Detailed Office Action
Status of the Application
Claims 1, 3-11 and 18-31 are pending.
Claims 2 and 12-17 are canceled.
Claims 21-31 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention. Applicant timely traversed the restriction (election) requirement in the reply filed December 16, 2024.
Applicant’s remarks filed July 24, 2025 in response to the non-final rejection mailed March 24, 2025, is acknowledged and have been fully considered.
Rejections previously applied to claim 2 are withdrawn in view of the amendment to cancel claim 2.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 7/24/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner and the reference therein has been indicated as such.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1, 3-7, 9-11, and 18-20 under 35 U.S.C. 11(b) for being unclear is withdrawn in view of the amendment to claim 1 to recite “a VWF moiety capable of binding to blood coagulation factor VIII (FVIII) and comprising at least a D' and D3 domain of VWF and lacking an A1 domain of VWF” which gives clarity to the limitation because it provides a structure and function to the VWF moiety and “an erythrocyte-binding moiety, wherein said erythrocyte-binding moiety is not a VWF moiety” which gives clarify to the structure of the element.
The rejection of claim 8 under 35 U.S.C. 112(b) for being indefinite is withdrawn in view of the amendment to claim 1 to recite “an erythrocyte-binding moiety, wherein said erythrocyte-binding moiety is not a VWF moiety” which provides clarity to claim 8 because it delineates the erythrocyte-binding moiety is not a VWF moiety potentially found on each peptide in the dimer with an inherent erythrocyte-binding ability.
Claim Rejections - 35 USC § 101
The rejection of claims 1, 3-4, 6-8, 10-11, and 18 under 35 U.S.C. 101 is withdrawn due to the newly added limitation to claim 1 to recite “wherein said erythrocyte-binding moiety is not a VWF moiety,” which distinguishes the claimed polypeptide from a naturally-occurring polypeptide.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 3-6, 9-11, and 18-20 under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Andrews (WO 2017/117631 A1; cited on the IDS filed May 10, 2022; hereafter “Andrews”), as evidenced by Nicolay (Scientific Reports, e-published July 19, 2018, Vol. 8, No. 1, p. 1 – 15; cited on Form PTO-892 mailed March 24, 2025; hereafter “Nicolay”) is withdrawn because Andrews does not teach the newly added limitation to claim 1 to recite “wherein said erythrocyte-binding moiety is not a VWF moiety.”
The rejection of claims 1, 6-7, 9-10, and 18 under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Furlan (Ann Hematol, published 1996, Vol. 72, p. 341 – 348; cited on Form PTO-892 mailed March 24, 2025), as evidenced by Nicolay is withdrawn because Furlan does not teach the newly added limitation to claim 1 to recite “wherein said erythrocyte-binding moiety is not a VWF moiety.”
Claim Rejections - 35 USC § 103
The rejection of claims 1, 3-7, 9-11, and 18-20 under 35 U.S.C. 103 as being unpatentable over Andrews as evidenced by Nicolay as applied to claims 1, 3-6, 9-11, and 18-20, in view of De Meyer (Blood, published May 21, 2009, Vol. 113, No. 21, p. 5049-5057; cited on Form PTO-892 mailed March 24, 2025; hereafter “De Meyer”), Hubbel (WO 2012/021512 A2; cited on Form PTO-892 mailed March 24, 2025; hereafter “Hubbel”), and Dong (Blood, published January 14, 2019, Vol. 133, No. 14, p. 1523-1533; cited on Form PTO-892 mailed March 24, 2025; hereafter “Dong”) is withdrawn because the combination of cited references does not teach or suggest the newly added limitation to claim 1 to recite “wherein said erythrocyte-binding moiety is not a VWF moiety.”
The rejection of claims 1, 3-11, and 18-20 under 35 U.S.C. 103 as being unpatentable over Andrews in view of De Meyer, Hubbel, and Dong is withdrawn because the combination of cited references does not teach or suggest the newly added limitation to claim 1 to recite “wherein said erythrocyte-binding moiety is not a VWF moiety.”
Claims 1, 3-11, and 18-20 are newly rejected under 35 U.S.C. 103 as being unpatentable over Andrews in view of Muzykantov (Expert Opinion on Drug Delivery, published March 2, 2010, Vol. 7, No. 4, p. 403-427; cited on the attached Form PTO-892; hereafter “Muzykantov”).
Regarding claims 1, 3, and 9-10, Andrews teaches a truncated Von Willebrand Factor (VWF) polypeptide comprising the D’-D3 domains of human VWF domain that can bind Factor VIII (FVIII) and be used to treat blood coagulation disorders (Abstract; para [0002, 0015-18, 0040, 0214, 0219, 0232, 0237, 0240]; claim 12; Tables 2 and 23-28; SEQ ID NO: 3 and 7). Andrews teaches a wild type VWF comprises multiple domains which are arranged in the following order: D1-D2-D'-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2-CK (para [0024]). An ordinary artisan would immediately envision a truncated VWF peptide only comprising VWF D’-D3 domains does not comprise a VWF A1 domain.
Regarding claims 4-5, Andrews teaches wherein the truncated VWF comprises the D-’D3 domains of wild-type VWF and mutations S764E/S766Y/V1083A which is referred to as the EYA mutant (para [0240]; claim 12; SEQ ID NO: 7). The EYA mutant is among the mutants evaluated with the most improved affinity to FVIII (i.e., 20-fold improvement) and off rate (i.e., 40-fold improvement) when under neutral pH conditions over wild-type (para [0240]). The EYA mutant was the evaluated mutant with the most improved affinity to FVIII (i.e., 100-fold improvement) and off rate (i.e., at least 100-fold improvement) when under acidic pH conditions over wild-type (para [0241]).
