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 .
Application Status and Withdrawn Claims
Applicant’s amendment filed June 24, 2026 amending claims 1, 34, 39 and 70, canceling claims 7 and 69, and adding new claims 75-78 is acknowledged. Claims 1-2, 22, 24, 34, 39, 42-47, 59, 64, 66-67, 70 and 73-78 are pending and under examination.
The cancelation of claim 69 and amendment of claim 70 overcomes the §102 rejection over Gelfman. The amendment to claim 1 and claim 70 overcomes the 112(b) rejection and the §103 rejections since the rejection in the previous office action did not address the SEQ ID NO.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant's amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 22, 24, 39, 47, 59, 64, 66, 70 and 73-78 are rejected under 35 U.S.C. 103 as being unpatentable over Grishanin (Grishanin et al., Molecular Therapy (2019), 27: 118-129 and Supplemental Material) as evidenced by Sigg (US 20140012227 A1), Dalkara (Dalkara et al., Science Translational Medicine (2013), 5: 189, 1-12) and Schaffer (US 20140294771 A1), and in view of Schaffer (US 20140294771 A1), Inatani (Inatani et al., Advances in Therapy (2021), 38: 1106-1115, published December 16, 2020) and Gelfman (Gelfman et al., Journal of Ocular Pharmacology and Therapeutics (2021), 37: 181-190, published April 1, 2021). Claim 73 is evidenced by Wu (Wu et al., Molecular Therapy (2020), 28: 3, 1-19). This is a new rejection necessitated by amendment.
Regarding claims 1-2 and 22, Grishanin teaches pre-clinical evaluation of using ADVM-022 for treating wet age-related macular degeneration (wAMD) in non-human primates to determine safe and effective options for treating wAMD (Abstract). Regarding (a), Grishanin teaches that the ADVM-022 genome consists of an aflibercept expression cassette flanked by viral inverted terminal repeats from AAV2 (page 125, ¶2). Grishanin is silent regarding the amino acid sequence of aflibercept. Sigg teaches the amino acid sequence for aflibercept is SEQ ID NO 1 ([0032], top of page 4), which is 100% identical to SEQ ID NO 35 of the present application. Therefore, the ADVM-022 taught in Grishanin inherently comprised a polynucleotide encoding an amino acid sequence with at least 95% identity to SEQ ID NO 35 and flanked by AAV2 inverted terminal repeats. Regarding (b), Grishanin teaches that ADVM-022 utilizes the AAV2.7m8 capsid that includes a 10-amino-acid insertion in loop IV of the AAV2 capsid protein, which was first described by Dalkara, reference 18 (page 125, ¶2). Grishanin is silent regarding the amino acid sequence of aflibercept. Schaffer is a US Patent Application Publication having the same disclosures as the Dalkara non-patent literature cited by Grishanin. Schaffer teaches that amino acid sequence of AAV2 VP1 (FIG 5), which is 100% identical to residues 1-733 out of 735 amino acids of SEQ ID NO 13 of the examined application. Schaffer teaches the AAV2.7m8 capsid comprises LGETTRP inserted between positions 587 and 588 of the AAV2 capsid protein ([0193], [0199]; Table 1). Therefore, the ADVM-022 taught in Grishanin inherently comprised an AAV2 capsid protein comprising an amino acid sequence LGETTRP inserted between positions 587 and 588 of the VP1 capsid protein, wherein the numbering corresponds to an AAV2 VP1 comprising the sequence of SEQ DI NO 13.
Regarding methods of treatment, Grishanin teaches that administering ADVM-022 resulted in robust levels of aflibercept in the retina and choroid tissues, which are the sites of neovascularization in wAMD (page 120, ¶1). Grishanin teaches ADVM-022 has the potential to treat neovascularization that precedes vision loss (page 119, ¶2). Grishanin teaches a dose of 2 x 1012 vg ADVM-022 administered to eyes of the non-human test subjects (Table 1). Grishanin also teaches administration of a similar vector carrying a GFP reporter coding sequence, AAV2.7m8-CMV-GFP (Figure S1; Supp Methods). Grishanin teaches administering AAV2.7m8-CMV-GFP particles at a dose of 5 x 1011 vg/eye (i.e., between about 2 x 1010 to about 6 x1011 vg/eye) is sufficient for delivery of the transgene to ocular tissues (Figure S1; Supp Methods).
Grishanin does not teach using ADVM-022 for treating glaucoma in humans. Grishanin does not doses of AAV2.7m8 for delivering aflibercept.
Schaffer teaches the AAV2.7m8 variant capsid vectors can be used for treating glaucoma ([0167]). Schaffer teaches the AAV2.7m8 variant capsid vectors can be used to deliver anti-VEGF polypeptides ([0152]).
Inatani teaches a clinical trial studying the efficacy of using aflibercept to treat neovascular glaucoma (Abstract). Inatani teaches that neovascular glaucoma is characterized by neovascularization of the iris and angle, which prevents normal drainage for the eye leading to elevated intraocular pressure (IOP) (¶ spanning pages 1107-1108). Inatani teaches that intravitreal aflibercept injection was approved in 2020 as a treatment for patients with neovascular glaucoma in Japan (page 1180, ¶2). Inatani teaches aflibercept treatment was associated with statistically significant and clinically meaningful reduction in interocular pressure (IOP), which support using aflibercept as a treatment of patients with neovascular glaucoma (page 1107, Conclusions).
