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 .
Disposition of Claims
Claims 1-16, 18-19, 21, and 23 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US 2023/0295238 A1, Published 21 September 2023. Applicant’s amended Specification as presented on 20 January 2023 is acknowledged and entered.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The information disclosure statement filed on 23 May 2023 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. Specifically, no copy of either Fingle et al. or Winter et al. was provided by Applicant. Additionally, there were copies of references submitted which were not listed on any filed IDS, specifically the Gilson and Brunton reference and the Hightower and Nover reference (Heat Shock and Development). It has been placed in the application file, but the information referred to therein in the specific non-compliant references has not been considered. The IDSes have been considered as a whole, however.
The information disclosure statements (IDSes) submitted on 23 May 2023, 14 June 2023, and 26 August 2024 have been considered, as a whole, by the examiner. Any individual references with strikethroughs, however, have not been considered.
Specification
The abstract of the disclosure is objected to because of a typographical error. It is suggested that it say “…provides a modified viral capsid…” or “…provides modified viral capsids…” instead of “…provides modified viral capsid…” in Line 1. modified A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
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 Objections
Claims 7 and 15-16 are objected to because of the following informalities: In Claim 7, it is suggested that it say “an N-terminal linker” instead of “a N-terminal linker”.
In Claim 15, it is suggested that it say “comprising an AAV capsid [cap] protein” instead of “comprising AAV cap protein”.
In Claim 16, it is suggested that it say “a conservatively modified variant thereof” instead of “a conservatively modified variant”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b); Second Paragraph
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 6, and dependent claims 7-8 thereof, is 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.
Regarding Claim 6, it recites the limitation “wherein the IR-binding moiety comprises the amino acid sequence shown in SEQ ID NO: 7 or 8, a conservatively modified variant or a functional fragment thereof”. The phrase “a functional fragment thereof” is not further utilized in the claim set and, while it is used throughout the instant Specification, no specific or special definition is provided in the Specification for this phrase. The lack of clarity regarding this phrase renders the claim indefinite because a person having ordinary skill in the art would not be able to determine how much variation is being claimed and thus what is and what is not encompassed by this phrase. It is suggested that the phrase be deleted, but Applicant is free to amend the claim as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 6 is rejected on the grounds of being indefinite. Claims 7-8 are also rejected since they depend upon Claim 6, but do not remedy the deficiencies of Claim 6.
Claim 16 is 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.
Regarding Claim 16, it recites the limitation “The modified capsid protein of claim 15, comprising the amino acid sequence as shown in any one of SEQ ID NOs: 1-5, or a conservatively modified variant”. As written, the phrase “a conservatively modified variant” is modifying “SEQ ID NOs: 1-5”. In the instant Specification, however, this phrase is only explained in the context of the IR-binding peptide or mimetic (see Paragraph 0042). As such, it is unclear if the use of this phrase in Claim 16 is referring to SEQ ID NOs: 1-5 as a whole or specifically and only the IR-binding peptide, which corresponds to SEQ ID NO: 7, that has been inserted into parent sequences in order to generate SEQ ID NOs: 1-5. This lack of clarity renders the claim indefinite. It is suggested that the claim be amended by removing the phrase, but Applicant is free to amend the claim as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 16 is rejected on the grounds of being indefinite.
Claim 18 is 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.
Regarding Claim 18, it recites the limitation “An engineered viral particle comprising the modified viral capsid of claim 17”. Claim 17 was cancelled, however, in the most recent claim set, so it is unclear which claim is the parent claim for Claim 18. It is suggested that the claim be amended by updating the dependency tree, for instance by making Claim 18 dependent on Claim 16, but Applicant is free to amend the claim as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 18 is rejected on the grounds of being indefinite.
Claim Interpretation
In light of the issues raised above, the claims are being interpreted as reading upon the following:
Claim 1 is drawn to a modified capsid protein of a virus, comprising a viral capsid polypeptide sequence that is conjugated to an insulin receptor (IR) binding moiety.
Claim 23 is drawn to a recombinant adeno-associated virus (rAAV) vector, comprising (1) a modified AAV genome comprising a transgene that is flanked by two AAV inverted terminal repeats (ITRs), and (2) a modified AAV capsid that is composed of both wild-type and modified AAV Cap proteins, wherein the modified Cap proteins comprise an inserted insulin receptor (IR) binding peptide or mimetic.