Regarding claim 6, Andrews teaches wherein the truncated VWF is a dimer (para [0013, 0017, 0038, 0043, 0088, 0090, 0240-0241]; claims 57 and 85). Andrews also VWF forms multimers between a single dimer to more than 20 dimers (para [0008]).
Regarding claim 11, Andrews teaches a pharmaceutical composition comprising the truncated VWF polypeptide (claim 61).
Regarding claims 18-20, Andrews teaches a nucleotide encoding the polypeptide comprising a the truncated VWF (claim 78). Andrews further teaches wherein a plasmid or vector comprises the polynucleotide (claim 79). Additionally, Andrews teaches wherein a host cell comprises the polynucleotide (claim 81).
Andrews does not teach wherein the polypeptide comprises an erythrocyte-binding moiety that is not a VWF moiety.
However, Andrews teaches the polypeptide comprising a truncated VWF also comprising a half-life extending moiety of human serum albumin directly fused to the C-terminal portion of the VWF peptide (para [0045-0048 and 0053]; claims 47-49).
Andrews teaches wherein therapeutic proteins are linked to antibodies or fragments thereof (para [0059]).
Muzykantov teaches using red blood cells as drug delivery vehicles for therapeutic proteins that must act within the vascular lumen (Title; Abstract; Figure 2). The therapeutic protein can be conjugated to fragments of a red blood cell binding antibodies to couple the therapeutic to red blood cells (Figure 2). The strategy has been shown to increase the half-life of a therapeutic protein as well as protect the therapeutic from inhibitors (p. 415, col 2, para 3 – p. 416, col 1, para 5).
In view of the combined teachings of Andrews and Muzykantov, it would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the truncated VWF polypeptide and/or dimer comprising the D’-D3 domains, such as the EYA variant, and a C-terminal half-life extending moiety taught by Andrews such that the C-terminal half-life extending moiety is substituted with a red blood cell-binding antibody fragment taught by Muzykantov to extend the half-life of the therapeutic when coupled to red blood cells. Thereby arriving at the invention of claims 1, 3-6, 9-11, and 18-20.
An ordinary artisan would have been motivated and had a reasonable expectation of success to substitute the C-terminal half-life extending moiety of the truncated VWF polypeptide and/or dimer taught by Andrews for the erythrocyte-binding antibody fragment taught by Muzykantov as well as to couple the VWF peptide(s) to red blood cells. This is because Muzykantov taught using red blood cells as drug delivery vehicles for therapeutic proteins that act within the vascular lumen wherein the therapeutic is coupled via a red blood cell-binding antibody fragment. Furthermore, Muzykantov taught the protein therapeutic coupled to red blood cells exhibited an increased half-life.
Regarding claims 7-8, Andrews does not explicitly teach wherein the polypeptide is a heterodimer.
In view of the combined teachings of Andrews and Muzykantov, it would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to form a heterodimer of the truncated VWF polypeptide comprising the D’-D3 domains of VWF and a human serum albumin (HSA) C-terminal half-life extending moiety taught by Andrews with the truncated VWF comprising the D’-D3 domains of VWF and wherein a red blood cell binding antibody fragment is fused to the C-terminus taught by Andrews and Muzykantov. Thereby arriving at the invention of claims 7-8.
An ordinary artisan would have been motivated to and had a reasonable expectation of success of forming a heterodimer from the truncated VWF polypeptide comprising the D’-D3 domains and a human serum albumin C-terminal half-life extending moiety taught by Andrews with the truncated VWF comprising the D’-D3 domains of VWF and wherein a red blood cell binding antibody fragment is fused to the C-terminus taught by Andrews and Muzykantov. The heterodimer would allow the complex to retain the beneficial properties of each individual peptide. The VWF-HSA peptide would impart an increased half-life to the therapeutic since Andrews taught the C-terminal half-life extending moiety can comprise an albumin. Additionally, the VWF-HSA peptide would facilitate the purification of the heterodimer because Andrews taught the use of an HSA affinity resin to purify the VWF-HSA dimers. The VWF peptide comprising the red blood cell binding antibody fragment would allow the heterodimer to be coupled to red blood cells to increase the half-life of the therapeutic.
Furthermore, “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). Andrews teaches a VWF peptide capable of binding FVIII and treating blood coagulation disorders comprising a C-terminal half-life extending moiety (i.e., HSA). Andrews and Muzykantov teach a VWF peptide capable of binding FVIII and treating blood coagulation disorders that is conjugated to a red blood cell binding antibody that extends the half-life of the peptide when coupled to red blood cells. Therefore, it is obvious to combine each VWF peptide into one composition because they are useful for the same purpose of binding FVIII, treating blood coagulation disorders, and extending the half-life of the peptide. When combined in one composition they could dimerize to form a heterodimer capable of extending the half-life of the VWF therapeutic.
Consequently, the invention of claim 1, 3-11, and 18-20 would have been obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
No claims are in condition for allowance.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SCOTT E. MULDER whose telephone number is (571)272-2372. The examiner can normally be reached Monday - Friday 7:30 AM - 3:30 PM.
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/SCOTT E. MULDER/Examiner, Art Unit 1656
/David Steadman/Primary Examiner, Art Unit 1656
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