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
Election/Restrictions
Applicant's election without traverse of the following species in the reply filed on 05/26/2026 is acknowledged.
1) Peptide insertion sequence: amino acid 2-8 of Seq Id NO: 27 (SQRETVW) which is considered to be the election of Seq ID NO: 27.
2) Amino acid insertion location: Position 587 relative to Seq ID NO: 1
3) An AAV capsid polypeptide: Seq ID NO: 7
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/AU2021/051497, filed 12/16/2021.
Applicant' s claim for the benefit of a prior-filed parent application AU2020904687, filed on 12/16/2020 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The effective priority for the instant application is 12/16/2020.
Claims Status
Claims 14 and 17-25 are canceled, no claims are newly added, claims 5-6 are withdrawn from consideration as being drawn to non-elected subject matter, and claims 1-13, 15-16 and 26 have been considered on the merits.
Specification
The disclosure is objected to because of the following informalities: The specification refers to Fig 3e on p37 [00119], however figure 3e is not present in the drawings.
Figure 2e of the drawings shows the data referred to by paragraph [0019], thus Figure 3e as recited in the specification is considered a typing error and interpreted as referring to Figure 2e.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Page 30 [0091] recites “https://tmcalculator.neb.com”.
Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Appropriate correction is required.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Figure 1 recites amino acid and nucleotide sequences but does not disclose sequence identifiers.
Claim Objections
Claims 1 and 8d are objected to because of the following informalities: The claims recite “SEQ ID Nos:”. Replacing the phrase with ---SEQ ID NOs:--- will improve consistency and overcome the objection.
Appropriate correction is required.
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 1-4, 7-13, 15-16 and 26 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.
Regarding claim 1: The claim is drawn to a broad genus of polypeptide sequences.
The claim recites the portion of the capsid polypeptide that is not the peptide modification comprises at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, or 96% sequence identity to positions 1-735, 138-735 or 203-735 of SEQ ID NO:1.
Positions 203-735 of SEQ ID NO:1 are examined as a representative, however the instant analysis also applies to the claimed sequences comprising positions 1-735 and 138-735 of SEQ ID NO:1.
The claim also requires a peptide modification comprising the sequence set forth in Seq ID NO: 27; a 9mer peptide sequence which is in the variable region 8 of the polypeptide. Variable region 8 of AAV2 comprises 16 amino acid region “VSTNLQRGNRQAATAD” (Figure 3; Govindasamy et al (Journal of Virology (2006) 80:1-15). The variable region 8 is positions 579-594 of Seq ID NO:1 of the instant invention.
Positions 203-735 of Seq ID NO: 1 is an amino acid sequence comprising 532 residues. The broadest reasonable interpretation of the claim limitation “at least 80% sequence identity” is an amino acid sequence that can differ from Seq Id NO: 1 positions 203-735 by up to 20% (about 106 residues) compared to positions 203-735 of Seq ID No: 1, and comprises a 7 amino acid insertion at any one of 16 positions.
Teachings of the instant specification
Table 4 of the instant specification teaches 20 AAV capsid polypeptide sequences (Seq ID NOs 2-21) that comprise a peptide modification after position 186 (numbering corresponding to that of Seq ID NO: 1) and comprise at least 80% identity with Seq ID No: 1 (p 38-44).
The instant specification further teaches the polypeptide variants were tested for packaging a gene cassette (p36 [00117]; Fig ) and that the top performing variant from the RC screen was not highly functional (p37 [00118]).
The instant specification further teaches the top functioning capsids were evaluated in animals and had equivalent specificity as the positive control, AAV-NP59 (p37 [00120]; Fig 23-f).
The state of the art
It is well known in the art that the effect of amino acid changes within polypeptide sequences which encode functional proteins is not predictable. It is well known in the art that proteins require specific structural features in order to perform a function.
