‘690 teaches, “In some embodiments, the construct may comprise any one or more of a polyadenylation tail sequence, a polyadenylation signal sequence, splice acceptor site, or selectable marker. In some embodiments, the polyadenylation tail sequence is encoded, e.g., as a “poly-A” stretch, at the 3′ end of the coding sequence. Methods of designing a suitable polyadenylation tail sequence and/or polyadenylation signal sequence are well known in the art.”, (para [0136]).
Regarding claim 107, ‘690 teaches, “In some embodiments, the constructs disclosed herein comprise one, two, or three ITRs.”, (para [0156]).
Regarding claim 108 and 109, ‘690 teaches, “In some embodiments, the present disclosure provides a method of treating alpha-1 antitrypsin deficiency (AATD) in a subject in need of AAT protein, comprising administering: i) a nucleic acid construct comprising a heterologous AAT protein coding sequence; ii) a RNA-guided DNA binding agent; and iii) an albumin guide RNA (gRNA) comprising a sequence chosen from: a) a sequence that is at least 95%, 90%, 85%, 80%, or 75% identical to a sequence selected from the group consisting of SEQ ID Nos: 2, 8, 13, 19, 28, 29, 31, 32, 33; . . .; d) a sequence that is at least 95%, 90%, 85%, 80%, or 75% identical to a sequence selected from the group consisting of SEQ ID NOs: 2-33; e) at least 17, 18, 19, or 20 contiguous nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 2-33. . , thereby treating AATD in the subject.”, (para [0010]).
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‘690 teaches all SEQ ID NOs: 2-33 with 100% match, see the alignment below of instant SEQ ID NOs: 2 and 33, and SEQ ID NO:2 and 33 of ‘690.
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Regarding claim 110, ‘690 teaches, “In some embodiments, the combination therapy comprises any one or more of the gRNAs comprising any one or more of the guide sequences disclosed in Table 1 or Table 2, together with a siRNA that targets ATT or mutant ATT. In some embodiments, the siRNA is any siRNA capable of further reducing or eliminating the expression of wild type or mutant AAT.”, (para [0266]).
Regarding claim(s) 111 and 112, ‘690 teaches, “In some embodiments, any of the guide RNAs described herein, RNA-guided DNA binding agents described herein, and/or donor construct (e.g., bidirectional construct) disclosed herein, alone or in combination, whether naked or as part of a vector, is formulated in or administered via a lipid nanoparticle;”, (para [0209]).
Wherein ‘690 teaches SERPINA1 gRNA at para [0083], table 2, and Figure 4.
Figure 14A demonstrates use of LNP dose repose and the amount of hA1AT.
Regarding claim(s) 113 and 114, Figure 15 (see above) depicts two ssAAV8 vectors containing bidirectional nucleic acid constructs.
Regarding claim 115, Figure 14A demonstrates a LNP comprising a bidirectional nucleic acid construct.
Regarding claim(s) 116 and 117, ‘690 teaches, “In some embodiments, provided herein is a host cell, described above, that comprises the bidirectional construct disclosed herein. In some embodiments the host cell expresses the transgene polypeptide encoded by the bidirectional construct disclosed herein.”, (para [0065]).
‘690 does not teach the nucleotide sequence of SEQ ID NO: 781 or SEQ ID NO:782.
Wang et al teaches, “. . . For gene expression in human cells, even wild-type human-derived gene sequences are not necessarily optimized to yield robust protein expression. This is in part because a natural sequence may not fully utilize the most preferred codon for an amino acid residue. In addition, elements of the transgene sequence itself, such as GC content, cryptic splice sites, transcription termination signals, motifs that affect RNA stability and nucleic acid secondary structures, can impact on expression. Therefore, codon optimization is widely used in rAAV gene therapy aiming to enhance gene expression. . .”, (see page 365, col 1, line 11-21).
Therefore, it would have been obvious to try one of ordinary skill in the art before the effective filing date of the claimed invention to modify the sequences of AAT1 (SEQ ID NOs: 700 and/or 702) as taught by ‘690 through codon-optimized as taught by Wang et al. SEQ ID NOs: 781 and 782 of the instant application are 100% identical to the translated sequence of SEQ ID NOs: 700 and 702 of ‘690. Wang et al teaches that even wild-type human-derived gene sequences are not necessarily optimized to yield robust protein expression, and that codon optimization is widely used in rAAV gene therapy. Given that these sequences (SEQ ID NOs: 700 and 702 of ‘690 and the translation of instant SEQ ID NOs: 781 and 782) are 100% identical, there are finite positions within the coding sequence to optimize and still yield a protein sequence that is at least 100% identical. One of skill in the art could have codon optimized the nucleotide sequence corresponding to SEQ ID NOs: 700 and/or 702 of ‘690, to predictably yield instant SEQ ID NOs: 781 and 782. One would have been motivated to do so to enhance gene expression of an rAAV, as taught by Wang et al.
Accordingly, claims 98-117 are unpatentable over ‘690 in view of Wang et al.
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.
Claim(s) 98-100, 102-104, 106-107, and 116 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 125, 127-128, 130, and 132-133 of copending Application No. 19/337,426 in view of Finn et al (supra) in further view of Wang et al (supra).
