DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of the species of SEQ ID NO: 10 (GLSPPTR) and retinal dystrophy in the reply filed on 2/27/26 is acknowledged.
Claims 16-32 are examined on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8/12/26 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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.
Withdrawn-Objections Specification
Objection withdrawn-Drawings
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.
The following is a quotation of the first paragraph of 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.
Rejection Maintained-Claims 16-32 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for delivering a heterologous nucleic acid sequence to a retinal cell by using a AAV2 with SEQ ID NO: 10 (GLSPPTR) inserted between amino acids 587 and 588 of SEQ ID NO:1, does not reasonably provide enablement for treating a photoreceptor cell disease, such as retinal dystrophy, in a subject by administering an AAV2 with a peptide of formula I or formula II, such as SEQ ID NO: 10, inserted between amino acids 587 and 588 of SEQ ID NO:1 and the claimed properties of claim 16, part (a) and (b). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Nature of the invention/Breadth of the claims. The claims are drawn to a method for treating a photoreceptor cell disease in a subject in need thereof, the method comprising administering a pharmaceutical composition of an adeno-associated virus 2 (AAV2) to the subject, wherein the AAV comprises a capsid protein comprising an insertion of at least 6-8 amino acids between the positions corresponding to position 587 and 588 of SEQ ID NO: 1, wherein the insertion sequence has from the N-terminus to the C-terminus, wherein the inserted sequence represented by formula I (as recited in claims 16, 17 and 20) or formula II (as recited in claims 18 and 19), with the elected species of SEQ ID NO: 10.
The AAV has the following properties (claim 16, part (a) and (b)): (a) viral AAV DNA is present in mouse retinal nuclear extracts after 24 hours, when the AAV is administered intravenously into the tail vein of a C57-BL6J mouse, and (b)(i) viral AAV DNA is present in MAC-sorted rods as detected by anti-CD73-coated magnetic beads 24 hours after AAV administration when the AAV is administered intravenously into the tail vein of a C57-BL6J mouse for rod sorting, and/or (ii) viral AAV DNA is present in FACS-sorted cones 24 hours after AAV administration when the AAV is administered intravenously into the tail vein of RG-eGFP mice (line R685933) for cone sorting, wherein the cones express eGFP and are FACS sorted based on their eGFP expression.
The AAV also comprises a heterologous nucleic acid for delivery of the heterologous nucleic acid to the photoreceptor cells of the subject.
The claimed method does not recite a specific heterologous nucleic acid that is to be delivered or another therapy that is intended to treat the photoreceptor cell disease, such as retinal dystrophy.
State of the prior art/Predictability of the art. The state of the prior art reveals that treating a photoreceptor cell disease by using a recombinant AAV can be unpredictable. More specifically, using a recombinant AAV with a mutated Capsid protein requires the use of specific mutations within the capsid protein and the delivery of specific therapeutic genes to the eye. Petrs-Silva et al. (Molecular Therapy, 2009, Vol. 16, No. 3, pages 463-471) tested the gene (eGFP) delivery efficiency of wild type and mutated AAV2 to eyes of mice through intravitreal injections. While AAV2 mutants Y730F and Y444F at high doses (10^9) achieved high eGFP intensity, these same mutants at lower doses (10^7 and 10^5) showed significant decrease in eGFP as summarized in Figure 5 (i) (see below).
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In addition, Zhong et al. (PNAS, 2008, Vol. 105, No. 22, pages 7827-7832) teach a similar study using AAV2 with capsid proteins having mutations. As summarized in figure 2 B (see below), while some mutations to the capsid protein achieved significant increases in eGFP expression in hepatocytes (see mutant Y730F), mutants Y252F, Y272F and Y704F exhibited a significant reduction in eGFP transduction of hepatocytes.
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Therefore, the state of the prior art teaches mutations of the capsid protein of AAV2 can impact the transduction efficiency of mammalian cells and these mutations are not predictable. Moreover, in order to achieve targeted therapy of photoreceptor cell diseases, a heterologous gene specific for correcting photoreceptor cell diseases is required to be delivered to the eye or tissues associated with the eye.
Working examples. No working example is disclosed in the specification in which a photoreceptor disease, such as retinal dystrophy (elected species), in a subject is treated by administering a recombinant AAV that comprises a peptide of formula I or formula II inserted into the capsid of the AAV at a location that corresponds to amino acids 587 to 588 of SEQ ID NO: 1. In working example 4, AAV2 with a capsid possessing GLSPPTR or NNPTPSR inserted into and expressing eGFP, were capable of delivering the nucleic acid sequence encoding eGFP to retinal cells of human retinal tissue. However, the delivery of the eGFP would not achieve treatment of a photoreceptor cell disease, such as retinal dystrophy.