Variants of amino acid sequences encoding AAV2 capsid polypeptides are known in the art. Maurer et al (Cell Reports (2018) 23;1817-1830) teach that variations of the AAV capsid affect a plurality of phenotypes including vector production and host tropism (abstract). Maurer further teach efforts to modulate AAV function by engineering the capsid is constrained because changes to the capsid may affect a multitude of functionalities, including assembly (p1819 col1 ¶2). Maurer teach that the selective advantage of a set of de novo mutations can be evaluated only if and when an assembly (multimerization of viral proteins to form a capsid) can be built from a given VP monomer (p1819 col1 ¶2). Maurer teach many capsid modifications inadvertently affect viral assembly by affecting interactions with viral or cellular assembly co-factors and/or disrupting the highly ordered icosahedral virion architecture, without which assembly cannot take place (p1826 col1 ¶1).
Alberts et al (The Shape and Structure of Proteins(2002) Molecular Biology of the Cell 4th ed. New York:Garland Science) further teach that only a very small fraction of the vast set of conceivable polypeptide chains would adopt a single, stable three-dimensional conformation, and that the vast majority of possible protein molecules could adopt many conformations, each conformation having different chemical properties (p7 ¶2). Alberts further teach the amino acid sequence (encoded by a nucleic acid sequence) of a present-day protein is extremely stable, but the conformation has chemical properties that perform a particular function in the cell, and proteins (polypeptides) are precisely build such that the change of even a few atoms in one amino acid can disrupt the structure of the whole molecule such that all function is lost (p7 ¶3).
This demonstrates that, while polypeptides encoding AAV2 capsid variants are known in the art, the effect of changes to the polynucleotide sequence is highly specific to the location and reside residue in question and the effects of such changes are unpredictable.
This supports the effect of changes of up to 20% of the amino acid residues encoding a polypeptide encoding an AAV2 capsid polypeptide is unpredictable and would require trial-and-error experimentation to identify the amino acid sequences which encode polypeptides with a structure that could form an AAV2 capsid.
Conclusion
As described supra, the instant specification provides 20 specific amino acid sequences which read on the claimed genus of capsid polypeptides. The instant specification teaches some variants have increased function compared to AAV2 and NP59 (Figure 3).
However the species of amino acid molecules disclosed in the instant specification are not sufficient to predict the broad genus of amino acid molecules encoding an AAV capsid polypeptides, wherein the amino acid sequence has at least 80% sequence identity to positions 203-735 of SEQ ID NO:1 in view of the unpredictability of amino acid changes to AAV polypeptides as known in the art.
Furthermore, the instant specification provides no guidance as how to avoid losing key structural or binding components for polypeptides with amino acid changes of up to 532 residues, and the art does not provide a remedy.
One of ordinary skill in the art would understand that capsid polypeptides require a specific structure to be able to form a viral capsid. One of ordinary skill in the art would also understand that the effect of amino acid changes in the polypeptide sequence encoding a functional capsid can have unpredictable effects on the capsid structure and thus activity.
This demonstrates that, while polypeptide sequences encoding AAV capsid polypeptide variants are known in the art, the effect of changes to amino acid sequence encoding said polypeptides must be tested empirically to determine how the sequence change affects polypeptide function (capsid formation).
MPEP states “[a] specification may call for a reasonable amount of experimentation to make and use a patented invention. What is reasonable in any case will depend on the nature of the invention and the underlying art”.
In the case of the instant claim 1, trial and error and/or laborious screening methods are required to identify an isolated nucleic acids that encode a polypeptide capable of performing the required function as claimed and the species examples provided in the art are not of a large enough breadth to impart predictability on the genus as claimed.
Note that claims 2-4, 7-13, 15-16 and 26 depend from claim 1 and fail to cure the deficiency.
Claim 26 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 USPQd 1400, 1404 (Fed. Cir. 1988) (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. While all of these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
The breadth of the claims
Regarding claim 26: The claim is drawn to a method of treating a liver-associated condition by administering to the subject the AAV vector of claim 9.
The instant specification is silent on an explicit definition of “treating” a disease or condition in a subject. Thus the broadest reasonable interpretation of “treating” encompasses not only reducing or alleviating any symptoms of a liver disease or condition, but also curing a liver disease or condition and preventing liver diseases or conditions.
