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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 November 4, 2025, has been entered.
Priority
The instant application, U.S. Application Number 17/348,515, filed June 15, 2021, claims priority from the earliest provisional application 63/039,252, filed June 15, 2020.
Claim Status
In the response filed Nov. 4, 2025, Applicant has canceled claims 1-46, 48-50, 52, 55-57, 58-62, 64-72, 74-75, 81, and 93-94.
Currently, claims 47, 51, 53-54, 63, 73, 76-80, 82-92, and 95-99 are under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 9/12/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
The rejection of claims 47, 51, 53-54, 57, 63, 73, 76-80, and 95-99 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 6, 28-40 and 53 of Application Number 18/562,148 (the ‘148 application) in view of in view of Chicoine, Louis G., et al. (Molecular Therapy 22.2: 338-347; published 2014, hereinafter as “Chicoine”), Tagawa, Yumi, et al., (Journal of the neurological sciences 157.1: 90-95, published 1998), Monteilhet, Virginie, et al. (Molecular Therapy 19.11: 2084-2091, published 2011) and Gashti, Casey N., ( Seminars in Dialysis. Vol. 29. No. 5, published 2016) is withdrawn due to the instant application having an earlier effective filing date (i.e. June 15, 2020), and the ‘148 application having a later effective filing date.
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 47, 51, 53-54, 63, 73, 76-80, 82-92, and 95-99 are rejected on the ground of non-statutory obviousness-type double patenting as being unpatentable over claims 1-2, 5-6, and 13-14 of Patent No. US12491265 B2 (Application Number 17/253,956, hereinafter as “’265 patent”), in view of Chicoine, Louis G., et al. (Molecular Therapy 22.2: 338-347; published 2014, hereinafter as “Chicoine”, prior art of record), “Study: Researchers Identify Way to Increase Gene Therapy Success.” (Nationwide Children’s Hospital, Nationwide Children’s Hospital, 30 Oct. 2013, hereinafter as “Nationwide Children’s Hospital”), Tagawa, et al., (Journal of the neurological sciences 157.1: 90-95, published 1998, prior art of record), Tse, Longping V., et al.,(Expert opinion on biological therapy 15.6: 845-855, published 2015), and Pham, Huy P., et al., (Transfusion and Apheresis Science 58.3: 237-246, published 2019).
This rejection is a new rejection, however, since it is substantially similar to a rejection set forth in the final Official action mailed on July 10, 2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Although the conflicting claims are not identical, they are not patentably distinct from each other because the competing claims are drawn to a disclosed species of the instant claims.
Regarding claim 47, 63, 73, 80, and 98-99, the ‘265 patent claims 1-2, 5-6, and 13-14 discloses a method of expressing a recombinant adeno-associated virus (rAAV) serotype rh.74 comprising the nucleotide sequences of SEQ ID NO: 9, and the systemic route of administration is an intravenous route and the rAAV administered was about 2x1014 vg/kg. Further, that the dose of the rAAV is determined by utilizing a super-coiled DNA standard. These disclosures expressly disclose the limitations of instant claim 47, 63, 73, 80, and 98-99.
The difference between cited application’s method and instant method is that instant method requires a first dose of the rAAV, followed by TPE, followed by a second dose of the rAAV.
However, Chicoine teaches Duchenne muscular dystrophy (DMD) is a monogenic disease potentially treatable by gene replacement (abstract) corresponding to the limitation of a method for treating a muscular dystrophy as claimed. Chicoine teaches the use of recombinant adeno-associated virus (AAV) will ultimately require a vascular approach to broadly transduce muscle cells (abstract) corresponding to the limitation of administering a first dose of recombinant adeno-virus associated.
Regarding claims 47, 51, 53-54, 57, 63, 73, 76-80, and 95-99 Chicoine teaches administrating two rounds of plasmapheresis corresponding to the limitation administering a second dose of therapeutic plasma exchange (TPE)(see e.g. pages 341-342, 345-347). Chicoine teaches the subject's plasmas is subject to at least two TPE prior to administration of the 2nd dose or rAAV (see e.g. page 341, col. 2). Further, Chicoine teaches a method of treating muscular dystrophy in a human subject in need thereof comprising the steps of a) subjecting the subject's plasma to at least one therapeutic plasma exchange (TPE) prior to administering recombinant adeno-virus associated (rAAV)(see e.g. page 341-342). Additionally, Chicoine discloses wherein the subject's plasma is subjected to TPE for at least 2 days prior to administration of the rAAV (see e.g. pages 345-347). Moreover, Chicoine teaches wherein the subject is administered an anti-inflammatory steroid about 24 hours prior to administration of the rAAV, which would have been obvious to control inflammation (see e.g. page 346).
