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 Application
1. Claims 1-9, 13-14, and 16-17 are pending and subject to examination on the merits. Claims 18-19 and 21 are withdrawn from consideration as being drawn to non-elected subject matter.
Priority
2. Acknowledgment is made for the Applicant’s claim for domestic priority based on the US provisional application PRO 62/944,718 filed 06 December 2019.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on 18 August 2025 been considered by the examiner. See initialed and signed PTO/SB/08’s.
Withdrawn Objections/Rejections
4. The objection to the specification for an embedded hyperlink is withdrawn, since the hyperlink was removed.
5. The objection to the specification for reciting trademarked terms without designation is withdrawn, since the specification was amended to include the trademark denotations.
6. The objection to claim 6 for reciting “the variant” is withdrawn, since the claim was amended to recite “the Factor VIII variant.”
7. The objection to claim 8 for reciting “said FVIII” is withdrawn, since the claim was amended to recite “the Factor VIII variant.”
8. The 35 U.S.C. 102 rejection of claims 1-6, 7-9, 13-16, and 22-23 as being anticipated by Varfaj et al (Varfaj et al., 2006, Biochem J—cited on the Information Disclosure Statement filed 15 February 2023) as evidenced by Healey et al (Healey et al., 1998, Blood—cited previously), Nogami et al (Nogami et al., 2004, Journal of Biological Chemistry—cited previously), and Bulbake et al (Bulbake et al., 2017, pharmaceutics—cited previously) is withdrawn, since the claims were amended to recite “an adeno-associated virus (AAV) vector comprising a...”
9. The 35 U.S.C. 103 rejection of claim 17 as being unpatentable over Varfaj et al. (Varfaj et al., 2006, Biochem J—cited on the Information Disclosure Statement filed 15 February 2023) as evidenced by Healey et al (Healey et al., 1998, Blood—cited previously), Nogami et al (Nogami et al., 2004, Journal of Biological Chemistry—cited previously), and Bulbake et al (Bulbake et al., 2017, Pharmaceutics—cited previously) as applied to claims 1-9, 13-16, and 22-23 above, and further in view of Liu et al (Liu et al., 2014, BMC Research Notes—cited previously).
New Rejection—necessitated by amendments
Claim Rejections - 35 USC § 103
10. 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.
11. 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.
12. Claims 1-9, 13-14, and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Varfaj et al (Varfaj et al., 2006, Biochem J—cited on the Information Disclosure Statement filed 15 February 2023) as evidenced by Healey et al (Healey et al., 1998, Blood—cited previously), Nogami et al (Nogami et al., 2004, Journal of Biological Chemistry—cited previously), and Bulbake et al (Bulbake et al., 2017, pharmaceutics—cited previously), and in view of Rangarajan et al (Rangarajan et al., 2017, NEJM—cited herein).
Regarding claims 1-6, drawn to an AAV comprising nucleic acid encoding a Factor VIII variant lacking the B domain (claim 6) and comprising a substitution mutation of the Arg at position 336 with Gln and the Arg at position 562 with Gln (claims 1-5), Varfaj et al. teaches the preparation of B-domainless Factor VIII cDNA by restriction, where the Arg 336 and 562 mutations were introduced by site-directed mutagenesis, creating specifically R336Q and R562Q mutations to investigate the roles of these two P1 residues in the prevention of activated-Protein-C catalyzed inactivation of Factor VIIIa (p. 356, Construction, expression and purification of recombinant Factor VIII mutants, lines 1-10; Title; Abstract). Regarding claims 7-8, drawn to the FVIII nucleic acid of claim 1 lacking the B-domain comprising the amino acids 1-740 and 1649-2332 of SEQ ID NO: 1 (claim 7) or amino acids 1-740 and 1690-2332 of SEQ ID NO: 1 (claim 8), Varfej et al. teaches the utilization of the B-domainless Factor VIII vector (pBS Factor VIII) kindly provided as gifts from Dr. Pete Lollar and Mr. John Healey (p. 356, first paragraph, last 3 lines), where Healey et al. describes/evidences that in the human FVIII SQ, B-domainless plasmid, the presence of a 14 amino acid sequence, corresponding to B-domain residues Ser741-Asn745, Pro1640-Arg1648, in place of the B-domain, produces a molecule designated as r-FVIII SQ, where this molecule is expressed more efficiently in mammalian cells and thus necessarily comprises amino acids 1-745 and 1640-2332 (p. 3703, Construction of porcine B-domain-deleted FVIII and a porcine B-domain-deficient FVIII, PSQ, 1st column, last paragraph - 2nd column, first paragraph).