The claim recites “a liver disease or condition” which is also extremely broad and encompasses any liver disease and condition from any etiologies including diseases and conditions with and without a genetic component.
Considering broad scope of the term “treating” in the claimed invention as discussed above, and the lack of description how the broad scope of “treating” which encompasses preventing and curing of a liver disease or condition the instant specification fails to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The claimed method does not particularly limit the scope of the subject being administered with AAV vector, and thus, the scope of the subject is broad to encompass any mammal including human.
Regarding the AAV vector of claim 9: the instant specification defines an AAV vector as “a vector in which the capsid is derived from an adeno-associated virus, including without limitation, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12 or AAV13, AAV from other clades or isolates, or is derived from synthetic, bioengineered or modified AAV capsid proteins, including chimeric capsid proteins. In” (p5 [0023]).
Thus the vector which is to be administered comprises the capsid polypeptide of claim 1 but does not require a transgene or viral genome.
The vector of claim 9 is silent as to any additional components of the vector (such as a therapeutic transgene), in addition to the claimed AAV capsid polypeptide of claim.
Thus the claim is interpreted as the administration of an AAV vector comprising the viral capsid polypeptide of claim 1, and does not require a transgene.
The instant specification
The instant specification teaches sequences which comprise an AAV2 capsid protein (Seq ID NO: 1-21) (Table 1 p9).
The instant specification teaches AAV vectors comprise a heterologous coding sequence which may be operably linked to a promoter to facilitate expression of the sequence, and that the coding sequence can encode a therapeutic polypeptide or a polynucleotide which has function or activity (p25 [0068]). The instant specification further teaches AAV vectors comprising the transgene LSP-eGFP-N6Barcode(BC) (p32 [0097]). However the claimed AAV vector required for the method of treating does not require any transgene.
Furthermore, while the instant specification discloses specific diseases and associated genes (Table 2), the specification is silent in regards to “treating” a disease or condition using the claimed AAV vector comprising the AAV capsid polypeptide. The instant is also silent on working examples of using the claimed AAV vector comprising the AAV capsid polypeptide to encode or deliver a transgene.
The state of the art
AAV vectors to deliver transgenes for treating liver disease are known in the art, as exemplified by Wang and Chandler, below.
Wang et al (Molecular Genetics and Metabolism (2017) 299-305; AAV gene therapy corrects OTC deficiency and prevents liver fibrosis in aged OTC-knock out heterozygous mice) teach that administration of an AAV encoding human OTC gene treats HetOTC-KO mice (abstract). Chandler et al (Human Gene Therapy (2011) 22:477-481; Adeno-Associated Virus Serotype 8 Gene Transfer Rescues a Neonatal Lethal Murine Model of Propionic Acidemia) teach AAV gene therapy restores PCC to greater than wild-type levels for Pcca-/- mice (abstract).
While AAV vectors to deliver therapeutic transgenes to treat liver disease are known in the art, the claimed method does not require the AAV vector to comprise a transgene. The art is silent on a therapeutic effect or treatment resulting from administration of an AAV vector comprising only AAV capsid, as required by the instant claim, in the absence of a therapeutic transgene.
Furthermore, AAV vectors comprising only capsid are unlikely to provide a therapeutic benefit, as Wright et al (Molecular Therapy (2014) 22:1;1-2; AAV Empty Capsids: For Better or for Worse?) teach “empty” AAV capsids, which lack a vector genome and transgene, are unable to provide a therapeutic benefit (p1 col1 ¶1).
Thus the art is silent on how an AAV vector comprising an AAV viral capsid polypeptide can treat a disease or condition and the effect of treating a condition or disease using the claimed AAV vector, which does not require a transgene, and the effect of administering the claimed AAV vector is unpredictable and would require trial-and-error experimentation for one of ordinary skill in the art to practice the method as claimed.
Furthermore, while no transgene is required by the claims, any transgene could be incorporated into the claimed AAV vector. However, the effect of administering an AAV vector encoding any transgene is also unpredictable and would require trial-and-error experimentation for one of ordinary skill in the art to practice the method as claimed.