Gelfman teaches pre-clinical studies for delivering ADVM-022 to ocular tissues (Abstract). Gelfman teaches testing doses of 2 x 1011 and 6 x 1011 and 2 x 1012 vg/eye of ADVM-022 (FIG 6B). Gelfman teaches that the doses resulted in sustained expression of aflibercept up to at least day 55 (Fig 2). Gelfman teaches that a mild to moderate inflammatory response to the ADVM-022 was dose dependent with increased inflammation with the higher dose of ADVM-022 (Fig 6).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used Grishanin’s ADVM-022 viral vector comprising the coding sequence for aflibercept and the engineered AAV2.7m8 capsid to treat neovascular glaucoma using the lower dose range tested in Gelfman. It would have amounted to using a known aflibercept viral delivery method at previously tested dosages to treat neovascularization in the eye to treat a known disease characterized by neovascularization in the eye. The skilled artisan would have predicted that ADVM-022 could be used to treat neovascular glaucoma, and been motivated to have done so, because 1) Grishanin teaches that it would be useful for treating ocular diseases characterized by neovascularization (i.e., neovascular glaucoma), 2) Schaffer teaches the AAV2.7m8 variant can be used to treat glaucoma, and 3) Inatani teaches that aflibercept administration can reduce neovascularization in neovascular glaucoma.
Regarding the specific dosage, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have administered the ADVM-022 particles to human eyes at a range of about 2 x 1010 to about 6 x1011 vg/eye. It would have amounted to optimizing AAV-based particle dosing by known means to yield predictable results. The skilled artisan would have predicted that a dose of ~ 2-6 x 1011 vg/eye would be sufficient for treatment in humans because Grishanin teaches that dose is sufficient for transgene delivery in related non-human primates and has only a mild inflammatory response. The skilled artisan would have been motivated to optimize dosing since that is a standard procedure in the art for determining therapeutic methods. Additionally, one would have been motivated to choose the lowest dose tested in preclinical studies in order to ensure the safety of the dose.
Regarding claim 24, Grishanin teaches the C11.CO.aflibercept expression cassette comprises in 5’ to 3’ order (a) a human CMV enhancer, (b) a human CMV promoter, (c) a 5’ UTR comprising a TPL eMLP, an synthetic intron, (d) the coding sequence for aflibercept (i.e., encoding an amino acid sequence of SEQ ID NO 35), (e) a human SAR (i.e., a second enhancer region) and (f) a human GH polyA sequence (i.e., a polyadenylation site) (Figure 1). Grishanin teaches the elements (a)-(f) are flanked by AAV2 inverted terminal repeats (Figure 1).
Regarding claim 39, Schaffer teaches the GH loop of AAV2.7m8 VP1 amino acid sequence comprises SEQ ID NO 36 (Fig. 18B), which is 100% identical to SEQ ID NO 38 of the present invention. Therefore, the ADVM-022 taught in Grishanin inherently comprised an AAV2 capsid protein comprising a GH loop that comprise the acid sequence of SEQ ID NO 38.
Regarding claims 47 and 74, Grishanin teaches doses of ADVM-022 provided in 50 mL (Table 1; page 125, ¶6).
Regarding claims 59, 64 and 66, Grishanin teaches that AAV2-based gene therapy can induce ocular inflammation, but that the inflammation was controlled with topical steroid treatment in previous clinical trials with AAV2 vectors (page 124, ¶3). Gelfman teaches there is mild inflammation even with the lower doses of ADVM-022 (Fig 6).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have additionally provided steroids during or after administration of the ADVM-022 viral vector during the method of treating glaucoma rendered obvious above. It would have amounted to the simple combination of known elements by known means to yield predictable results. The skilled artisan would have predicted that a topical steroid can be provided with the ADVM-022 treatment because Grishanin teaches that topical steroids have used in combination with other AAV2 gene therapy methods. One would have been motivated to do so to reduce ADVM-022-inducted inflammation at the lower doses.
Regarding claim 70, the teachings of Grisanin, Schaffer, Inatani and Gelfman and the obviousness of the using the claimed dose of ADVM-022 or the treatment of neovascular glaucoma are recited above for claim 1. Additionally, Inatani teaches that neovascular glaucoma leads to elevated intraocular -pressure (IOP) (¶ spanning pages 1107-1108). Inatani teaches aflibercept treatment reduced IOP (Fig. 1). As such, it would have been entirely predictable that the obvious treatment for neovascular glaucoma would also result in the reduction of IOP.
Regarding claim 73, Grishanin teaches the aflibercept coding sequence is under the control of the CMV promoter (i.e., a strong promoter) (Fig 1). Grishanin is silent regarding whether CMV is active in the ciliary body. Wu teaches delivery of a GFP coding sequence whose expression is driven by the CMV promoter to ciliary bodies extracted from human eyes (Figure 5). Wu teaches detecting CMV-promoter driven GFP expression in cells of the ciliary body (Figure 5). Therefore, the ADVM-022 taught in Grishanin inherently comprised a strong promoter that is active in the ciliary body.
