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 .
Status of the Claims
Claims 1, 15, 16, 27-29, 31-33, and 35-36 are pending,
Claims 2, 6, 10, 12-13, 37, and 44-46 cancelled,
Claims 1, 28, 32, and 36 are newly amended,
Claims 1, 15, 16, 27-29, 31-33, and 35-36 have been examined on the merits.
Withdrawn Objections & Rejections
Applicant's response filed 10/02/2025 has been considered. Rejections and/or objections not reiterated from the previous Office action mailed 05/02/2025are hereby withdrawn.
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application.
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, 15-16, 27-29, 31, 33 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Wilson et al (WO 2019/164854 A1, as cited in the IDS filed 10/06/2022) and further in view of Fang et al (2010 US 7750138 B2).
This is a new rejection due to the Amendments filed 10/02/2025, however relies on references of record from the action filed 05/02/2025.
Regarding claims 1, 15-16, 27, 29 and 35: The claim recites “comprising the nucleic acid sequence of SEQ ID NO: 1”. Seq ID NO:1 is a nucleotide sequence of 1659 bp.
MPEP 2111.03 reads “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps”. Thus the claim is interpreted as requiring the nucleic acid sequence of Seq ID NO:1, but can also include additional components.
Wilson teach a composition for intra-retinal injection comprising a recombinant adeno-associated virus (rAAV) with an AAV8 capsid for treatment of ocular conditions (Abstract).
The recombinant adeno-associated viral vector (nucleic acid) disclosed by Wilson packages a vector genome that provides for the production of a soluble antigen-binding fragment (Fab) of a human monoclonal antibody (MAb) (transgene) that binds and inhibits human vascular endothelial growth factor (hVEGF) (Claim 1, p2 ln 20-26).
The rAAV taught by Wilson comprises a genome comprising an ITR flanking the encoded transgene (claim 1, p2/3 ln 29-32/1-6; Fig 1), a promoter linked to the transgene, a CMV enhancer, and an AAV8 capsid (claim 1, Fig 1). The ITR may be an ITR from AAV2 (p19 ln 20-25).
Wilson do not teach the nucleic acid comprises the nucleic acid sequence of Seq ID NO:1 of the instant claim 1.
Seq ID NO 1 of the instant invention is a nucleic acid which encodes a fusion protein comprising 4 polypeptide domains. Domains 1 and 2 (nucleotides 1-74 and 78-375 of Seq ID NO:1) encode polypeptides domains of FLT1 (VEGFR1). Nucleotides 376-965 of Seq ID No: 1 encode a polypetide domain of a soluble VEGFR2 splice variant (Genbank EU826563). Nucleotides 976-1656 encodes an FC gamma polypeptide.
Fang teach a DNA sequence encoding an angiogenesis-inhibiting recombinant chimeric protein (Abstract). The chimeric protein FP3 is encoded by the nucleic acid sequence of SEQ ID NO 6 in the disclosure of Fang, and this sequence has ~99% sequence identity to Seq ID No: 1 of the instant application.
The nucleotide sequence of Seq ID NO:1 of the instant application and Seq ID NO:6 of Feng share 100% sequence identity excepting for two nucleotide positions; A684 of the instant Seq ID 1 is absent from Seq ID No 6 of Fang, and the Sequence of Fang comprises C690 which is absent from Seq Id NO:1 of the instant application (highlighted below; “Query” refers to Seq ID NO:1 of the instant application):
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The nucleotide differences between Seq ID NO:1 and Seq ID NO:6 are found in the nucleic acid sequence comprising nucleotides 376-965 of Seq ID No: 1, which encodes the polypetide domain of the soluble VEGFR2 splice variant (Genbank EU826563), as discussed supra.
The nucleotide differences between Seq ID NO:1 and Seq ID NO:6 encode polypeptides which are identical except for three amino acids differences; Seq ID NO: 1 encodes amino acids “KPF” and Seq ID NO:6 encodes amino acids “NLS” when translated using reading frame 1 corresponding to the 5’ ATG of both sequences.
