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
1. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 22 April 2026 has been entered.
Status of the Application
2. Claims 1, 6-9, 13-14, 16-17, and 24 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 Claims 18-19 and 21 are withdrawn from consideration as being drawn to non-elected subject matter.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
3. 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
4. The information disclosure statement (IDS) submitted on 22 April 2026 been considered by the examiner. See initialed and signed PTO/SB/08’s.
Claim Rejections - 35 USC § 103
5. 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.
6. 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.
7. Claims 1, 6-9, 13-14, 16-17, and 24 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), and Nogami et al (Nogami et al., 2004, Journal of Biological Chemistry—cited previously), and in view of Bulbake et al (Bulbake et al., 2017, pharmaceutics—cited previously), and in view of Rangarajan et al (Rangarajan et al., 2017, NEJM—cited previously).
Regarding claims 1 and 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 (claim 1), 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, 13-14, and 24 drawn to an AAV vector encoding the Factor VIII mutant with a signal peptide and regulatory sequence and 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 Bulbake et al. teaches is a pharmaceutical acceptable carrier that has been successfully translated into real-time clinical applications (abstract), and further, regarding claim 24, drawn to a pharmaceutical composition for intravenous injection, Bulbake et al. teaches liposomal formulations used in intravenous injections (p. 3, “2.1 Stealth Liposome Technology”).
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., however, does not teach the utilization of an AAV vector encoding the Factor VIII mutant or human cells comprising said AAV vector (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 to combine the teachings of Varfaj et al., as evidenced by Healey et al. and Nogami et al., and in view of 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. because utilizing a FVIII with R336Q + R562Q substitutions necessarily results in FVIII that is not inactivated like FVIII with R336+R562 which would then increase the therapeutic efficacy of FVIII treatment for hemophilia. 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 in view of 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 for successful treatment of humans with hemophilia.
Double Patenting
8. 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.
9. Claims 1, 6-9, and 13-17 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-3, 7-10, 13-17 of copending Application No. 18/856,176 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘176 claims would anticipate the instant claims.
The instant claims in their broadest are drawn to an AAV vector comprising a nucleic acid encoding FVIII variant comprising amino acid substitution mutations, R336Q and R562Q, wherein said AAV vector lacks the B-domain, wherein said AAV comprises amino acids 1-740 and 1690=2332 of SEQ ID NO: 1, whreein said FVIII variant comprises a pharmaceutically acceptable carrier, and wherein the AAV is in a host cell.
The ‘176 claims in their broadest are drawn to a FVIII variant comprising amino acid substitution mutations, R336Q, R562Q, and additionally amino acids 519 and 665, wherein said FVIII variant lacks the B-domain, wherein said variant comprises amino acids 1-740 and 1690=2332 of SEQ ID NO: 1, wherein said FVIII variant comprises a pharmaceutically acceptable carrier, and wherein the variant is encoded by an AAV, and wherein said variant encoded by an AVV is in a host cell.
It is notable that SEQ ID NO: 1 of the instant claims and the ‘176 claims is 100% identical. Thus the only difference between the instant claims and the ‘176 claims is that the ‘176 claims also recite mutations at amino acid positions 519 and 665. However, the ‘176 claims would still anticipate the instant claims because the instant claims are written in the open “comprising” language, which would necessarily allow for these other mutations to occur in the amino acid sequence.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant’s Arguments and Examiner’s Rebuttal:
The Applicant traverses the previous obviousness rejection of claims 1-9, 13-14, and 16-17 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 previously). This rejection has been modified above to include new claim 24, where specifically the Bulbake et al. reference is utilized as teaching claim limitations and is recited as a secondary teaching rather than an evidentiary resource.
The applicant first argues that the skilled artisan would only select a therapeutic FVIII for insertion into an AAV for treatment. Further, the applicant claims that the FVIII-QQ utilized in Varfaj et al. do not teach this variant FVIII to be therapeutic. The examiner agrees insofar that the Varfaj et al. was not utilized as a teaching to determine or demonstrate therapeutic effectiveness of the FVIII-QQ variant. It was utilized to teach that the variant exists and has been utilized in a mammalian model system. Additionally, the teachings of Varfaj et al. do not have to have the same motivations, rationales, or goals of the instant claims/inventors in order to teach the limitations of the claims as written.
Second, the applicant argues that the hemostatic effect of FVIII-QQ is surprising in the context of FVIIIa regulation. The examiner respectfully disagrees that this argument is applicable to the current claims. There is nothing in the claim limitations about APC cleavage or FVIIIa regulations thereof. Further, the applicant argues that this a surprising result; however, the expression of FVIII-QQ by an AAV in a mammalian cell, i.e. the combination of the above teachings, would demonstrate the same results.
Third, the applicant argues that there would be no expectation of success in therapeutically using an APC cleavage mutant FVIII. However, the standard of obviousness is not absolute expectation of success, it merely has to be a reasonable expectation of success. Given the teachings are all focused on the utilization of AAV vectored FVIII’s in context of mammalian host cells, there would be a reasonable expectation of success to be able to utilize the FVIII-QQ in the same AAV vector.
Next, the applicant argues that there is no motivation to combine the teachings set forth above to manufacture a FVIII-QQ variant AAV as a pharmaceutical composition. The examiner respectfully disagrees. The examiner outlines above a motivation, where specifically one would be motivated to combine the teachings 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).
Last, the applicant argues that the references are void of any suggestion that FVIII-QQ would possess any superior properties compared to wild-type FVIII. The examiner respectfully disagrees given that the combination would result in the same properties of the instant claims.
The examiner does not find the arguments presented by the Applicant persuasive, and for these reasons, the rejections of record above apply.
Conclusion
10. All claims are rejected.
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
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