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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/6/2026 has been entered.
Claim Status
Claims 106, 110-114, and 118-123 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The claims 118-123 are directed to a non-elected invention comprising nucleic acid and viral vector that were withdrawn in the office action dated 11/27/2019. Thus, the new claims 118-123 are continuously withdrawn.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.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 106 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 106 recites the limitation "at least 92% of the FVIII variant is in the single chain polypeptide" in the wherein clause (D). There is insufficient antecedent basis for this limitation in the claim because a single human Factor VIII variant polypeptide is either 100% as a single chain polypeptide or NOT a single chain polypeptide, rendering the metes and bounds of claim 106 indefinite.
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 (i) Pu et al. (The American Journal of Human Genetics 92, 366–374, March 7, 2013, previously cited 12/12/2025) and (ii) Winge et al.
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.
wherein at least 92% of the hFVIII variant is in the single chain polypeptide form, as determined by optical densitometry following SDS-PAGE analysis under reducing conditions.
It is noted that the wherein limitation (D) of purity and analytic method does not change the function or structure of a human Factor VIII comprising B domain deletion; thus, it play little patent weight.
Low et al. teach the factor VIII protein is a variant derived from a wild-type human, factor VIII protein [0039]. Low et al. teach the factor VIII protein variant is a single chain FVIII polypeptide [Abstract, 0059-0062, claim 1-2). 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 (p373, col 1, para 2).
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.
Similarly, Nguyen et al. teach hFVIII-BDD deletion variants as single polypeptides 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
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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 elected peptide species, in claim 106 shown above.
With respect to the limitation (D), Winge et al. is cited to demonstrate large-scale of recombinant human FVIII protein with B domain deletion (p166, Fig 1, legend) by sequential purification process to remove host cell protein/DNA and pathogens before formulation was known in the art (p167, Fig 2). Winge et al. show the impurities are < 2% of the final product (p172, col 2, para 1 and p173, Fig 6). Winge et al. further teach protein analysis based on optical densitometry of Bradford assay (p169, col 1, Sec 2.13.4. Total protein) followed by SDS-PAGE analysis (p172, Fig 4-5).
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine Low et al. and Nguyen et al. because (a) 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]) and (b) 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. 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 (p373, col 1, para 2). The combination would have reasonable expectation of success because both Low et al. and Nguyen et al. teach a recombinant human single chain of factor VIII comprising a B domain deletion. Winge et al. is further cited to show large scale purification and purity analysis of human factor VIII variants with B-domain deletion was known to one of ordinary skill in the art.
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
The cited references, alone or in combination, do not teach or suggest the claimed hFVIII Δ3-SP/DE variant having this particular functional profile. In particular, the amendment of “at least 92% single chain polypeptide form as determined by optical densitometry following SDS-PAGE analysis under reducing conditions” (Remarks, p5, para 3).
The application discloses the combined A3-SP/DE variant exhibited 92% single chain polypeptide form in one SDS-P AGE study and 98% single chain form in a second SDS-PAGE study, compared to 24% for hFVIII-BDD (Remarks, p5, para 4).
Response to Arguments
Applicant's arguments filed 4/6/2026 have been fully considered but they are not persuasive for the reasons as follows.
Applicant’s arguments (i) and (ii) are not persuasive because both Low et al. and Nguyen et al. teach a single chain FV III polypeptide variants with B domain deletion. Each reference also teaches further mutations of furin cleavage sites in the polypeptides to make and use the single chain polypeptides of FV III with B domain deletion. The benefits of making and using a single chain polypeptide FV III with B domain deletion are known and/or expected as taught in the cited references described above not repeated here. See MPEP 716.02(II) Expected Beneficial results are evidence of obviousness.
Furthermore, Winge et al. is cited to demonstrate large-scale of recombinant human FVIII protein with B domain deletion (p166, Fig 1, legend) by sequential purification process to remove host cell protein/DNA and pathogens before formulation was known in the art (p167, Fig 2). Winge et al. show the impurities are < 2% of the final product (p172, col 2, para 1 and p173, Fig 6). Winge et al. further teach protein analysis based on optical densitometry of Bradford assay (p169, col 1, Sec 2.13.4. Total protein) followed by SDS-PAGE analysis (p172, Fig 4-5). Another reference of Kaufman et al. (US 2012/0028900 A1) is further cited to show the analysis of Factor VIII protein by optical density [0189] and SDS-PAGE [0147] well known in the art.
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 cited 11/27/2019) in view 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 (i) Pu et al. (The American Journal of Human Genetics 92, 366–374, March 7, 2013) and (ii) Winge et al. (Protein Expression and Purification 115 (2015) 165-175).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.
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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. in view of Nguyen et al. and evidenced by (i) Pu et al. and (ii) Winge et al. 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 (i) Pu et al. and (ii) Winge 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 (i) Pu et al. and (ii) Winge et al. are obvious to the instant claims 106 and 110-114.
Response to Arguments
Applicant's arguments (Remarks, p5, para 4) filed 4/6/2026 have been fully considered but they are not persuasive because the request of this rejection to be held in abeyance until allowable subject matter is indicated does not overcome the rejection of record.
Conclusion
No claim is allowed.
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/J.L/Examiner, Art Unit 1658
16-May-2026
/Melissa L Fisher/ Supervisory Patent Examiner, Art Unit 1658
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