Further limitations on the modified capsid protein of a virus according to Claim 1 are:
2. The modified capsid protein of claim 1, wherein the virus is an adeno- associated virus (AAV) or an adenovirus.
3. The modified capsid protein of claim 1, wherein the IR-binding moiety is a peptide or peptide mimetic.
4. The modified capsid protein of claim 2, wherein the AAV is of serotype 9 (AAV9), serotype 8 (AAV8), serotype 2 (AAV2) or serotype 1 (AAV1).
5. The modified capsid protein of claim 2, wherein the IR-binding moiety is conjugated to variable region VIII (VR-VIII) or IV (VR-IV) of the capsid polypeptide sequence.
6. The modified capsid protein of claim 5, wherein the IR-binding moiety comprises the amino acid sequence shown in SEQ ID NO:7 or 8, or a conservatively modified variant thereof.
7. The modified capsid protein of claim 6, wherein the IR-binding moiety is flanked by an N-terminal linker and a C-terminal linker for conjugation.
8. The modified capsid protein of claim 7, wherein the N-terminal linker comprises amino acid residue(s) GA, L or A, and the C-terminal linker comprises amino acid residue(s) AG or A.
9. The modified capsid protein of claim 5, wherein the IR-binding moiety is inserted into VR-VIII of the AAV capsid polypeptide sequence.
10. The modified capsid protein of claim 9, wherein the IR-binding moiety is inserted after any one of amino acid residues 587-591, and wherein amino acid numbering is based on AAV9 VP1 capsid polypeptide.
11. The modified capsid protein of claim 10, wherein the IR-binding moiety is inserted after amino acid residue 589.
12. The modified capsid protein of claim 5, wherein the IR-binding moiety is inserted into VR-IV of the AAV capsid polypeptide sequence.
13. The modified capsid protein of claim 12, wherein the IR-binding moiety is inserted after any one of amino acid residues 451-455, and wherein amino acid numbering is based on AAV9 VP1 capsid polypeptide.
14. The modified capsid protein of claim 13, wherein the IR-binding moiety is inserted after amino acid residue G453.
15. The modified capsid protein of claim 2, comprising an AAV capsid protein VP1 sequence with an inserted IR-binding peptide.
16. The modified capsid protein of claim 15, comprising the amino acid sequence as shown in any one of SEQ ID NOs: 1-5.
18. An engineered viral particle comprising the modified viral capsid of claim 16.
19. A polynucleotide encoding the modified capsid protein of claim 1.
21. An isolated host cell that harbors the polynucleotide of claim 19.
Claim Rejections - 35 USC § 112(a); First Paragraph
Claims 6-8 and 16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant application attempts to tie function to sequence identity in the context of a modified capsid protein of a virus, comprising a viral capsid polypeptide sequence that is conjugated to an insulin receptor (IR) binding moiety, wherein the IR-binding moiety comprises the amino acid sequence shown in SEQ ID NO: 7 or 8, a conservatively modified variant or a functional fragment thereof, and wherein the modified capsid protein comprises an AAV capsid protein VP1 sequence with an inserted IR-binding peptide and wherein the modified capsid protein comprises the amino acid sequence as shown in any one of SEQ ID NOs: 1-5, or a conservatively modified variant.
There is no sequence identity threshold provided in the claims which would allow a person of ordinary skill in the art to identify how much variation is encompassed, and thus being claimed, by the phrases “a functional fragment thereof” and “a conservatively modified variant”. As noted above, the phrase “a functional fragment thereof” is not further utilized in the claim set and, while it is used throughout the instant Specification, no specific or special definition is provided in the Specification for this phrase. As such, a person having ordinary skill in the art would not be able to determine how much variation is being claimed and thus what is and what is not encompassed by this phrase. Also as noted above, the phrase “a conservatively modified variant” is explained in the context of the IR-binding peptide or mimetic (see Paragraph 0042). This paragraph states that some “of the variants have an amino acid sequence that is substantially identical to that of the exemplified peptide”. It also states that in “some embodiments, the variant has an amino acid sequence that contains one or more conservatively substituted residues relative to the sequence of the exemplified peptide (e.g., S519)”. Paragraph 0026 defines what constitutes a conservative amino acid substitution while Paragraph 0031 describes how to determine the sequence identity or similarity “between two or more nucleic acid sequences, or two or more amino acid sequences”. Paragraph 0042 additionally states that “the variant contains deletion of one or more amino acid residues at the N-terminus and/or C-terminus of the exemplified IR-binding peptide” and that “the IR-binding peptide that can be used in the invention can be a shortened S519 peptide that has the first 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more N-terminal residues of SEQ ID NO: 7 deleted”, while Paragraph 0062 states that “a S519 variant peptide containing a deletion of one or more terminal residues described herein can be used”.