The nucleotide sequence of the VEGF2 domain encoded by Seq ID NO:6 does not share 100% sequence identity with a VEGF2 variant according to a BLAST search, but most closely aligns with the VEGFR2 variant encoded by Seq ID No:1 (~99% sequence identity with Genbank EU826563).
It would have been prima facie obvious to substitute the VEGF2 domain taught by Genbank EU826563 into Seq ID NO: 6 as taught by Fang et al because both inventions share a sequence disclosure of a VEGF2 domain in an otherwise identical protein domain, and the sequence disclosed by Genbank is naturally occurring. There would have been a reasonable expectation that the VEGFR2 domain protein of Genbank EU826563 would work equivalently to the VEGF2 domain in the invention of Fang because the Genbank sequence is a naturally occurring VEGFR2 sequence, and the results would have been predictable.
Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Regarding Claim 28: : The claim recites “comprising a nucleic acid least 90% identical to the nucleic acid sequence of SEQ ID NO: 2”. Seq ID NO:2 is a nucleotide sequence of 6832 bp.
MPEP 2111.03 reads “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps”. Thus the claim is interpreted as requiring the nucleic acid sequence of Seq ID NO:1 but can also include additional components.
Thus the claim is interpreted as requiring a nucleotide comprising at least 90% sequence identity to seq ID NO:2, but does not exclude additional nucleic acids that may be present.
Residues 1942-3600 Seq of Seq ID 2 share 100% sequence identity with Seq ID NO: 1. As discussed supra, Seq ID NO: 1 (and therefore residues 1942-3600 of seq ID NO: 2) shares ~99% sequence identity with Sequence 6 as taught by Fang.
Of nucleotide sequence of Seq ID 2 that excludes Seq ID no: 1, Nucleotides 201-1935 of Seq ID NO:2 shares ~99% identity with the vector pPyCAG_BstXI_IB (Genbank JQ994232.1) (thus nucleotides 1-1935 of Seq ID NO: 2 comprise ~90% sequence identity with the expression vector).
Nucleotides 3601-4011 of Seq ID NO:2 share greater than 95% sequence identity with the HSyn-NaVbeta1-myc vector (Genbank OQ348126.1).
It would have been obvious to combine the prior art elements, the vectors taught by Genbank JQ994232.1 and Genbank OQ348126.1 with the fusion protein taught by Fang to generate a nucleic acid sequence at least 90% identical to the nucleic acid sequence of Seq ID NO:2 of the instant disclosure. Combining known vectors with known transgenes is common practice in molecular biology and one of ordinary skill in the art would have had a reasonable expectation of success because exchanging and combining functional components of genetic elements of vectors to generate new functional combinations is common molecular biology practice.
Regarding claim 31: The claim recites “comprises a nucleic acid least 90% identical to the nucleic acid sequence of SEQ ID NO: 3”. Seq ID NO:3 is a nucleotide sequence comprising 6832 bp.
MPEP 2111.03 reads “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps”. Thus the claim is interpreted as requiring the nucleic acid sequence of Seq ID NO:1 but can also include additional components.
Thus the claim is interpreted as requiring a nucleotide comprising at least 90% sequence identity to seq ID NO:3, but does not exclude additional nucleic acids that may be present.
Residues 1942-3600 of Seq ID 3 share 100% with Seq ID NO: 1, discussed supra.
Residues 3601-6832 of Seq ID NO:3, sequence directly 3’ of the encoded fusion protein share greater than 95% sequence identity with the Hsyn-NaVbeta1-myc vector (OQ348126.1).
Residues 1-1941 of Seq ID No:3 are identical to residues 1-1941 of Seq ID NO:2, and thus also comprise ~90% sequence identity with the vector pPyCAG_BstXI_IB (Genbank JQ994232.1).
It would have been obvious to combine the prior art elements, the vectors taught by Genbank JQ994232.1 and Genbank OQ348126.1 with the fusion protein taught by Fang to produce a nucleic acid sequence at least 90% identical to the nucleic acid sequence of Seq ID NO:2 of the instant disclosure. Combining known vectors with known transgene coding sequences is common practice in molecular biology and one of ordinary skill in the art would have had a reasonable expectation of success because exchanging and combining functional components of genetic elements of vectors to generate new functional combinations is common molecular biology practice.