Regarding claims 75-78, Grishanin teaches the level of aflibercept expression was steady between 3 months and 13 months after ADVM-022 administration (Fig 2). Additionally, Gelfman teaches that aflibercept levels are sustained over 30 months at a dose of 2 x 1012 vg ADVM-022 (Fig 3). Given that the expression level between the doses at 1 month (Fig 2), it would have been entirely predictable that the lower initial doses of ADVM-022 would have also resulted in sustained aflibercept expression such that direct aflibercept injection would not be required 6 months after ADVM-022 treatment.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Grishanin (Grishanin et al., Molecular Therapy (2019), 27: 118-129 and Supplemental Material) as evidenced by Sigg (US 20140012227 A1), Dalkara (Dalkara et al., Science Translational Medicine (2013), 5: 189, 1-12) and Schaffer (US 20140294771 A1), and in view of Schaffer (US 20140294771 A1), Inatani (Inatani et al., Advances in Therapy (2021), 38: 1106-1115, published December 16, 2020) and Gelfman (Gelfman et al., Journal of Ocular Pharmacology and Therapeutics (2021), 37: 181-190, published April 1, 2021), as applied to claims 1-2, 7, 22, 24, 39, 47, 59, 64, 66, 70 and 73-78 above, and further in view of Keravala (US 20200010851 A1, published January 9, 2020). This is a new rejection necessitated by amendment.
The teachings of Grishanin, Sigg, Dalkara, Schaffer, Inatani and Gelfman are recited above and applied as for claims 1-2, 22, 24, 39, 47, 59, 64, 66, 70 and 73-78. Briefly, Grishanin teaches the ADVM-022 gene therapy vector comprising an expression cassette comprising in 5’ to 3’ order (a) a human CMV enhancer, (b) a human CMV promoter, (c) a 5’ UTR comprising a TPL eMLP, an synthetic intron, (d) the coding sequence for aflibercept (i.e., encoding an amino acid sequence of SEQ ID NO 35), (e) a human SAR (i.e., a second enhancer region) and (f) a human GH polyA sequence (i.e., a polyadenylation site) (Figure 1).
Grishanin, Sigg, Dalkara, Schaffer and Inatani do not teaches the nucleic acid sequences of the elements depicted in Figure 1 of Grishanin.
Keravala teaches optimized nucleic acid expression cassettes and vectors for expression gene in mammalian cells ([0005]), including for expression of aflibercept ([0020]). Keravala teaches a polynucleotide cassette comprising a CMV enhancer, CMV promoter, 5’UTR with TPL and eMLP, a coding sequence of a protein of interest, a full EES sequence second enhancer, and an HGH polyadenylation sequence (FIG 1, Cassette No. 11). Keravala teaches construct 11 drove high expression of transgenes, including for aflibercept, in HeLa cells (FIGs 2 and 7-8), HEK293 cells (FIGs. 3, 6 and 9), pig retinal explants (FIG. 4A-B, 10A-B; [0049]), and ARPE19 cells (FIG. 5). Regarding (a), Keravala teaches the sequence of the CMV enhancer is SEQ ID NO 1 ([0032]), which is 100% identical to SEQ ID NO 22 of the examined application. Regarding (b), Keravala teaches the sequence of the CMV promoter is SEQ ID NO 4 ([0032]), which is 100% identical to SEQ ID NO 23 of the examined application. Regarding (c), Keravala teaches the 5’ UTR comprising the TPL sequence and eMLP sequences comprising SEQ ID NOs 11 and 12 ([0032]), which are 100% identical to SEQ ID NOs 24 and 25, respectively, of the examined application. Regarding (d), Keravala teaches the enhancer sequence is the full EES sequence with SEQ ID NO 13 ([0032]), which is 100% identical to SEQ ID NO 26 of the examined application. Regarding (e), Keravala teaches the HGH polyadenylation signal sequence has SEQ ID NO 14 ([0032]), which is 100% identical to SEQ ID NO 27 of the examined application. Keravala teaches the AAV expression cassettes can be delivered by AAV particles including the variant comprising the 7m8 variant ([0039], [0049]).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used Keravala’s Cassette No. 11 for expressing aflibercept delivered by the AAV2.7m8 capsid in the method rendered obvious above for claim 1. It would have amounted to using known expression control elements/sequences by known means to yield predictable results. The skilled artisan would have predicted that Keravala’s Cassette 11 could be used in the obvious method to treat glaucoma because 1) Keravala teaches that aflibercept can be delivered in such as cassette, packaged into AAV2.2m8 virions, and delivered to pig ocular cells and 2) the expression cassette of Grishanin has many of the same genetic elements. The skilled artisan would have been motivated to use Keravala’s cassette because of its ability to drive high transgene expression in a variety of cells including in ocular tissues.
Claims 42-46 and 67are rejected under 35 U.S.C. 103 as being unpatentable over Grishanin (Grishanin et al., Molecular Therapy (2019), 27: 118-129 and Supplemental Material) as evidenced by Sigg (US 20140012227 A1), Dalkara (Dalkara et al., Science Translational Medicine (2013), 5: 189, 1-12) and Schaffer (US 20140294771 A1), and in view of Schaffer (US 20140294771 A1) and Inatani (Inatani et al., Advances in Therapy (2021), 38: 1106-1115, published December 16, 2020) and Gelfman (Gelfman et al., Journal of Ocular Pharmacology and Therapeutics (2021), 37: 181-190, published April 1, 2021), as applied to claims 1-2, 7, 22, 24, 39, 47, 59, 64, 66, 70 and 73-78 above, and further in view of Gasmi (WO 2021050094 A1, published March 28, 2021). This is a new rejection necessitated by amendment.