Paragraph 0027, however, states that “conservative amino acid substitutions, e.g., substituting one acidic or basic amino acid for another, can often be made without affecting the biological activity of a peptide or protein described herein (e.g., an IR-binding peptide or mimetic)” and that minor “variations in sequence of this nature may be made in any of the peptides disclosed herein, provided that these changes do not substantially reduce (e.g., by 15% or more) the biological activity of the peptide or fusion polypeptide, e.g., IR-binding activity”. While this description provides a way to distinguish between the claimed and unclaimed variants, Applicant has not provided evidence that any of the claimed variants encompassed by the claim language would actually meet this standard. Furthermore, Paragraph 0026 states that not “all residue positions within a protein will tolerate an otherwise ‘conservative’ substitution” and that “if an amino acid residue is essential for a function of the protein, even an otherwise conservative substitution may disrupt that activity, for example the specific binding of an antibody to a target epitope may be disrupted by a conservative mutation in the target epitope”. Despite the information provided in this paragraph, Applicant has failed to actually disclose exactly which amino acid residues are essential for the IR-binding peptide, for instance. Thus, it would be unclear to a person having ordinary skill in the art to know what to change and what not to change. Yet, based on the information provided in Paragraph 0042, Applicant is also attempting to claim variants of SEQ ID NO: 7 with 20 amino acids deleted, for example. SEQ ID NO: 7 is only 36 amino acids long. This means that the claim language, in theory, encompasses variants with only about 45% sequence identity to instant SEQ ID NO: 7.
Finally, while it is not explicitly stated, it is assumed that the IR-binding peptide or peptide mimetic and rAAV shown in the data provided have sequences that are 100% identical to the claimed sequences, instant SEQ ID NOs: 1-5 and 7-8. Even if that is not the case, the data shown to do not explicitly include any claimed variants having less than 100% sequence identity relative to the claimed sequences. As a result, it is not clear what was tested, it does not appear that any claimed variants were tested, and the essential characteristics of the genera being claimed by Applicant have not been disclosed.
As such, it does not appear that Applicant was in possession of the full scope of the claimed invention at the time of filing and thus Claims 6-8 and 16 do not meet the written description requirement.
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 21 is 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).
In Paragraph 0056 of the instant Specification, human cells are explicitly contemplated. It is suggested that the claim be amended to recite “An isolated host cell”, but Applicant is free to amend the claim as they deem necessary.
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.
Claims 1-16, 18-19, 21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Danos et al. (US 2022/0186256 A1), Loiler (US 2020/0157570 A1), Alonso et al. (US 2012/0093775 A1), Schaffer and Frederiksen (US 2009/0197800 A1), and Nonnenmacher et al. (US 2022/0042044 A1)
Danos et al. teach recombinant AAV (rAAV), specifically AAV9, comprising engineered capsid proteins comprising peptide insertions from heterologous proteins, wherein the peptides are inserted within or near variable region IV or VIII of the virus capsid (see Abstract; Paragraphs 0002, 0006), which reads on instant Claims 1-2, 4-5, 12, and 18. Danos et al. also teach a nucleic acid encoding the engineered capsid protein and introducing it into a host cell (see Paragraphs 0347, 0355), which reads on instant Claims 19 and 21. Additionally, Danos et al. teach that these peptide insertions can be made after an amino acid residue corresponding to one of the amino acids 262-273, 451 to 461, or 585-593 of the AAV9 capsid, including after amino acid residue G453 (see Paragraphs 0006-0007, 0030), which reads on instant Claims 10-11, 13-15. Furthermore, Danos et al. teach rAAVs incorporating the engineered capsid proteins wherein the genomes comprise an expression cassette for expression of a transgene of therapeutic interest (see Paragraphs 0009-0010), wherein said expression cassette is flanked by ITRs (see Paragraph 0350), which reads on instant Claim 23.