Additionally, while AAV vectors which comprise a transgene that can be administered to treat a liver disease or condition are known in the art, “a liver disease or condition” is extremely broad and encompasses many diseases and conditions with differing etiologies. An AAV vector that delivers a transgene for treatment of a liver disease or condition would not be effective to treat any liver disease or condition.
For example, Wang et al teach that administration of an AAV encoding human OTC gene treats Het OTC-KO mice (abstract). However, one would not have a reasonable expectation of success for administration of the AAV vector taught by Wang to treat a different liver disease or condition, such as propionic acidemia (an autosomal recessive disorder of metabolism), a liver disorder taught by Chandler (abstract).
Thus the effect of an AAV vector for treatment of any liver disease or condition is unpredictable and would require trial-and-error experimentation for one of ordinary skill in the art to practice the method as claimed.
Conclusion
The instant disclosure is drawn to a method of use of an AAV vector comprising an AAV capsid polypeptide to treat a liver-associated disease or condition in a subject. While the instant specification discloses specific AAV capsid sequences, and is thus enabled for the AAV vector comprising the AAV capsid polypeptide of claim 1, the instant disclosure provides no guidance or evidence that an AAV vector comprising said AAV capsid protein has any effect on a liver-associated disease or condition and the art does not remedy the deficiency.
The art teaches that empty capsids lacking a transgene do not provide a therapeutic effect and is silent on how an AAV vector comprising a capsid polypeptide as claimed will have a function for treating a liver disease or condition in a subject.
Furthermore, while the instant specification speculates on liver diseases and proteins that could be therapeutic (Table 2), the instant specification is silent on working examples of the claimed AAV vector comprising a therapeutic transgene and the effect of the vector on a disease.
While the art teaches AAV vectors which can deliver therapeutic transgenes for the treatment of liver diseases and conditions, the art also teaches that such gene therapy vectors must be tested and optimized. Colella et al (Molecular Therapy Methods & Clinical Development (2018) 8:87-104; Emerging Issues in AAV-Mediated In Vivo Gene Therapy) teach that a key step in the development of an AAV vector-based gene therapy drug is the early selection of the combination of optimal transgene expression cassette, serotype, and viral genome for clinical use (p96 col1 ¶2). Thus one of ordinary skill in the art would have to empirically test a specific transgene with a specific AAV capsid polypeptide to determine if the AAV vector was enabled to treat a specific disease.
Based on the above discussion, it has been concluded that the instant specification does not enable any person skilled in the art to which it pertains, or with
which it is most nearly connected, to make/use the invention commensurate
with the claims without undue experimentations.
Claim 26 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 breadth of the claims
Regarding claim 26: The claim is drawn to a method of treating any liver-associated disease or condition by administering to the subject an AAV vector of claim 9 which comprises the capsid polypeptide comprising modifications as disclosed in claim 1.
The instant specification is silent on an explicit definition of “treating” a disease or condition in a subject. Thus the broadest reasonable interpretation of “treating” encompasses not only reducing or alleviating any symptoms of a liver disease or condition, but also curing a liver disease or condition and preventing liver diseases or conditions.
The claim further recites “a liver disease or condition” which is also extremely broad and encompasses any liver diseases and conditions from differing etiologies including diseases and conditions without a genetic cause.
Considering broad scope of the term “treating” in the claimed invention as discussed above, and the lack of description how the broad scope of “treating” which encompasses preventing and curing of a liver disease or condition, the instant specification fails to provide sufficient written description for the entire scope of the claimed invention.
The claimed method does not particularly limit the scope of the subject being administered with AAV vector, and thus, the scope of the subject is broad to encompass any mammal including human.
Regarding the AAV vector of claim 9: the instant specification defines an AAV vector as “a vector in which the capsid is derived from an adeno-associated virus, including without limitation, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12 or AAV13, AAV from other clades or isolates, or is derived from synthetic, bioengineered or modified AAV capsid proteins, including chimeric capsid proteins. In” (p5 [0023]).
