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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 4/2/2026 has been entered.
Claims 3-6, 10-11, 18, 21 have been canceled, claims 2, 9, 20, 22-25 have been withdrawn from consideration as being drawn to non-elected subject matter, and claims 1, 7-8, 12-17, 19 and 26 have been considered on the merits. All arguments have been considered.
It is noted that applicant has elected SEQ ID NO:21 (amino acid sequence) and SEQ ID NO:20 (nucleic acid sequence) in the reply filed on 8/28/2025 as indicated in the OA mailed on 9/22/2025. The elected species are directed to a modified human arrestin-1 protein and the corresponding nucleic acid sequence. Therefore, the claims directed to non-human species, i.e. claim 2 directed to SEQ ID NO:4 (mouse arrestin) and claim 9 directed to SEQ ID NO:30 (bovine arrestin) are withdrawn as drawn to non-elected subject matter.
The claim rejection under 35 USC 35 U.S.C. 112(a) has been withdrawn due to the instant amendment.
The claim rejection under 35 USC 112(b) has been withdrawn due to the instant amendment.
The claim rejection under 35 USC 112(d) has been withdrawn due to the instant amendment.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 1, 7-8, 12-17 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Eisenbach-Schwartz et al. (US PAT. 9089509) in view of Ostermaier et al. (2014, PNAS; of record), Lefevre et al. (1997, Nucleic Acids Research; of record) and Liu et al. (US 2006/0100148A1; of record)
Regarding claims 1 and 7, Eisenbach-Schwartz et al. teach human S-Antigen (S-Ag; SEQ ID NO:35; col.15, line 59) which is identical to SEQ ID NO:18 of the instant claim (see alignment below). It is known in the art that S-Ag is also known as S-arrestin or arrestin-1.
RESULT 1
US-12-308-880A-35
(NOTE: this sequence has 33 duplicates in the database searched)
Sequence 35, US/12308880A
Patent No. 9089509
GENERAL INFORMATION
APPLICANT: YEDA RESEARCH AND DEVELOPMENT CO. LTD
APPLICANT: Eisenbach-Schwartz, Michal
APPLICANT: Butovsky, Oleg
TITLE OF INVENTION: METHOD OF TREATMENT OF AGE-RELATED MACULAR DEGENERATION
FILE REFERENCE: YEDA-068 US
CURRENT APPLICATION NUMBER: US/12/308,880A
CURRENT FILING DATE: 2009-11-13
PRIOR APPLICATION NUMBER: PCT/IL07/000798
PRIOR FILING DATE: 2007-06-28
PRIOR APPLICATION NUMBER: US 60/806,041
PRIOR FILING DATE: 2006-06-28
NUMBER OF SEQ ID NOS: 51
SEQ ID NO 35
LENGTH: 405
TYPE: PRT
ORGANISM: Homo sapiens
Query Match 100.0%; Score 2073; Length 405;
Best Local Similarity 100.0%;
Matches 405; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MAASGKTSKSEPNHVIFKKISRDKSVTIYLGNRDYIDHVSQVQPVDGVVLVDPDLVKGKK 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MAASGKTSKSEPNHVIFKKISRDKSVTIYLGNRDYIDHVSQVQPVDGVVLVDPDLVKGKK 60
Qy 61 VYVTLTCAFRYGQEDIDVIGLTFRRDLYFSRVQVYPPVGAASTPTKLQESLLKKLGSNTY 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VYVTLTCAFRYGQEDIDVIGLTFRRDLYFSRVQVYPPVGAASTPTKLQESLLKKLGSNTY 120
Qy 121 PFLLTFPDYLPCSVMLQPAPQDSGKSCGVDFEVKAFATDSTDAEEDKIPKKSSVRLLIRK 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 PFLLTFPDYLPCSVMLQPAPQDSGKSCGVDFEVKAFATDSTDAEEDKIPKKSSVRLLIRK 180
Qy 181 VQHAPLEMGPQPRAEAAWQFFMSDKPLHLAVSLNKEIYFHGEPIPVTVTVTNNTEKTVKK 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VQHAPLEMGPQPRAEAAWQFFMSDKPLHLAVSLNKEIYFHGEPIPVTVTVTNNTEKTVKK 240
Qy 241 IKAFVEQVANVVLYSSDYYVKPVAMEEAQEKVPPNSTLTKTLTLLPLLANNRERRGIALD 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 IKAFVEQVANVVLYSSDYYVKPVAMEEAQEKVPPNSTLTKTLTLLPLLANNRERRGIALD 300
Qy 301 GKIKHEDTNLASSTIIKEGIDRTVLGILVSYQIKVKLTVSGFLGELTSSEVATEVPFRLM 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 GKIKHEDTNLASSTIIKEGIDRTVLGILVSYQIKVKLTVSGFLGELTSSEVATEVPFRLM 360
Qy 361 HPQPEDPAKESYQDANLVFEEFARHNLKDAGEAEEGKRDKNDVDE 405
|||||||||||||||||||||||||||||||||||||||||||||
Db 361 HPQPEDPAKESYQDANLVFEEFARHNLKDAGEAEEGKRDKNDVDE 405
Eisenbach-Schwartz et al. do not teach the human arrestin-1 having E to G/A and D to G/A mutations in the position 365 and 366, respectively.
