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 .
Claim Status
Claims 106, 110-114, and 118-122 are pending.
Claim 106 is currently amended.
Claims 1-105, 107-109, and 115-117 are cancelled.
In response to the species election dated 7/12/2019. Applicant elected the species of a polypeptide hFVIII-Δ3-S1657P/D1658E (Δ3-SP/DE) of Group I.
The new claims 118-122 are directed to a non-elected invention comprising nucleic acid and viral vector that were withdrawn in the office action dated 11/27/2019. Thus, The new claims 118-122 are continuously withdrawn.
Claims 106 and 110-114 have been examined.
Priority
This application is a 371 of PCT/US2017 /013461 filed on 01/13/2017, which claim the benefit of PRO 62/297,352 and PRO 62/278,767 filed on 02/19/2016 and 01/14/2016.
Withdrawn Objection and Rejection
The objection of claims 106 and 108 is withdrawn because the amendment to claim 106 overcomes the objection.
The rejection of claims 106, 108, 110-114 and 116 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn because the amendment to the claims overcome the rejection.
Modified Rejection
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.
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.
Claims 106 and 110-114 are rejected under 35 U.S.C. 103 as being unpatentable over Low et al. (US 2015/0191526 A1, previously cited 4/9/2021) in view of Nguyen et al. (Blood (2014) 124 (21): 104, previously cited 11/27/2019) and evidenced by Pu et al. (The American Journal of Human Genetics 92, 366–374, March 7, 2013).
Claim 106 is directed to a human Factor VIII (hFVIII) variant comprising:
the hFVIII variant comprises a B domain deletion;
the hFVIII variant comprises deletion of the first three underlined amino acids of the PACE/furin cleavage site of R1645HQR1648 with R1648 unchanged;
the hFVII variant comprises amino acid substitutions S1657P and D1658E.
Low et al. teach a single chain human factor VIII variant comprising B domain deletions [Fig 2, 0063], reading on the limitation of A.
Low et al. teach the factor VIII protein is a variant derived from a wild-type human, factor VIII protein [0039]. Low et al. suggest the B-domain deletion of a human factor VIII variant further comprising at least a substitution or mutation (e.g., deletion) selected one from R1645, R1648, S1657, D1658, or any combination thereof to form a single chain of factor VIII. Low et al. suggest the substitution or mutation is an amino acid other than its native amino acid, e.g., S1657→P and D1658→E to prevent or reduce cleavage at the corresponding internal processing domain (p5, [0053]), reading on the limitation (C). Pu et al. is further cited to show common knowledge of Ser-to-Pro substitution on a protein prodomain processing to reduce accessibility to processing proteases such as furin, as a result of a conformational change induced by the rigidity of proline known in the art.
Low et al. and evidenced by Pu et al. do not explicitly teach deletion of the first three amino acid residues from PACE/furin cleavage site of R1645HQR1648.
PNG
media_image1.png
162
578
media_image1.png
Greyscale
Similarly, Nguyen et al. teach hFVIII-BDD deletion variants with diminished PACE-Furin cleavage (p1, Abstract). Nguyen et al. teach that beneficial hFVIII expression of del1645-47 from the underlined motif of R1645H1646Q1647R1648 motif with R1648 unchanged was 3-fold higher than the protein of hFVIII-BDD without mutation and higher expression level than other hFVIII-BDD deletion variants comprising del1645, del1645-48, and del1645-46 (p2, para 1), reading on the limitation of B. Because Nguyen et al. teach the benefit of del1645-47 hFVIII-BDD variant with R1648 unchanged comprising enhancement of protein expression of human factor VIII variant with B-domain deletion with diminished PACE-Furin cleavage as suggested by Low et al. and evidenced by Pu et al., one of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine Low’s hFVIII-BDD deletion variants comprising deletion of R1645 with Nguyen’s teaching the benefit of hFVIII del1645-47 of R1645H1646Q1647R1648 motif to generate an hFVIII variants, reading on the limitations of A, B, and C of hFVIII variant (Δ3-SP/DE), the elect6ed peptide species, in claim 106 shown above.