The teachings of Grishanin, Sigg, Dalkara, Schaffer, Inatani and Gelfman are recited above and applied as for claims 1-2, 7, 22, 24, 39, 47, 59, 64, 66, 70 and 73-78. Briefly, Grishanin teaches the ADVM-022 gene therapy vector comprising the claimed polypeptide coding sequence and claimed AVV capsid protein for the treatment of neovascular diseases of the eye. The obviousness of using ADVM-022 to treat neovascular glaucoma is recited above in paragraph 14. Schaffer also teaches the rAAV virions can be formulated in a pharmaceutical composition with acceptable carriers, diluents, excipients and buffers, including phosphates and emulsifying agents, and which are known in the art ([0161]-[0162])
Grishanin, Sigg, Dalkara, Schaffer Inatani and Gelfman do not teach the specific formulations for administering ADVM-022 to the eyes of human patients.
Regarding claims 42-46, Gasmi teaches treating ocular neovascular disease in an individual comprising administering a unit dose of rAAV particles encoding SEQ ID NO 35 (i.e., aflibercept) and an AAV capsid having LGETTRP inserted into position 587-588 of VP1 capsid (i.e., AAV2.7m8) (Abstract). Gasmi teaches pharmaceutical formulations for the rAAV particles ([0177]-[0200]). Gasmi teaches a specific pharmaceutical formulation comprises 6 x 1012 vg/mL or 6 x 1011 vg/mL rAAV with about 180 mM sodium chloride, about 5 mM monobasic sodium phosphate, about 5 mM dibasic sodium phosphate and about 0.001% (w/v) poloxamer 188 (i.e., a surfactant) with a pH of 7.3 ([0185]). Gasmi also teaches the formulations can comprise about 2x 1012 vg/mL of rAAV particles ([0179]). Gasmi uses the formulations recited in examined claim 44 in a phase I clinical trial for treating the neovascular disease wAMD ([0229], Table 1). Gasmi summarized the results of the phase I clinical trial as “AAV2.7m8-aflibercept provided a clear benefit for improving retinal anatomy and stabilizing vision, while exhibiting an acceptable safety profile. Specifically, patients maintained vision during the study, and AAV2.7m8-aflibercept was shown to be safe and well tolerated, with observed inflammation generally being mild and responsive to steroid eye drops.” ([0290])
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used the formulations and rAAV concentrations reported in Gasmi in the method rendered obvious above for claim 1. It would have amounted to the simple combination of known elements by known means to yield predictable results. The skilled artisan would have predicted that the formulations would be functional to treat neovascular glaucoma, and been motivated to use the same formulations because Gasmi teaches the formulations for treating another neovascular ocular disease and concluded that the formulations are safe, well tolerated and provide a clear benefit for stabilizing vision.
Regarding claim 67, Gasmi teaches combining the AAV2.7m8-aflibercept treatment with a topical steroid comprising difluprednate 0.05% at a dose of about 1 mg to about 3 mg ([0021]). Gasmi also teaches another Phase I study combining the AAV2.7m8-aflibercept treatment with topical steroids, 0.05% difluprednate drops ([0303]-[0307]-Table 9).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have also provided difluprednate at 0.05% at a dose of about 1 mg to about 3 mg as reported in Gasmi in the method rendered obvious above for claim 1. It would have amounted to simple combination of known elements by known means to render predictable results. The skilled artisan would have predicted that the combination of difluprednate and AAV2.7m8-aflibercept would be functional to treat neovascular glaucoma because Gasmi teaches the formulations for treating another neovascular ocular disease and concluded that the formulations are safe, well tolerated and provide a clear benefit for stabilizing vision. The skilled artisan would have been motivated to use difluprednate for the purpose of treating inflammation which can occur with AAV2 gene delivery to the eye as taught by Gasmi, Grishanin and Gelfman.
Response to Arguments - §103
Applicant argues that the skilled artisan would not have arrived at the claimed 3-100x lower dosage based on the levels of ADVM-022 used in Grishanin and the aflibercept injected in Inatani (Remarks, page 11). Applicant argues that Grishanin’s disclosure of vector genome lower dosage of the reporter protein would not have provided a reasonable expectation for the skilled artisan trying to determine a therapeutic dose since the marker protein is not a therapeutic protein (page 12, ¶2). Applicant further argues that the skilled artisan would not have had a reasonable expectation that the lower dose would be therapeutic since it would have provided at least 3x lower aflibercept concentration to ocular tissues than Inatani’s injection method (page 13). To the extent the arguments apply to the current obviousness rejection, they have been thoroughly considered but are not persuasive for the following reasons.
First, Gelfman teaches ADVM-022 doses in the claimed range provide aflibercept concentrations in the eye that were similar to aflibercept injections, which decrease overtime given the stability of the protein in the eye. Because the aflibercept concentration is steady over time when provided as a gene expression therapy, the skilled artisan would have expected that the initial protein concentration from ADVM-022 would not have to be as high as the initial aflibercept injection concentration. Both Grishanin and Gelfman provide vg concentrations in the claimed range that were sufficient for transgene expression from a CMV promoter, and as such, the skilled artisan would have chosen those concentrations to test for effectiveness when optimizing ADVM-022 dosing for treatment for neovascular glaucoma.
Second, Gelfman and Grishanin provide a motivation to test ADVM-022 for treatment with lower doses. It is clear from both references that although mild-to-moderate, ADVM-022 does induce an inflammatory response and that the response is dose-dependent. As such, the skilled artisan would have been motivated to use the lowest dose possible for measurable and sustained aflibercept expression, including Gelfman’s two lowest dosages, which are in the claimed range.