Ostermaier et al. teach scanning mutagenesis of bovine arrestin-1 and a single amino acid residue of arrestin-1 was mutated to alanine (i.e. aka alanine scanning) (see p.1825, Results and Discussion; Table S1). Ostermaier et al. carried out the scanning mutagenesis for understanding the functional aspect of arrestin-1 in arrestin-GPCR complexes (Abstract).
Thus, it would have been obvious to a person skilled in the art to carry out the scanning mutagenesis for human arrestin-1 taught by Eisenbach-Schwartz et al. and by doing so, one skilled in the art would arrive E365A or D366A mutation in the human arrestin with a reasonable expectation of success.
Eisenbach-Schwartz et al. in view of Ostermaier et al. do not teach that both of E365A and D366A in the bovine arrestin-1.
However, it is known in the art that multiple alanine mutations or alanine stretch scanning mutagenesis can be utilized for functional mapping of a protein according to Lefevre et al. Lefevre et al. teach substitution of a stretch of two to six residues by alanines (Abstract), and this method is efficient to probe protein structure and function (see entire document).
It would have been obvious to a person skilled in the art to use two or more alanine substitution in human arrestin-1 (i.e. SEQ ID NO:18) taught by Eisenbach-Schwartz et al. A person of ordinary skilled in the art would have been motivated to do so because Lefevre et al. teach that alanine stretch mutagenesis method can be used as a probe to rapidly scan a whole protein sequence in search of secondary structures or to characterize the catalytic or functional role of a stretch of residues and this method is relatively simple, and highly reliable, as a simple screening can be performed at each step (p.448, 2nd col.). By using the alanine stretch mutagenesis taught by Lefevre et al. over the single alanine mutagenesis of Ostermaier et al., one skilled in the art would be able to study function of human arrestin-1 of Eisenbach-Schwartz et al. The stretch alanine mutagenesis in the position 365 and 366 of human arrestin would meet the limitation of claims 1 and 7 directed to alanine substitutions corresponding to positions 365 and 366 of SEQ ID NO:18.
Regarding claim 12, as Eisenbach-Schwartz et al. in view of Ostermaier et al. and Lefevre et al. teach E361A and D362A double mutation of bovine arrestin-1, it is inherent that the mutants were produced by the nucleic acid encoding thereof.
Regarding claim 13-14 directed to the nucleic acid encoding the arrestin-1 variant of claim 1 having SEQ ID NO:17, the nucleic acid sequence encoding human arrestin-1 of claim 1 contains the nucleic acid sequence for encoding E365G/A and D366G/A selected from the group consisting of: GCNGCN, GCNGGN, GGNGCN, GGNGGN, GCNGAR, GGNGAR, GAYGCN, and GAYGGN, wherein N is A, G, C or T, Y is C or T, and R is A or G, Eisenbach-Schwartz et al. in view of Ostermaier et al. and Lefevre et al. do not teach the limitation.
However, it would have been obvious to a person skilled in the art to modify the GAGGAC sequence to known codon for alanine for the mutants taught by Eisenbach-Schwartz et al. in view of Ostermaier et al. and Lefevre et al. One skilled in the art would recognize that the codon sequence of GAG (glutamate) or GAC (aspartate) would be mutated to GCT, GCC, GCA or GCG, as these 4 codons encode alanine. Thus, one skilled in the art would use one of these 4 codon for alanine mutation for E365A and D366A of Eisenbach-Schwartz et al. in view of Ostermaier et al. and Lefevre et al. with a reasonable expectation of success.
Regarding claim 15-17, Ostermaier et al. teach the use of EgWoMiPi vector for expression of arrestin-1 mutants in bacterial and mammalian cells (p.6, Materials and Methods). The vector of Ostermaier et al. is considered as a plasmid vector. Thus, it would have been obvious to a person skilled in the art to use a vector for express the mutated human arrestin-1 of Eisenbach-Schwartz et al. in view of Ostermaier et al. and Lefevre et al.