Regarding claim 33: Figure 13A of Wilson discloses transduced cells within retinal layers include RPE cells, photoreceptors and ganglion cells. Transduced cells read on a host cell comprising the nucleic acid.
Claims 32 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Wilson et al (WO 2019/164854 A1, as cited in the IDS filed 10/06/2022) and further in view of Fang et al (2010 US 7750138 B2) as applied to claims 1, 15-16, 27-29, 31, 33 and 35 above, and further in view of Wimmer et al (Journal of Ocular Pharmacology and Therapeutics(2015) 31:5;276-283), Kozak (J Biol Chem (1991)266(30)1-4) and Gautam et al (Journal of Gene Medicine (2016)18:312-321).
This is a new rejection due to the Amendments filed 10/02/2025, however relies on references of record from the action filed 05/02/2025.
Regarding Claims 32 and 36: The teachings of Wilson and Fang are discussed supra. Wilson teach an rAAV vector to deliver a VEGF blocker for ocular therapy. Wilson teach the rAAV vector comprises a 5’ AAV ITR, a CMV enhancer, a chicken beta-actin promoter (CBA), chicken beta-actin intron, a transgene encoding an anti VEGF agent, a rabbit beta-globin poly A signal, and a 3’ AAV ITR (Figure 1, p5 ln 5-12). Wilson also teach a rAAV vector with AAV capsid type 8 (Example 2 p 48 ln 3-6).
Wilson does not teach a Kozak sequence is 5’ adjacent of the transgene in the rAAV vector or that the capsid protein is from AAV2.
Wimmer et al (Journal of Ocular Pharmacology and Therapeutics(2015) 31:5;276-283) teach an AAV2/5 vector comprising an anti-VEGF molecule for delivery to the retina (abstract). Wimmer teach the vector mediates gene transfer in retinal cells (p280 col2 ¶3).
Kozak teach structural features in eukaryotic mRNAs that modulate the initiation of translation (title). Kozak teaches the nucleotide sequence GCCGCCAUGG (known as the Kozak consensus sequence) is the optimal context for initiation of translation in eukaryotic cells (cultured monkey cells) (p1 col1 para 1).
Gautam teach viral vectors encoding a Kozak consensus sequence directly upstream of the transgene transcription start site express significantly more transgene (C-peptide) than vectors not encoding the Kozak consensus sequence (p317 col 2 para 2, Fig 4b)
It would have been prima facie obvious to one of ordinary skill in the art to adapt the AAV vector disclosed by Wilson with the Kozak consensus sequence taught by Kozak in the location upstream of the transgene, as taught by Gautam, and to use the capsid protein of AAV5 as taught by Wimmer.
One of ordinary skill in the art would have been motivated to so because increased expression of the anti-VEGF transgene would result in increased inhibition of VEGF and an increased therapeutic effect, and use of the AAV5 capsid has been used successfully for gene transfer to retinal cells, a target for anti0-VEGF therapy.
One would have had a reasonable expectation of success because one of ordinary skill in the art would understand that exchanging functional components of a vector is common practice in molecular biology.
Response to Arguments
The responses are directed to the Arguments filed 10/02/2025.
Regarding Arguments directed to Claim Objections:
Applicant's arguments filed on 10/02/2025 have been fully considered and they are persuasive.
Applicant submits claim 32 has been amended to recite "cytomegalovirus (CMV)" and "chicken beta-actin (CBA)," thereby rendering this objection moot.
The objection to claim 32 is withdrawn.
Regarding Arguments directed to Double Patenting Rejections:
Applicant's arguments filed on 10/02/2025 have been fully considered and they are persuasive.
Applicant submits a Terminal Disclaimer over co-pending Application No. 17/685,457 which obviates this rejection.
The Double patenting rejection over 17 /685,457 is withdrawn.
Regarding Arguments directed to 35 USC § 112:
Applicant's arguments filed on 10/02/2025 have been fully considered and they are persuasive.