Thus the vector which is to be administered comprises the capsid polypeptide of claim 1 but does not require a transgene or viral genome.
The vector of claim 9 is silent as to any additional components of the vector (such as a therapeutic transgene), in addition to the claimed AAV capsid polypeptide of claim.
Therefore the claim is interpreted as the administration of an AAV vector comprising the viral capsid polypeptide of claim 1, and does not require a transgene.
Thus the claimed method is extremely broad.
The instant specification
The instant specification teaches Sequences which comprises an AAV2 capsid protein (Seq ID NO: 1-21) (Table 1 p9).
The instant specification teaches AAV vectors comprise a heterologous coding sequence which may be operably linked to a promoter to facilitate expression of the sequence, and that the coding sequence can encode a therapeutic polypeptide or a polynucleotide which has function or activity (p25 [0068]). The instant specification further teaches AAV vectors comprising the transgene LSP-eGFP-N6Barcode(BC) (p32 [0097]).
The instant specification teaches exemplary liver-associated diseases with associated genes OTC, ASS, CPS1, ASL, ARG1, PCCA, PCCB, MMUT, PAH, FAH, SLC37A4, ATP7B, ATP7B, ABCB4, ABCB11, ATP8B1, and AGXT (Table 2).
However the instant specification is silent as to specific working examples or disclosures of using the disclosed vectors or genes to treat (reduce or ameliorate) symptoms or progression of any liver disease or condition.
The instant specification is also silent in regards to “treating” a disease or condition using the claimed AAV vector comprising the AAV capsid polypeptide absent a transgene.
The state of the art
AAV vectors to deliver therapeutic transgenes treat liver associated diseases and conditions are known in the art, as exemplified by Wang and Chandler, below.
Wang et al (Molecular Genetics and Metabolism (2017) 299-305; AAV gene therapy corrects OTC deficiency and prevents liver fibrosis in aged OTC-knock out heterozygous mice) teach and AAV encoding human OTC gene treats HetOTC-KO mice (abstract).
Chandler et al (Human Gene Therapy (2011) 22:477-481; Adeno-Associated Virus Serotype 8 Gene Transfer Rescues a Neonatal Lethal Murine Model of Propionic Acidemia) teach AAV gene therapy restores PCC to greater than wild-type levels for Pcca-/- mice (abstract).
While AAV vectors comprising transgenes which could reasonably provide a therapeutic effect in the context of specific liver disease are known in the art, Colella et al (Molecular Therapy Methods & Clinical Development (2018) 8:87-104; Emerging Issues in AAV-Mediated In Vivo Gene Therapy) teach that predicting the therapeutic effect of transgenes delivered by AAV vectors is unpredictable and requires experimentation and optimization. Colella teach that AAV vectors comprise a protein capsid and a DNA genome, each of which can contribute to shaping the host immune response to vector-mediated transfer, and that cell-mediated immunity directed against the AAV capsid plays an important role in the safety and efficacy of AAV gene transfer in humans (p90 col1/2 ¶2/2).
Colella also teach little knowledge is available on the immunogenicity of transgenes in humans in the context of gene therapy, and that evaluation of transgene immunogenicity is complex (p89 col1/2 ¶3/2). Colella further teach that a key step in the development of an AAV vector-based gene therapy drug is the early selection of the combination of optimal transgene expression cassette, serotype, and viral genome for clinical use (p96 col1 ¶2). Colella teach the transgene requires rational design to maximize expression, selection of the most suitable AAV genome, selection of the most appropriate capsid, testing of the vector efficiency in vitro and in small animals, and assessment of the immunogenicity of the optimized vector (p96 col1 ¶2).
Conclusion
As described above, the claimed method is drawn to the treatment of a liver associated disease or condition by administering the claimed AAV vector which encodes a capsid polypeptide.
As discussed above, the term “treat” is extremely broad and the instant specification is silent as to specific working examples or disclosures of using the disclosed vectors or genes to treat (reduce or ameliorate) symptoms or progression of any liver disease or condition and thus fails to demonstrate possession of the claimed invention.