With respect to claim 110 and 112-113, it would be obvious to expect the hFVIII variant taught by the cited references superior to a wild type FVIII or a B domain deletion of hFVIII variant with an intact PACE/furin cleavage site. Nguyen et al. teach that a benefit of hFVIII B domain deletion variant expression of del1645-47 from the underlined motif of R1645H1646Q1647 R1648 motif with R1648 unchanged was 3-fold higher than the protein of hFVIII-BDD without mutation and higher expression level than other hFVIII-BDD deletion variants comprising del1645, del1645-48, and del1645-46 (p2, para 1). Low et al. suggest the used of mutated cleavage site of PACE-Furin to create a recombinant single chain FVIII that did not separate into the heavy and light chains to facilitate secretion of a recombinant single chain FVIII [0174, page 19].
With respect to claim 111, Low et al. teach B-domain deleted factor FVIII is aggregated and degraded through proteasomal and lysosomal pathways before secretion know in the art. Low et al. suggest the used of mutated cleavage site of PACE-Furin to create a recombinant single chain FVIII that did not separate into the heavy and light chains to facilitate secretion of a recombinant single chain FVIII [0174, page 19].
With respect to claim 114, Low et al. suggest a single chain FVIII polypeptide formulated with a pharmaceutically acceptable carrier [0021, claim 32].
Applicant’s Arguments (Remarks, p1, last two para to p2, para 1)
The amendment to claim 106 overcomes the rejection of record
The Examiner has acknowledged unexpected results when expressed in cells or in a subject following AAV-mediated delivery.
Response to Arguments
Applicant's arguments filed 9/2/2025 have been fully considered but they are not persuasive for the reasons as follows.
Applicant’s argument (i) is not persuasive because the amendment does not overcome the modified rejection based on Low et al. in view of Nguyen et al. and evidenced by Pu et al. described above not repeated here.
Applicant’s argument (ii) is not persuasive because (a) the argument is not commensurate in scope of the claims because AAV is used to deliver nucleic acid not polypeptide as claimed and (b) there is NO “.unexpected result”. Nguyen et al. teach that a benefit of hFVIII B domain deletion variant expression of del1645-47 from the underlined motif of R1645H1646Q1647 R1648 motif with R1648 unchanged was 3-fold higher than the protein of hFVIII-BDD without mutation and higher expression level than other hFVIII-BDD deletion variants comprising del1645, del1645-48, and del1645-46 (p2, para 1). Low et al. suggest the used of mutated cleavage site of PACE-Furin to create a recombinant single chain FVIII that did not separate into the heavy and light chains to facilitate secretion of a recombinant single chain FVIII [0174, page 19]. The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). See MPEP 716.02(b).
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 106 and 110-114 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 8,816,054 (the ‘054 patent, previously
PNG
media_image2.png
458
487
media_image2.png
Greyscale
cited 11/27/2019) in view of Low et al. (US 2015/0191526 A1, previously cited 4/9/2021) and Nguyen et al. (Blood (2014) 124 (21): 104, previously cited 11/27/2019).
Claim 1 of the ‘054 patent disclosed one or more amino acids at PACE/furin cleavage site of a human FVIII variant are deleted as follows.
Claim 2 of the ‘054 patent disclosed a pharmaceutical composition comprising a FVIII variant and in a biologically compatible carrier.
Claims 1-2 of the ‘054 patent do not explicitly teach R1648 is not substituted or deleted.
The relevancy of Low et al. (US 2015/0191526 A1, previously cited 4/9/2021) in view of Nguyen et al. (Blood (2014) 124 (21): 104, previously cited 11/27/2019) and evidenced by Pu et al. (The American Journal of Human Genetics 92, 366–374, March 7, 2013) as applied to claims 106 and 110-114 described above not repeated here.
Because Low et al. in view of Nguyen et al. and evidenced by Pu et al. teach beneficial deletion of the first three amino acids in the PACE/furin cleavage site of R1645HQR1648 with R1648 unchanged, one of ordinary skill in the art would have found it obvious to modify the FVIII variant taught by claims 1-2 of the ‘054 patent.
Thus, claims 1-2 of the ‘054 patent in view of Low et al., Nguyen et al. and evidenced by Pu et al. are obvious to the instant claims 106 and 110-114.
Response to Arguments
Applicant's arguments filed 9/2/2025 have been fully considered but they are not persuasive. See response to arguments above.
Conclusion
No claim is 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 JIA-HAI LEE whose telephone number is (571)270-1691. The examiner can normally be reached Mon-Fri from 9:00 AM to 6:00 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached at 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/J.L/Examiner, Art Unit 1658
05-December-2025
/LI N KOMATSU/ Primary Examiner, Art Unit 1658