Claim 125 of ‘426 recites, “A method of introducing a nucleic acid encoding alpha-1 antitrypsin (AAT) to a cell or a population of cells, the method comprising delivering to the cell or population of cells:(a) a bidirectional nucleic acid construct comprising:(i) a first segment comprising a first coding sequence for an AAT polypeptide; and(ii) a second segment comprising a reverse complement of a second coding sequence for the AAT polypeptide;(b) a Cas9 nuclease; and(c) a gRNA that targets the albumin locus at a genomic coordinate listed in Table 1.”
Claim 127 of ‘426 recites, ““A bidirectional nucleic acid construct comprising:(a) a first segment comprising a first coding sequence for an alpha-1 antitrypsin (AAT) polypeptide; and (b) a second segment comprising a reverse complement of a second coding sequence for the AAT polypeptide, wherein the bidirectional nucleic acid construct does not comprise: (i) a promoter that drives the expression of the first coding sequence; (ii) a promotor that drives the expression of the second coding sequence; and (iii) a homology arm.” wherein the second coding sequence adopts a different codon usage from the first coding sequence.”
Claim 128 recites of ‘426 recites, “The bidirectional nucleic acid construct of claim 126, wherein the second segment is 3' of the first segment.”
Claim 130 of ‘426 recites, “The bidirectional nucleic acid construct of claim 126, wherein the polyadenylation sequences comprise polyadenylation signal sequences or polyadenylation tail sequences.”
Claim 132 of ‘426 recites, “The bidirectional nucleic acid construct of claim 126, wherein the construct comprises a first splice acceptor site 5' of the first segment and a second splice acceptor site 3' of the second segment.”
Claim 133 of ‘426 recites, “The bidirectional nucleic acid construct of claim 126, wherein the construct comprises one or more of the following terminal structures: hairpin, loops, inverted terminal repeats (ITR), or toroid.”
Claim(s) 125 and 127 of ‘426 do not require SEQ ID NOs: 781 and 782.
Finn et al teaches bi-directional nucleic acid constructs. More specifically, Finn et al teaches, “In some embodiments, the donor construct comprises a heterologous AAT gene that encodes a functional AAT protein. In some embodiments, the functional AAT protein is a human wild-type AAT protein sequence according to SEQ ID NO: 700. In some embodiments, the functional AAT protein is a human wild-type AAT protein sequence according to SEQ ID NO: 702.”, (para [0141]).
When instant SEQ ID NOs: 781 and 782 are translated, they are 100% identical to SEQ ID NOs: 700 and 702 of Finn et al (see in above 103 rejection).
Moreover, Finn et al teaches, “For example, coding sequence (1) and/or coding sequence (2) that encodes for heterologous AAT can be codon optimized, such that coding sequence (1) and the reverse complement of coding sequence (2) possess less than 100% complementarity. In some embodiments, the coding sequence of the second segment encodes heterologous AAT using one or more alternative codons for one or more amino acids of the same (i.e., same amino acid sequence) heterologous AAT encoded by the coding sequence in the first segment. An “alternative codon” as used herein refers to variations in codon usage for a given amino acid, and may or may not be a preferred or optimized codon (codon optimized) for a given expression system. Preferred codon usage, or codons that are well-tolerated in a given system of expression is known in the art.”, (para [0146]).
Finn et al does not teach the nucleotide sequence of SEQ ID NO: 781 or SEQ ID NO:782.
Wang et al teaches, “. . . For gene expression in human cells, even wild-type human-derived gene sequences are not necessarily optimized to yield robust protein expression. This is in part because a natural sequence may not fully utilize the most preferred codon for an amino acid residue. In addition, elements of the transgene sequence itself, such as GC content, cryptic splice sites, transcription termination signals, motifs that affect RNA stability and nucleic acid secondary structures, can impact on expression. Therefore, codon optimization is widely used in rAAV gene therapy aiming to enhance gene expression. . .”, (see page 365, col 1, line 11-21).
Therefore, it would have been obvious to try one of ordinary skill in the art before the effective filing date of the claimed invention to modify the first coding sequence for an alpha-1 antitrypsin (AAT) polypeptide and the second segment comprising a reverse complement of a second coding sequence for the AAT polypeptide of claim(s) 125 and 127 of ‘426 with SEQ ID NO:700 and 702 as taught by Finn et al through codon-optimized as taught by Wang et al. SEQ ID NOs: 781 and 782 of the instant application are 100% identical to the translated sequence of SEQ ID NOs: 700 and 702 of Finn et al. Wang et al teaches that even wild-type human-derived gene sequences are not necessarily optimized to yield robust protein expression, and that codon optimization is widely used in rAAV gene therapy. Given that these sequences (SEQ ID NOs: 700 and 702 of Finn et al and the translation of instant SEQ ID NOs: 781 and 782) are 100% identical, there are finite positions within the coding sequence to optimize and still yield a protein sequence that is at least 100% identical. One of skill in the art could have codon optimized the nucleotide sequence corresponding to SEQ ID NOs:700 and 702 of Finn et al, to predictably yield instant SEQ ID NOs: 781 and 782. One would have been motivated to do so to enhance gene expression of an rAAV, as taught by Wang et al.
Accordingly, claim(s) 98-100, 102-104, 106-107, and 116 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 19/337,426 in view of Finn et al (supra) in further view of Wang et al (supra).
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/L.M.T./Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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