Lastly, it is noted that Applicant never tests the claimed dosage 1) for aflibercept expression in ocular tissues, or 2) specifically for treatment of glaucoma. Applicant’s sole example is prophetic and describes a clinical trial for treatment of diabetic macular edema. The prophetic example didn’t even specifically set out to test dosages for treatment in glaucoma. Thus, the Specification provides no guidance as to the effectiveness of treating glaucoma with the claimed dosages. If Applicant believes that the claimed method of treatment was not predicted to treat glaucoma with the claimed lower dosage of ADVM-022 based on the prior art, Applicant should provide evidence and/or explain how the claimed method is enabled based on their own evidence.
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.
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Claims 1-2, 22, 24, 34, 39, 42-47, 59, 64, 66-67, 70, and 73-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-2, 4-9, 11, 16, 22-30, 32-35, 37-38, 40-41, 44-46, 49-53, 57, 60-61, 63, 72-74, 80, 82, 84-86, 88-89, 91-93, 100, 109-119 and 122 of copending Application No. 17017469 in view of Schaffer (US 20140294771 A1) and Inatani (Inatani et al., Advances in Therapy (2021), 38: 1106-1115, published December 16, 2020). This is an updated rejection to reflect claim amendments and new claims.
Copending claim 1 recites A method of reducing inflammation associated with administering recombinant adeno-associated virus (rAAV) particles for treating wet age-related macular degeneration (AMD) in an individual, the method comprising administering a topical steroid and a unit dose of about 1 x 1010 vector genomes (vg) to about 6 x 1011 vg of rAAV particles to one eye of the individual by intravitreal administration, wherein the individual is a human, and wherein the rAAV particles comprise: a) a nucleic acid encoding a polypeptide comprising an amino acid sequence with at least about 95% identity to the amino acid sequence of SEQ ID NO: 35 [which is 100% identical to SEQ ID NO 35 of the examined application] and flanked by AAV2 inverted terminal repeats (ITRs), and b) an AAV2 capsid protein comprising an amino acid sequence LGETTRP (SEQ TD NO: 14) inserted between positions 587 and 588 of the capsid protein, wherein the amino acid residue numbering corresponds to an AAV2 VP1 capsid protein; wherein the timing of the administration of the topical steroid starts at about one week prior to administration of the unit dose of rAAV particles, and wherein the topical steroid treatment is difluprednate. Copending claim 16 recites wherein the unit dose of rAAV particles is:(a) between about 6 x 1010 to about 6 x 1011 vector genomes per eye (vg/eye); (b) between about 6 x 1010 to about 2 x 1011 vg/eye;(c) between about 2 x 1011 to about 6 x 1011 vg/eye;(d) about 2 x 1011 vg/eye; or (e) about 6 x 1011 vg/eye. Copending claim 32 recites wherein the polypeptide is aflibercept. Copending claim 34 recites wherein the nucleic acid comprises, in the 5' to 3' order:(a) a first enhancer region;(b) a promoter region;(c) a 5'UTR region;(d) a nucleic acid encoding a polypeptide comprising an amino acid sequence with at least about 95% identity to the amino acid sequence of SEQ ID NO: 35;(e) a second enhancer region; and(f) a polyadenylation site;and flanked by AAV2 inverted terminal repeats (ITRs). Copending claim 44 recites wherein the nucleic acid further comprises (a) a first enhancer region comprising a CMV sequence comprising the sequence of SEQ ID NO: 22 or a sequence having at least 85% identity thereto; (b) a promoter region comprising a CMV sequence comprising the sequence of SEQ ID NO: 23 or a sequence having at least 85% identity thereto; (c) a 5'UTR region comprising, in 5' to 3' order, a TPL sequence comprising the sequence of SEQ ID NO: 24 or a sequence having at least 85% identity thereto, and an eMLP sequence comprising the sequence of SEQ ID NO: 25 or a sequence having at least 85% identity thereto; (d) a second enhancer region comprising a full EES sequence comprising the sequence of SEQ ID NO: 26 or a sequence having at least 85% identity thereto; and (e) a HGH polyadenylation site comprising the sequence of SEQ ID NO: 27 or a sequence having at least 85% identity thereto, wherein each of the recite SEQ ID NOs are identical to the instantly claimed SEQ ID NOs. Copending claims 51-52 recite wherein the unit dose of rAAV particles is in a pharmaceutical formulation [comprising] the rAAV particles, sodium chloride, sodium phosphate and a surfactant. Copending claim 53 recites wherein the pharmaceutical formulation comprises:(a) about 150 to about 200 mM sodium chloride, about 1 to about 10 mM monobasic sodium phosphate, about 1 to about 10 mM dibasic sodium phosphate, about 0.0005% (w/v) to about 0.005% (w/v) poloxamer 188, and about 6 x 1013 to about 6 x 1010 vector genomes (vg) per mL (vg/mL) of the rAAV particles, wherein the pharmaceutical formulation has a pH of about 7.0 to about 7.5;(b) about 180 mM sodium chloride, about 5 mM monobasic sodium phosphate, about 5 mM dibasic sodium phosphate, about 6 x1012 vg/mL of the rAAV particles, and about 0.001% (w/v) poloxamer 188, wherein the pharmaceutical formulation has a pH of about 7.3;(c) about 180 mM sodium chloride, about 5 mM monobasic sodium phosphate, about 5 mM dibasic sodium phosphate, about 2 x1012 vg/mL of the rAAV particles, and about 0.001% (w/v) poloxamer 188, wherein the pharmaceutical formulation has a pH of about 7.3; or (d) about 180 mM sodium chloride, about 5 mM monobasic sodium phosphate, about 5 mM dibasic sodium phosphate, about 6 x1011 vg/mL of the rAAV particles, and about 0.001% (w/v) poloxamer 188, wherein the pharmaceutical formulation has a pH of about 7.3. Copending claim 80 recites wherein the steroid treatment comprises difluprednate 0.05% at a dose of about 1 mg to about 3 mg. Copending claims 93 recite at least 50-100% of the individuals do not require an anti-VEGF rescue treatment for at least 36-52 weeks after the dose of rAAV particles.