Regarding claims 8 and 26 directed to SEQ ID NO:21 (elected species), which has E365G and D366G in human arrestin-1 of SEQ ID NO:18, while Eisenbach-Schwartz et al. in view of Ostermaier et al. and Lefevre et al. teach alanine scanning of human arrestin-1 as discussed above, they do not teach the limitation directed to glycine substitutions.
Liu et al. teach amino acid scanning experiments to determine the amino acid residue required for the activity of peptide, and utilized both Gly scanning and Ala scanning (para. 257).
It would have been obvious to a person skilled in the art to use human arrestin-1 protein of Eisenbach-Schwartz et al. to carry out glycine scanning study taught by Liu et al. with a reasonable expectation of success. As discussed above, based on the teaching by Lefevre et al., double glycine substitutions would be within the purview of the artisan. By doing so, one skilled in the art would arrive the E365G and D366G as claimed for SEQ ID NO:21.
It is also noted that the use of both Ala scanning and Gly scanning taught by Liu et al., one skilled in the art would reasonably arrive to other embodiment of E to G/A and D to G/A substitutions in SEQ ID NO:18 of the claims.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim(s) 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Eisenbach-Schwartz et al. in view of Ostermaier et al. and Lefevre et al. as applied to claims 1, 7-8, 12-17 and 26 above, and further in view of Michalakis et al. (WO2018/172961; IDS ref.).
Claim 19 directed to the vector encoding the arrestin-1 variant of claim 17 being AAV, Eisenbach-Schwartz et al. in view of Ostermaier et al. and Lefevre et al.do not teach the AAV vector.
Michalakis et al. teach the transgene including S-antigen visual arrestin (SAG) or variant thereof (p.17, lines 1-3) and an AAV vector for the expression of the transgene (p.24, lines 1-17).
It would have been obvious to a person skilled in the art to use the AAV vector for expression of human arrestin-1 comprising E365A and D366A taught by Eisenbach-Schwartz et al. in view of Ostermaier et al. and Lefevre et al. with a reasonable expression of success. A person of ordinary skilled in the art would have been motivated to do so because Michalakis et al. teach the expression of SAG from any variant or source thereof, and one skilled in the art would consider the AAV vector is suitable for expressing the arrestin-1 mutants including E365A and D366A taught by Eisenbach-Schwartz et al. in view of Ostermaier et al. and Lefevre et al.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Arguments
Applicant’s arguments with respect to claim(s) 1-3, 6-9 and 11-18 have been considered but not found persuasive.
It is noted that the claim rejections presented above have cited a new reference, Eisenbach-Schwartz et al. as a primary reference due to the amended claims requires SEQ ID NO:18 with E365A and D366A. However, the rationale of introducing double alanine mutagenesis is based on the teachings of Ostermaier and Lefevre.
Applicant alleged that Ostermaier et al. does not teach alanine substitution at both positions 365 and 366, and Ostermaier neither sought out nor intended to generate any double substitutions. The claim rejection has acknowledged that Ostermaier does not teach double alanine substitution and in order to address the deficiency the claim rejection cites Lefevre as it teaches multiple substitutions of alanine, i.e. alanine-stretch scanning mutagenesis. Thus, it would have been obvious to a person skilled in the art to use a known technique to study functional aspects of a protein, i.e. arrestin, as the purpose of scanning mutagenesis taught by Ostermaier and Lefevre are studying protein structure and function (i.e. functional mapping). Applicant argued that Lefevre fails to teach or suggest any alanine substitution in arrestin. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Lefevre does not need to teach all the limitation of the claims as it is not a sole reference cited in the 103 rejection. The 103 rejection is based on combined teachings of the cited references.
Applicant stated that neither Ostermaier nor Lefevre provides any predictable solution nor any indication of expectation of success. The Examiner respectfully disagrees with this allegation. The scanning mutagenesis taught by Ostermaier and Lefevre are extremely well known in the art and the substitutions can be readily produced for the technique.
Applicant stated that selection of positions 365 and 366 of arrestin-1 is only through impermissible hindsight.
As the technique is to scan all the residues by single or stretch of amino acids by substitution, one skilled in the art would arrive the claimed modified human arrestin-1 with E365A and D366A as this particular modified arrestin is within the scope of the modified arrestin intended by alanine stretch scanning mutagenesis.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant is advised to provide any evidence to show that the specific mutagenesis in the residue at 365 and 366 of SEQ ID NO:18 (i.e. human arrestin) as claimed provides any unexpected property or results to the claimed modified arrestin in order to overcome the obviousness rejections.
Conclusion
No claims are allowed.
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/TAEYOON KIM/Primary Examiner, Art Unit 1631
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