Loiler teaches rAAV comprising modified capsid proteins with heterologous proteins inserted into the capsid protein, wherein said heterologous proteins are fused or conjugated to the interior or exterior surface of the viral capsid protein via one or more linkers (see Paragraphs 0108-0109, 0111, 0160). Loiler also teaches rAAV wherein said linkers are flexible or rigid, said linkers can flank both the amino and carboxy terminal ends of the peptide or protein insertion, and can comprise the sequence KESGSVSSEQLAQFRSLD (see Paragraphs 0114, 0127), which reads on instant Claims 7-8.
Alonso et al. teach the use of viral vectors, such as rAAV9, expressing Insulin-like grown factor I (IGF-I) (see Abstract; Paragraphs 0048-0050). Alonso et al. also teach rAAV virions comprising a capsid and a recombinant viral genome wherein an exogenous targeting sequence in the form of a protein or peptide has been inserted or substituted into the native capsid, such as VP1, and that IGF-I can bind insulin receptor (see Paragraphs 0003, 0135-0137, 0140), which reads on instant Claims 1-4, 15. Alonso et al. also teach a recombinant AAV vector with a genome comprising one or more transgenes flanked by at least one AAV ITR and wherein the capsid proteins from any known serotype, such as wild-type, can be used and wherein the sequences encoding said capsid proteins can be modified to comprise an exogenous target sequence (see Paragraphs 0083-0086), which reads on instant Claim 23.
Schaffer and Frederiksen teach insulin receptor-binding peptides which can be expressed from a nucleic acid and delivered using a vector (see Abstract; Paragraphs 0006, 0139, 0143). Specifically, they teach SEQ ID NO: 20 (see Sequence Listing), which is 100% identical to instant SEQ ID NO: 7, which reads on instant Claims 1, 3, 5-7, 9-16, and 23.
Nonnenmacher et al. teach rAAV comprising modified capsid proteins, wherein the capsid proteins comprise targeting peptide inserts for enhanced tropism to a target tissue (see Abstract). Nonnenmacher et al. also teach SEQ ID NO: 3645, which is 94.4% identical to instant SEQ ID NO: 4 (Sequence Listing), which reads on instant Claim 16.
A person having ordinary skill in the art would have been motivated to modify the teachings of Danos et al. with those of Loiler, Alonso et al., Schaffer and Frederiksen, and Nonnenmacher et al. in order to generate a rAAV9 which exhibited enhanced delivery of therapeutic molecules in a subject. The targeting peptide inserts disclosed by Nonnenmacher et al. and Alonso et al. would enhance or further enhance the ability of the rAAV9 disclosed by Danos et al. to target and transduce targets cells, tissues, and/or organs. Such modifications would enhance the delivery of therapies to specific targets and reduce the risk of off-target effects, as disclosed by Danos et al. While Danos et al. focuses on delivery to the retina and central nervous system (CNS), the principles used could easily be applied for targeting other areas of the body, such as the liver, using the IGF-I peptide disclosed by Alonso et al. and/or the insulin receptor-binding peptides disclosed by Schaffer and Frederiksen and wherein said peptides would be conjugated to the capsid protein using the linkers disclosed by Loiler. Finally, given the combined teachings of the prior art references, specifically the sequences taught by Schaffer and Frederiksen and Nonnenmacher et al., the linker sequences taught by Loiler, and the insertion sites taught by Danos et al., it would have been obvious for a person of ordinary skill to arrive at the claimed modified capsid protein sequences of the instant application, such as SEQ ID NO: 4 (instant Claim 16).
Such modifications, combining prior art elements according to known methods to yield predictable results, would have had a reasonable expectation of success and arrived at the claimed invention prior to the effective filing date of the claimed invention. For at least these reasons, instant Claims 1-16, 18-19, 21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over the prior art.
Conclusion
No claims are allowed.
The prior art made of record, but not relied upon, and considered pertinent to applicant's disclosure is listed below:
Schaffer et al. (US 2009/0197805 A1)
Schaffer et al. teach peptidic insulin receptor antagonists. This reference has not been utilized, as rejection would have been redundant to those set forth above.
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/CAREY ALEXANDER STUART/Examiner, Art Unit 1671
/JANET L ANDRES/Supervisory Patent Examiner, Art Unit 1671