In working example 5, applicants tested the ability of an AAV2 with a capsid possessing GLSPPTR or NNPTPSR inserted between amino acids 587 and 588 of the capsid and the ability of that AAV2 to deliver a heterologous gene encoding Cnga3 to mice deficient in Cnga3. This AAV2 was delivered intravitreally and after 2 months, ERG measurement was performed on the mice and an increase in ERG amplitude was detected. Therefore, it would appear that the AAV2 with a capsid possessing GLSPPTR or NNPTPSR and containing a gene encoding Cnga3 were capable of repairing photoreceptor cells.
Guidance in the specification. The specification provides guidance towards treating photoreceptor cell diseases, such as retinal dystrophy [see paragraph 191].
Amount of experimentation necessary. Additional research is required in order to determine how effective delivering an AAV to a subject will achieve treatment of a photoreceptor cell disease, such as retinal dystrophy, wherein the AAV comprises the insertion of a peptide of at least 6-8 amino acids as defined by formula I or II, such as SEQ ID NO: 10 and wherein the AAV may be an AAV2 and the AAV may possess a heterologous gene.
Additional research is also required to determine if the claimed properties of: “(a) viral AAV DNA is present in mouse retinal nuclear extracts after 24 hours, when the AAV is administered intravenously into the tail vein of a C57-BL6J mouse, and (b)(i) viral AAV DNA is present in MAC-sorted rods as detected by anti-CD73-coated magnetic beads 24 hours after AAV administration when the AAV is administered intravenously into the tail vein of a C57-BL6J mouse for rod sorting, and/or (ii) viral AAV DNA is present in FACS-sorted cones 24 hours after AAV administration when the AAV is administered intravenously into the tail vein of RG-eGFP mice (line R685933) for cone sorting, wherein the cones express eGFP and are FACS sorted based on their eGFP expression.” would be attributable to AAV with a mutated capsid protein possessing a peptide of formula I or formula II, inserted between amino acids 587 and 588 of SEQ ID NO:1.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to use the claimed methods.
Response to arguments:
Applicant presents the following arguments in traversal of the rejection:
Applicant’s response has been fully considered, however, it is not persuasive.
The claimed method is drawn to treating a photoreceptor cell disease in a subject, wherein the disease is retinal dystrophy by administering an AAV that comprises a heterologous nucleic acid encoding a therapeutic polypeptide or a therapeutic nucleic acid and a capsid protein that comprises inserted amino acid sequence of formula I (claim 16) or the amino acids of SEQ ID NO:s 10 or 15. The claims do not recite a specific therapeutic polypeptide or a therapeutic nucleic acid for treating retinal dystrophy. The delivery of a specific polypeptide or nucleic acid would need to be at a therapeutic level for the treatment to be achieved of retinal dystrophy. However, the claims do not require a specific amount of the polypeptide or nucleic acid to be delivered and the claims do not recite a specific therapeutic polypeptide or a therapeutic nucleic acid for treating retinal dystrophy.
With regard to Pavlou et al., they teach the AAV with the capsid variant inserts of AAV2.GL and AAV2.NN and AAV2.SS achieved the brightest eGFP fluorescence with AAV2.GL and AAV2.NN were identified as optimal candidates for analysis since the highest eGFP. [see left column of page 3] AAV2.GL comprises the insert RGNAAAGLSPPTRAARQ, which comprises SEQ ID NO: 10 of the instant invention and AAV2.NN comprises the insert RGNAAANNPTPSRAARQ, which comprises SEQ ID NO: 15 of the instant invention. Pavlou et al. also teach the use of AAV2.7m8, which comprises the insertion of LALGETTRP in the capsid protein. When compared to the delivery of eGFP to cells, AAV2.7m8 was less efficient compared to AAV2.GL and AAV2.NN (see Figure 2).
In addition, the examples provided by applicant reveal that the amount of delivered heterologous gene (eGFP) is highly dependent on the peptide inserted into the capsid protein of the AAV since eGFP levels were varied based on the inserted peptide used (see Figure 2). Furthermore, as stated above, Pavlou et al. tested AAV2 capsids with 5 different inserted peptides (see Table 1) and determined that AAV2.GL and AAV2.NN were identified as optimal candidates for delivery of eGFP. This unpredictable delivery of a heterologous gene by recombinant AAV particles with mutated capsid proteins is further confirmed by Petrs-Silva et al. (see above) and Zhong et al. (see above). Additional research is required in order to determine how effective delivering an AAV to a subject will achieve treatment of a photoreceptor cell disease, such as retinal dystrophy, wherein the AAV comprises the insertion of a peptide of at least 6-8 amino acids as defined by formula I or II, such as SEQ ID NO: 10 or 15 and wherein the AAV may be an AAV2 and the AAV may possess a heterologous gene that is generic.
Rejection withdrawn in view of amendments-Claim 31 is rejected on the basis that it contains an improper Markush grouping of alternatives.
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.
Rejection withdrawn in view of amendments-Claim 22 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.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BENJAMIN P BLUMEL whose telephone number is (571)272-4960. The examiner can normally be reached M-F 8-5 EST.
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/BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1648
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