The copending claims do not recite using the compositions and formulations for treating neovascular glaucoma.
Schaffer teaches the AAV2.7m8 variant capsid (i.e., the copending claimed AAV2 capsid variant virion) can be used for treating glaucoma ([0167]).
Inatani teaches a clinical trial studying the efficacy of using aflibercept to treat neovascular glaucoma (Abstract). Inatani teaches that neovascular glaucoma is characterized by neovascularization of the iris and angle, which prevents normal drainage for the eye leading to elevated intraocular pressure (IOP) (¶ spanning pages 1107-1108). Inatani teaches that intravitreal aflibercept injection was approved in 2020 as a treatment for patients with neovascular glaucoma in Japan (page 1180, ¶2). Inatani teaches aflibercept treatment was associated with statistically significant and clinically meaningful reduction in interocular pressure (IOP), which support using aflibercept as a treatment of patients with neovascular glaucoma (page 1107, Conclusions).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used the copending AAV2.7m8-aflibercept formulations to treat neovascular glaucoma. It would have amounted to using a known aflibercept viral delivery method known to treat neovascularization in the eye to treat a known disease characterized by neovascularization in the eye. The skilled artisan would have predicted that the copending AAV2.7m8-aflibercept vector could be used to treat neovascular glaucoma, and been motivated to have done so, because 1) Schaffer teaches the AAV2.7m8 variant can be used to treat glaucoma, and 2) Inatani teaches that aflibercept administration can reduce neovascularization in neovascular glaucoma.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 22, 24, 34, 39, 42-47, 59, 64, 66, 67, 70, and 73-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-17, 47 and 50-52 of copending Application No. 17479968 in view of Schaffer (US 20140294771 A1), Gelfman (Gelfman et al., Journal of Ocular Pharmacology and Therapeutics (2021), 37: 181-190, published April 1, 2021), and Inatani (Inatani et al., Advances in Therapy (2021), 38: 1106-1115, published December 16, 2020). Claims 24 and 34 are rejected in further view of Keravala (US 20200010851 A1, published January 9, 2020). Claims 42-46, 59, 64, 66 and 67 are rejected in further view of Gasmi (WO 2021050094 A1, published March 28, 2021). Claims 75-78 are rejected in view of Grishanin (Grishanin et al., Molecular Therapy (2019), 27: 118-129 and Supplemental Material). This is an updated rejection to reflect claim amendments and new claims.
Copending claim 1 recites A method of ameliorating one or more symptoms associated with wet age-related macular degeneration (wAMD), the method comprising administering a unit dose of a pharmaceutical composition by intravitreal injection to an eye of a primate subject in need thereof, wherein the unit dose is between 5E10 vector genomes (vg) to 7E12 vg, wherein the pharmaceutical composition comprises:(a) a rAAV2 variant comprising an amino acid sequence LGETTRP, SEQ ID NO: 4, inserted between positions 587 and 588 of capsid protein VP1, and a nucleic acid sequence encoding a polypeptide having an amino acid sequence with at least 95% homology to SEQ ID NO: 1 (i.e., identical to SEQ ID NO 35 of the examined application), and(b) a pharmaceutically acceptable excipient. Copending claim 5 recites wherein the unit dose is between 2E12 to 6E12 vector genomes. SEQ ID No 4 is 100% identical to SEQ ID NO 13 of the examined application. Therefore, the copending claims recite a VP1 wherein the insertion is in between positions 587 to 588 relative to SEQ ID NO 13. Copending claim 9 recites wherein the subject is a human. Copending claim 50 recites wherein the nucleic acid sequence encoding a polypeptide having an amino acid sequence with at least 95% homology to SEQ ID NO: 1 is under the transcriptional control of a cytomegalovirus (CMV) promoter. Copending claims 6-7 recite wherein the unit dose is in a volume that is not more than 50 mL or 100 mL.
The copending claims do not recite using the compositions and formulations for treating neovascular glaucoma. The copending claims do not recite additional regulatory elements of the sequences for the CMV promoter (claims 24 and 34). The copending claims do not recite specific formulations for the AAV2.7m8-aflibercept (claims 42-46). The copending claims do not recite coadministration with a steroid (claims 59, 64, 66, 67).
The teachings of Gelfman, Schaffer and Inatani are recited above in paragraph 13, 44-45 and incorporated here. The obviousness of using the copending AAV2.7m8-aflibercept virion to treat neovascular glaucoma is recited above in paragraph 46. It would have been obvious to use modify the copending method for neovascular glaucoma using the instantly claimed dosages because it would have amounted to optimizing AAV-based particle dosing by known means to yield predictable results. The skilled artisan would have predicted that a dose of ~ 2-6 x 1011 vg/eye would be sufficient for treatment in humans because Grishanin teaches that dose is sufficient for transgene delivery in related non-human primates and has only a mild inflammatory response. The skilled artisan would have been motivated to optimize dosing since that is a standard procedure in the art for determining therapeutic methods. Additionally, one would have been motivated to choose the lowest dose tested in preclinical studies in order to ensure the safety of the dose.