Furthermore, while AAV vectors to treat liver disease are known in the art, the AAV vectors taught in the art comprise therapeutic transgenes and, as taught by Colella, a specific AAV vector must be tested and optimized for use regarding a specific disease of interest and a specific transgene of interest and the outcome of the delivery of any transgene by a specific capsid must be tested.
Additionally, while AAV vectors to treat a liver disease or condition are known in the art, claimed AAV vector comprising the capsid of claim 1 is not limited to any specific transgene or disease, and the effect of delivering a specific transgene for treatment of a specific disease or condition must be tested empirically to determine the effect of the specific transgene on the specific condition.
M.P.E.P. §2163 states “To satisfy the written description requirement, 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. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66
USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19
USPQ2d at 1116.”
MPEP states “[a] specification may call for a reasonable amount of experimentation to make and use a patented invention. What is reasonable in any case will depend on the nature of the invention and the underlying art”.
While the instant specification provides examples of 17 genes that are associated with liver disease or conditions which could be delivered by the claimed AAV vector comprising the claimed AAV capsid polypeptide to treat a liver-associated disease or condition in a subject which could comprise any transgene for gene therapy.
However the species of transgenes disclosed in the instant specification and art are not sufficient to predict the genus of any transgene which, when delivered by the AAV vector would treat ANY liver disease or condition. Furthermore Colella et al (Molecular Therapy Methods & Clinical Development (2018) 8:87-104; Emerging Issues in AAV-Mediated In Vivo Gene Therapy) teach that a key step in the development of an AAV vector-based gene therapy drug is the early selection of the combination of optimal transgene expression cassette, serotype, and viral genome for clinical use (p96 col1 ¶2). Thus one of ordinary skill in the art would have to empirically test a specific transgene with a specific AAV capsid polypeptide to determine if the AAV vector could treat a disease or condition.
In the case of the instant claim 26, there is a high degree of uncertainty of the effect of the claimed AAV vector treat a disease as claimed, and one of ordinary skill in the art would be required to perform trial and error and/or laborious screening methods to identify an AAV vector comprising the claimed capsid polyprotein which would treat a liver disease or condition. Furthermore examples provided in the art and instant specification are not of a large enough breadth to impart predictability on the genus as claimed. Thus, the instant specification fails to provide sufficient written description for the entire scope of the claimed invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1-4, 7-13, 15-16 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Muller et al (Nature Biotechnology (2003) 21;1040-1046; Random peptide libraries displayed on adenoassociated virus to select for targeted gene therapy vectors) in view of Govindasamy et al (Journal of Virology (2006) 80:1-15; Structurally Mapping the Diverse Phenotype of Adeno-Associated Virus Serotype).
Regarding claims 1-4, 7-9 and 15-16: The instant claims are drawn to an AAV capsid polypeptide, comprising a peptide modification relative to the AAV2 capsid polypeptide set forth in SEQ ID NO: 1, wherein: the peptide modification is in variable region 8 (VRVIII); the peptide modification comprises an insertion of 9 amino acids relative to the AAV2 capsid polypeptide set forth in SEQ ID NO: 1, and comprises the sequence set forth in any one of SEQ ID NOs:22-41; and the portion of the capsid polypeptide that is not the peptide modification comprises at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, or 96% sequence identity to positions 1-735, 138-735 or 203-735 of SEQ ID NO: 1.
Muller et al. teach the foundational AAV2 random peptide display library platform, wherein random 7-amino acid peptides (9-mer with two amino acids added at each end due to two SfiI restriction sites, see Figure 1 (b) on page 1041) are inserted into the AAV2 capsid at the VRVIII site, immediately following R588, which abolish heparin (R588 is known to bind heparan sulfate proteoglycans (HSPGs) in the relevant field of art) while preserving capsid assembly and packaging, and the library is screened to isolate variants with altered tropism (see RESULTS on page 1041). It is noted by the Examiner that this identical library-construction strategy is used in the instant specification for producing peptides (9-mer) of SEQ ID NOs: 22-41, which were inserted at the SfiI-engineered N587 site of AAV2 set forth in SEQ ID NO: 1 which is essentially an identical backbone. Muller et al. further teach packaging the modified capsids into recombinant AAV vectors, providing nucleic acids (plasmids) encoding the variant capsid genes, and using host cells, i.e. HEK293 cells, for vector production (see Figure 2 on page 1042, and related discussions).