Applicant submits claim 1 is amended to recite “comprising the nucleic acid sequence of SEQ ID NO: 1”.
This is found persuasive because the claim limitation “anti-VEGF agent” of claim 1 is limited by Seq ID NO:1 and one of ordinary skill in the art could reasonably conclude the inventor had possession of the claimed invention.
The rejection over 35 USC § 112 is withdrawn.
Regarding Arguments directed to 35 USC § 102:
Applicant's arguments filed on 10/02/2025 have been fully considered and they are persuasive.
Applicant submits that claim 1 as currently amended to recite “comprising the nucleic acid sequence of SEQ ID NO: 1” is not anticipated by Wilson et al.
This is found persuasive and the rejection over USC § 102 is withdrawn. A new rejection under 35 USC §103 is entered and a response to the relevant argument is below.
Regarding claims 1, 15-16, 27, 29 and 35: The claim recites “comprising the nucleic acid sequence of SEQ ID NO: 1”. Seq ID NO:1 is a nucleotide sequence of 1659 bp.
MPEP 2111.03 reads “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps”. Thus the claim is interpreted as requiring the nucleic acid sequence of Seq ID NO:1, but can also include additional components.
Wilson teach a composition for intra-retinal injection comprising a recombinant adeno-associated virus (rAAV) with an AAV8 capsid for treatment of ocular conditions (Abstract).
The recombinant adeno-associated viral vector (nucleic acid) disclosed by Wilson packages a vector genome that provides for the production of a soluble antigen-binding fragment (Fab) of a human monoclonal antibody (MAb) (transgene) that binds and inhibits human vascular endothelial growth factor (hVEGF) (Claim 1, p2 ln 20-26).
The rAAV taught by Wilson comprises a genome comprising an ITR flanking the encoded transgene (claim 1, p2/3 ln 29-32/1-6; Fig 1), a promoter linked to the transgene, a CMV enhancer, and an AAV8 capsid (claim 1, Fig 1). The ITR may be an ITR from AAV2 (p19 ln 20-25).
Wilson do not teach the nucleic acid comprises the nucleic acid sequence of Seq ID NO:1 of the instant claim 1.
Seq ID NO 1 of the instant invention is a nucleic acid which encodes a fusion protein comprising 4 polypeptide domains. Domains 1 and 2 (nucleotides 1-74 and 78-375 of Seq ID NO:1) encode polypeptides domains of FLT1 (VEGFR1). Nucleotides 376-965 of Seq ID No: 1 encode a polypetide domain of a soluble VEGFR2 splice variant (Genbank EU826563). Nucleotides 976-1656 encodes an FC gamma polypeptide.
Fang teach a DNA sequence encoding an angiogenesis-inhibiting recombinant chimeric protein (Abstract). The chimeric protein FP3 is encoded by the nucleic acid sequence of SEQ ID NO 6 in the disclosure of Fang, and this sequence has ~99% sequence identity to Seq ID No: 1 of the instant application.
The nucleotide sequence of Seq ID NO:1 of the instant application and Seq ID NO:6 of Feng share 100% sequence identity excepting for two nucleotide positions; A684 of the instant Seq ID 1 is absent from Seq ID No 6 of Fang, and the Sequence of Fang comprises C690 which is absent from Seq Id NO:1 of the instant application (highlighted below; “Query” refers to Seq ID NO:1 of the instant application):
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The nucleotide differences between Seq ID NO:1 and Seq ID NO:6 are found in the nucleic acid sequence comprising nucleotides 376-965 of Seq ID No: 1, which encodes the polypetide domain of the soluble VEGFR2 splice variant (Genbank EU826563), as discussed supra.
The nucleotide differences between Seq ID NO:1 and Seq ID NO:6 encode polypeptides which are identical except for three amino acids differences; Seq ID NO: 1 encodes amino acids “KPF” and Seq ID NO:6 encodes amino acids “NLS” when translated using reading frame 1 corresponding to the 5’ ATG of both sequences.