Regarding claims 24 and 34, Keravala teaches optimized nucleic acid expression cassettes and vectors for expression gene in mammalian cells ([0005]), including for expression of aflibercept ([0020]). Keravala teaches a polynucleotide cassette comprising a CMV enhancer, CMV promoter, 5’UTR with TPL and eMLP, a coding sequence of a protein of interest, a full EES sequence second enhancer, and an HGH polyadenylation sequence (FIG 1, Cassette No. 11). Keravala teaches construct 11 drove high expression of transgenes, including for aflibercept, in HeLa cells (FIGs 2 and 7-8), HEK293 cells (FIGs. 3, 6 and 9), pig retinal explants (FIG. 4A-B, 10A-B; [0049]), and ARPE19 cells (FIG. 5). Regarding (a), Keravala teaches the sequence of the CMV enhancer is SEQ ID NO 1 ([0032]), which is 100% identical to SEQ ID NO 22 of the examined application. Regarding (b), Keravala teaches the sequence of the CMV promoter is SEQ ID NO 4 ([0032]), which is 100% identical to SEQ ID NO 23 of the examined application. Regarding (c), Keravala teaches the 5’ UTR comprising the TPL sequence and eMLP sequences comprising SEQ ID NOs 11 and 12 ([0032]), which are 100% identical to SEQ ID NOs 24 and 25, respectively, of the examined application. Regarding (d), Keravala teaches the enhancer sequence is the full EES sequence with SEQ ID NO 13 ([0032]), which is 100% identical to SEQ ID NO 26 of the examined application. Regarding (e), Keravala teaches the HGH polyadenylation signal sequence has SEQ ID NO 14 ([0032]), which is 100% identical to SEQ ID NO 27 of the examined application. Keravala teaches the AAV expression cassettes can be delivered by AAV particles including the variant comprising the 7m8 variant ([0039], [0049]). It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used Keravala’s Cassette No. 11 for expressing aflibercept delivered by the AAV2.7m8 capsid in the copending method rendered obvious to use as a treatment for neovascular glaucoma. It would have amounted to using known expression control elements/sequences by known means to yield predictable results. The skilled artisan would have predicted that Keravala’s Cassette 11 could be used in the obvious variation of the copending method to treat glaucoma because 1) Keravala teaches that aflibercept can be delivered in such as cassette, packaged into AAV2.2m8 virions and delivered to pig ocular cells and 2) the copending claims require at least a CMV promoter. The skilled artisan would have been motivated to use Keravala’s cassette because of its ability to drive high transgene expression in ocular tissues.
Regarding claims 42-46, Gasmi teaches treating ocular neovascular disease in an individual comprising administering a unit dose of rAAV particles encoding SEQ ID NO 35 (i.e., aflibercept) and an AAV capsid having LGETTRP inserted into position 587-588 of VP1 capsid (i.e., AAV2.7m8) (Abstract). Gasmi teaches pharmaceutical formulations for the rAAV particles ([0177]-[0200]). Gasmi teaches a specific pharmaceutical formulation comprises 6 x 1012 vg/mL or 6 x 1011 vg/mL rAAV with about 180 mM sodium chloride, about 5 mM monobasic sodium phosphate, about 5 mM dibasic sodium phosphate and about 0.001% (w/v) poloxamer 188 (i.e., a surfactant) with a pH of 7.3 ([0185]). Gasmi also teaches the formulations can comprise about 2x 1012 vg/mL of rAAV particles ([0179]). Gasmi uses the formulation recited in claim 44 in a phase I clinical trial for treating the neovascular disease wAMD ([0229], Table 1). Gasmi summarized the results of the phase I clinical trial as “AAV2.7m8-aflibercept provided a clear benefit for improving retinal anatomy and stabilizing vision, while exhibiting an acceptable safety profile. Specifically, patients maintained vision during the study, and AAV2.7m8-aflibercept was shown to be safe and well tolerated, with observed inflammation generally being mild and responsive to steroid eye drops.” ([0290])
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used the formulation and rAAV concentrations reported in Gasmi in the obvious variant in the copending method to treat glaucoma. It would have amounted to simple combination of known elements by known means to render predictable results. The skilled artisan would have predicted that the formulations would be functional to treat neovascular glaucoma, and been motivated to use the same formulations because Gasmi teaches the formulations for treating another neovascular ocular disease and concluded that the formulations are safe, well tolerated and provide a clear benefit for stabilizing vision.
Regarding claims 59, 64, 66 and 67, Gasmi teaches combining the AAV2.7m8-aflibercept treatment with a topical steroid comprising difluprednate 0.05% at a dose of about 1 mg to about 3 mg ([0021]). Gasmi also teaches another Phase I study combining the AAV2.7m8-aflibercept treatment with topical steroids, 0.05% difluprednate drops ([0303]-[0307]-Table 9).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have also provided difluprednate at 0.05% at a dose of about 1 mg to about 3 mg as reported in Gasmi in the obvious variant of the copending method to treat glaucoma. It would have amounted to simple combination of known elements by known means to render predictable results. The skilled artisan would have predicted that difluprednate could be provided and the combination with be AAV2.7m8-aflibercept functional to treat neovascular glaucoma because Gasmi teaches the formulations for treating another neovascular ocular disease and concluded that the formulations are safe, well tolerated and provide a clear benefit for stabilizing vision. The skilled artisan would have been motivated to use difluprednate for the purpose of treating inflammation which can occur with AAV2 gene delivery to the eye.