Even though prior art does not teach the exact peptide sequences of SEQ ID NOs: 22-41, a POSITA would have arrived at these exact 9-mer sequences with routine experimentation. It is noted by the Examiner that the specific peptide sequences set forth in SEQ ID NOs: 22-41 are NOT structurally or functionally inventive, as they are simply expected products of a known optimization technique applied to a known starting capsid AAV2 and known cloning/production strategy as taught by Muller et al. which is identically used/followed in the instant case. See KSR International Co. v. Teleflex Inc., 550 U.S.--, 82 USPQ2d 1385 (2007). Also see MPEP 2144.05.
While Muller is disclosed to a peptide after position 588 and the instant disclosure is drawn to a peptide insertion after position 587, a peptide insertion anywhere within variable region 8 is considered obvious in view of Govindasamy and Muller.
Muller further teach the peptides are positioned such that they are exposed on the surface of the vector capsid at a site critical for viral attachment to the target cells, diminishing the vector’s nonspecific endogenous tropism (p1 col2 ¶2). Muller further teach mutations and insertions within the cap gene allow for efficient assembly of intact, genome-containing AAV, but diminish their binding to heparin (p2 col1 ¶2).
Govindasamy teach the variable regions of AAV2 map to surface loops of the capsid, and that variable region 8 corresponds to residues 579-594 (p9 col2 ¶2; Table 3). Govindasamy further teach variable region 8 comprises critical residues R585 and R588 that are required for AAV2 heparin binding (p13 col1 ¶3).
Thus it would have been obvious for one of ordinary skill in the art to insert a peptide into the capsid of AAV2 at any of the positions known to be critical for heparin binding within variable region 8 so as taught by Govindasamy (before or after R585 or before or after R587) so that the peptide would be exposed on the surface at a site critical for viral attachment to target cells and heparin binding is diminished.
A POSITA would have had a reasonable expectation of success to make and use such AAV capsid polypeptides because all of the required biochemical reagents and techniques were readily available and rampantly used as evidenced by Muller et al. prior to the filing of the instant application and the structural knowledge of where to insert the peptides (surface exposed residues critical for heparin binding) was also known, as taught by Govindasamy.
For the reasons provided herein, the invention as claimed is prima facie obvious over the combined teachings of the prior art.
Regarding claims 10-11: The claims recite the intended results of increased transduction efficiency of human hepatocytes.
The result of using the claimed AAV vector does not impart or imply structure to the claimed vector, and thus any vector that reads on the structure of vector as required by the instant claims is considered to produce the same result if used as described.
Regarding claim 12-13: The teachings of Muller are discussed above. Muller further teach AAV vectors are attractive as a gene therapy vector because they achieve long-term transgene expression in vivo (p1 col1 ¶1).
Long-term transgene expression from an AAV vector reads on a heterologous coding sequence which encodes a therapeutic peptide, polypeptide or polynucleotide as required by the claims.
Regarding claim 26: The claim is drawn to a method of use of the claimed composition. The claim recites “A method of treating a liver-associated disease or condition in a subject”. This is considered equivalent to an intended use phrase (e.g. for of treating a liver-associated disease or condition in a subject) and does not confer or imply active steps for the claimed method”.
MPEP 2111.04 states “The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met.”
The active step of the method is administering to the subject an AAV vector of claim 9.
The teachings of Mueller and Asokan are discussed supra. Mueller further teach vectors comprising the capsid were injected intravenously into mice. This reads on administering to the subject an AAV vector of claim 9.
Conclusion
No claims are allowed.
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/ANDREA LYNNE MORRIS SPENCER/Examiner, Art Unit 1631
/TAEYOON KIM/Primary Examiner, Art Unit 1631
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