The nucleotide sequence of the VEGF2 domain encoded by Seq ID NO:6 does not share 100% sequence identity with a VEGF2 variant according to a BLAST search, but most closely aligns with the VEGFR2 variant encoded by Seq ID No:1 (~99% sequence identity with Genbank EU826563).
It would have been prima facie obvious to substitute the VEGF2 domain taught by Genbank EU826563 into Seq ID NO: 6 as taught by Fang et al because both inventions share a sequence disclosure of a VEGF2 domain in an otherwise identical protein domain, and the sequence disclosed by Genbank is naturally occurring. There would have been a reasonable expectation that the VEGFR2 domain protein of Genbank EU826563 would work equivalently to the VEGF2 domain in the invention of Fang because the Genbank sequence is a naturally occurring VEGFR2 sequence, and the results would have been predictable.
Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Regarding Arguments directed to 35 USC § 103:
Applicant's arguments filed on 10/02/2025 have been fully considered and they are persuasive.
Regarding claims 32 and 36: Applicant submits the combination of references do not disclose the limitation of amended claim 1; “the nucleic acid sequence of SEQ ID NO: 1”.
The rejections are withdrawn. However a new rejection under 35 USC § 103 is entered on the record and the arguments are discussed below.
Claims 32 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Wilson et al (WO 2019/164854 A1, as cited in the IDS filed 10/06/2022) and further in view of Fang et al (2010 US 7750138 B2) as applied to claims 1, 15-16, 27-29, 31, 33 and 35 above, and further in view of Wimmer et al (Journal of Ocular Pharmacology and Therapeutics(2015) 31:5;276-283), Kozak (J Biol Chem (1991)266(30)1-4) and Gautam et al (Journal of Gene Medicine (2016)18:312-321).
This is a new rejection due to the Amendments filed 10/02/2025, however relies on references of record from the action filed 05/02/2025.
Regarding Claims 32 and 36: The teachings of Wilson and Fang are discussed supra. Wilson teach an rAAV vector to deliver a VEGF blocker for ocular therapy. Wilson teach the rAAV vector comprises a 5’ AAV ITR, a CMV enhancer, a chicken beta-actin promoter (CBA), chicken beta-actin intron, a transgene encoding an anti VEGF agent, a rabbit beta-globin poly A signal, and a 3’ AAV ITR (Figure 1, p5 ln 5-12). Wilson also teach a rAAV vector with AAV capsid type 8 (Example 2 p 48 ln 3-6).
Wilson does not teach a Kozak sequence is 5’ adjacent of the transgene in the rAAV vector or that the capsid protein is from AAV2.
Wimmer teach an AAV2/5 vector comprising an anti-VEGF molecule for delivery to the retina (abstract). Wimmer teach the vector mediates gene transfer in retinal cells (p280 col2 ¶3).
Kozak teach structural features in eukaryotic mRNAs that modulate the initiation of translation (title). Kozak teaches the nucleotide sequence GCCGCCAUGG (known as the Kozak consensus sequence) is the optimal context for initiation of translation in eukaryotic cells (cultured monkey cells) (p1 col1 para 1).
Gautam teach viral vectors encoding a Kozak consensus sequence directly upstream of the transgene transcription start site express significantly more transgene (C-peptide) than vectors not encoding the Kozak consensus sequence (p317 col 2 para 2, Fig 4b)
It would have been prima facie obvious to one of ordinary skill in the art to adapt the AAV vector disclosed by Wilson with the Kozak consensus sequence taught by Kozak in the location upstream of the transgene, as taught by Gautam, and to use the capsid protein of AAV5 as taught by Wimmer.
One of ordinary skill in the art would have been motivated to so because increased expression of the anti-VEGF transgene would result in increased inhibition of VEGF and an increased therapeutic effect, and use of the AAV5 capsid has been used successfully for gene transfer to retinal cells, a target for anti0-VEGF therapy.
One would have had a reasonable expectation of success because one of ordinary skill in the art would understand that exchanging functional components of a vector is common practice in molecular biology.
Conclusion
No claims are allowed.
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/ANDREA LYNNE MORRIS SPENCER/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631