Regarding claims 75-78, Grishanin teaches the level of aflibercept expression was steady between 3 months and 13 months after ADVM-022 administration (Fig 2). Additionally, Gelfman teaches that aflibercept levels are sustained over 30 months at a dose of 2 x 1012 vg ADVM-022 (Fig 3). Given that the expression level between the doses at 1 month (Fig 2), it would have been entirely predictable that the lower initial doses of ADVM-022 would have also resulted in sustained aflibercept expression such that direct aflibercept injection would not be required 6 months after ADVM-022 treatment.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 22, 24, 34, 39, 42-47, 59, 66, 70, and 73-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7-9, 11, 17, 19-21, 29-37, 39-64, 101-102, 107-108 and 114-123 of copending Application No. 18834864 in view of Schaffer (US 20140294771 A1) and Inatani (Inatani et al., Advances in Therapy (2021), 38: 1106-1115, published December 16, 2020). Claims 75-78 are rejected further in view of Grishanin (Grishanin et al., Molecular Therapy (2019), 27: 118-129 and Supplemental Material). This is an updated rejection to reflect claim amendments and new claims.
Copending claims 1 and 3 recite A method for treating [for reducing retinal fluid in an individual with] an ocular neovascular disease in an individual, the method comprising administering a unit dose of about 1 x 1010 vector genomes(vg) to about 2 x 1011 vg of recombinant adeno-associated virus (rAAV) particles to one eye of the individual, wherein the individual is a human, and wherein the rAAV particles comprise: a) a nucleic acid encoding a polypeptide comprising an amino acid sequence with at least about 95% identity to the amino acid sequence of SEQ ID NO: 35 (i.e., 100% identical to SEQ ID NO 35 of the examined application) and flanked by AAV2 inverted terminal repeats (ITRs), and b) an AAV2 capsid protein comprising an amino acid sequence LGETTRP (SEQ TD NO:14) inserted between positions 587 and 588 of the capsid protein, wherein the amino acid residue numbering corresponds to an AAV2 VP1 capsid protein an wherein the method further comprises administering an implant containing a steroid for the one eye. Copending claim 17 recites wherein the unit dose of rAAV particles is between about 6 x 1010 to about 2 x 1011 vector genomes per eye (vg/eye). Copending claim 32 recites wherein the polypeptide is aflibercept. Copending claim 34 recites wherein the nucleic acid comprises, in the 5' to 3' order:(a) a first enhancer region;(b) a promoter region;(c) a 5'UTR region;(d) a nucleic acid encoding a polypeptide comprising an amino acid sequence with at least about 95% identity to the amino acid sequence of SEQ ID NO: 35;(e) a second enhancer region; and(f) a polyadenylation site;and flanked by AAV2 inverted terminal repeats (ITRs). Copending claims 44 recites wherein the nucleic acid further comprises (a) a first enhancer region comprising a CMV sequence comprising the sequence of SEQ ID NO: 22; (b) a promoter region, comprising a CMV sequence comprising the sequence of SEQ ID NO: 23; (c) a 5'UTR region comprising, in 5' to 3' order, a TPL sequence comprising the sequence of SEQ ID NO: 24, and an eMLP sequence comprising the sequence of SEQ ID NO: 25; (d) a second enhancer region comprising a full EES sequence comprising the sequence of SEQ ID NO: 26; and (e) a HGH polyadenylation site comprising the sequence of SEQ ID NO: 27, which are 100% identical to the same SEQ ID NOs in the examined application. Copending claims 51-52 recites wherein the unit dose of rAAV particles is in a pharmaceutical formulation comprising the rAAV particles, sodium chloride, sodium phosphate and a surfactant. Copending claims 52-56 recite wherein the pharmaceutical formulation comprises about 180 mM sodium chloride, about 5 mM monobasic sodium phosphate, about 5 mM dibasic sodium phosphate, about 6 x 1012 vg/mL, 2 x 1012 vg/mL or 6 xz1011 vg/mL of the rAAV particles, and about 0.001% (w/v) poloxamer 188, wherein the pharmaceutical formulation has a pH of about 7.3. Copending claims 57-59 recite wherein the unit dose of rAAV particles administered to the one eye isand/or to the contralateral eye in a volume of about 25 mL to about 250 mL, including about 30 mL.
The copending claims do not recite using the compositions and formulations for specifically treating neovascular glaucoma.
The teachings of Schaffer and Inatani are recited above in paragraph 44-45 and incorporated here. The obviousness of using the copending AAV2.7m8-aflibercept virion to treat neovascular glaucoma is recited above in paragraph 46.
Regarding claims 75-78, Grishanin teaches the level of aflibercept expression was steady between 3 months and 13 months after ADVM-022 administration (Fig 2). Additionally, Gelfman teaches that aflibercept levels are sustained over 30 months at a dose of 2 x 1012 vg ADVM-022 (Fig 3). Given that the expression level between the doses at 1 month (Fig 2), it would have been entirely predictable that the lower initial doses of ADVM-022 would have also resulted in sustained aflibercept expression such that direct aflibercept injection would not be required 6 months after ADVM-022 treatment.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments – NSDP
Applicant’s requested reconsideration of the NSDP rejections in view of the claim amendments (Remarks, page 15). Each of the rejections have been reconsidered and modified to reflect claim amendments and new claims.
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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