Regarding claims 9 and 13-14 drawn to an AAV vector encoding the Factor VIII mutant with a signal peptide and regulatory sequence with a pharmaceutically acceptable carrier, Varfaj et al. teaches the subcloning of Factor VIII mutants in a pBluescript™ II KS (-) vector, which was transfected into cells utilizing FuGENE™ 6 for protein expression and purification utilizing the method of Nogami et al., [reference 17] (p. 356, Construction, expression and purification of recombinant Factor VIII mutants, lines 16-18). Notably, the pBluescript™ II KS(-) vector is the same vector used in the specification (p. 14, line 32). Importantly, Nogami et al. demonstrates/evidences the method of plasmid transfection using liposomes (p.15764, Construction, Expression, and Purification of Factor VIII Mutants, paragraph 2), which as evidenced by Bulbake et al. is a pharmaceutical acceptable carrier that has been successfully translated into real-time clinical applications (abstract).
Regarding claim 16, drawn to a host cell comprising the expression vector of claim 15, Varfej et al. teaches the transfection of the Factor VIII mutants in BHK cells (p. 356, Construction, expression and purification of recombinant Factor VIII mutants, line 16).
Varfaj et al., as evidenced by Healey et al., Nogami et al., and Bulbake et al. does not teach the utilization of an AAV encoding the Factor VIII mutant or human cells (claim 17).
Regarding the utilization of an AAV encoding the Factor VIII, Rangarajan et al. teaches an AAV5-hFVIII-SQ vector, where there is a codon-optimized adeno-associated virus serotype 5 vector encoding a B-domain-deleted human factor VIII (Methods). Additionally, Rangarajan et al. teaches the introduction to 9 men with severe hemophilia A as a single intravenous dose at different dosages, wherein said AAV necessarily enter the cells resulting in human host cells, and then followed through 52 weeks (Methods), where bleeding events post treatment were reduced in the intermediate and high dosage cohorts (results).
Therefore, it 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 combine the teachings of Varfaj et al., as evidenced by Healey et al., Nogami et al., and Bulbake et al. with Rangarajan et al. to produce a AAV vectored Factor VIII mutant to treat hemophilia in human patients as taught by Rangarajan et al. One would be motivated to combine these teachings to arrive at the instant claims to reduce the frequency of infusions, which would increase adherence to therapy and quality of life (p. 2520, Column 1, paragraph 2). There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Varfaj et al., as evidenced by Healey et al., Nogami et al., and Bulbake et al. with Rangarajan et al. to produce a AAV vectored Factor VIII mutants, since Rangarajan et al. teaches an AAV vector encoding Factor VIII.
Applicant’s Arguments and Examiner’s Rebuttal:
The Applicant traverses the previous anticipation rejection of claims 1-9, 13-16, and 22-23 over Varfaj et al., as evidenced by Healey et al., Nogami et al., and Bullbake et al. Additionally, the applicant traverses the previous obviousness rejection of claim 17 over Varfaj et al., as evidenced by Healey et al., Nogami et al., and Bullbake et al. in further view of Liu et al.
First, the applicant argues that the claim amendment to recite “an adeno-associated vector” to claim 1 overcomes the anticipation rejection, and the examiner agrees. The examiner withdrew the previous anticipation rejection and replaced it with the new rejection of record found above that teaches the utilization of the AVV encoded FVIII.
Second, the applicant argues that the examiner asserted that the pBluescript™ plasmid was an AVV vector. The examiner acknowledges that this was erroneous; the examiner meant “expression vector”/”plasmid” as both were part of the claims being rejected in the original rejection.
Third, the applicant argues that the obviousness rejection over claim 17 is improper since there is no demonstration or motivation of utilizing the Factor VIII mutant in an AAV process. The examiner agrees that the previous rejection of record did not address Factor VIII in context of an AAV system. However, the present rejection demonstrates that there would be no surprising results, since Rangarajan et al. teaches an AAV vector encoding B-domainless Factor VIII.
Last, the applicant argues that there are unexpected, superior results when utilizing Factor VIII QQ. The examiner disagrees, since Varfaj et al. teaches the specific mutations, and therefore, is teaching the identical therapeutic protein which should therefore yield the same results.
The examiner does not find the arguments presented by the Applicant persuasive, and for these reasons, the rejections of record above apply.
Conclusion
13. All claims are rejected.
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.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CIARA A MCKNIGHT whose telephone number is (703)756-4791. The examiner can normally be reached M-F 8:00am-4:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached on (571) 272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CIARA A MCKNIGHT/Examiner, Art Unit 1656
/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656