Accordingly, it would have been obvious to claim the invention of cited application and combine the method steps of a first dose of the rAAV, followed by TPE, followed by a second dose of the rAAV as taught by Chicoine because Chicoine suggests that an intervening plasmapheresis is able to eliminates the negative impact of AAV antibodies generated from a first dose that would normally inhibit the second dose (see e.g. Abstract). Further, Chicoine discloses the groups of sero-negative (i.e. naïve or no pre-existing antibodies) and sero-positive (naturally infected) animals receiving the gene transfer with AAVrh.74. and that the post plasmapheresis titer of the sero-positive animals was not different from that of sero-negative animals (see e.g. page 341-342, Figure 5), and that the levels of AAVrh.74 binding antibodies in the post-vector period had no effect on transgene expression in the sero-positive pheresed groups. Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success. Additionally, the prior art of Nationwide Children’s Hospital discloses that levels of micro-dystrophin gene expression increased in animals that did not at first receive plasmapheresis (see e.g. page 2). Further, the prior art of Jeune discloses that combining high vector doses and plasmapheresis would allow for treatment of up to 90% of potential patients who had previously undetectable levels of neutralizing factors (see e.g. page 64). Thus, a person of ordinary skill in the art of gene therapy would have been able to use the invention of cited application with the combined method steps of a first dose of the rAAV, followed by TPE, followed by a second dose of the rAAV as taught by Chicoine with a reasonable expectation of success.
Although Chicoine teaches performing two rounds of plasmapheresis (i.e. two rounds of three plasma volume exchanges over 2 consecutive days)(i.e. total of six TPE exchanges)(see page 342).
Chicoine is silent regarding seven, eight, nine or ten therapeutic plasma exchange (TPE).
However, the prior art of Tagawa discloses a range of three to ten therapeutic plasma exchange (TPE) (i.e. plasmaphereses) in patients (see page 91, col. 1). Further, the prior art of Tse discloses that after six plasma volumes of plasmapheresis (i.e. TPE) over a 2-day period, sero-positive animals had similar transduction efficiencies as sero-negative animals (see e.g. page 849).
Further, the following is noted from the MPEP: MPEP 2144.05: “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
MPEP 2144.05(I) teaches “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.” Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
In regards to overlapping ranges, MPEP 2144.05(I) states, “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”, continuing in regards to ranges are close, “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)”.
Accordingly, it would have been obvious for a person of ordinary skill in the art to modify the methods of the cited application and Chicoine with seven or more therapeutic plasma exchange (TPE) (i.e. plasmaphereses) as taught by Tagawa and Tse because Tse discloses that a clinical study found that multiple sessions of plasmapheresis are required to reduce naturalizing antibodies (NAbs) for effective gene therapy. Additionally, the prior art of Nationwide Children’s Hospital discloses that as gene therapy becomes more prevalent that patient may need to receive more than one treatment and plasmapheresis would allow them to be treated again (see e.g. page 3). Thus, a person of ordinary skill in the art would have optimized the number of TPE for the patient with predictable results and a reasonable expectation of success.
Regarding claims 47, 51, 53-54, 57, 63, 73, 76-80, and 95-99, Chicoine does not explicitly state the plasma volume of about 1 to 1.5 plasma volume.
Further, the prior art of Pham discloses that TPE exchanges that about 1 to 1.5 plasma volumes per treatment provide the most benefit (see page 238).
Accordingly, it would have been obvious for a person of ordinary skill in the art to modify the methods of the cited application and Chicoine with TPE exchanges that are about 1 to 1.5 plasma volumes per treatment as taught by Monteilhet and Pham because Pham discloses that treating volumes in excess of a 1.5-plasma volume exchange confers little benefit due to the diminishing return effect, while placing the patient at higher risk for procedural complications (see page 238). Further, Monteilhet discloses that the standard plasma exchange procedure consisted of removal of one and half plasma volume during each session (page 2089). Therefore, a person of ordinary skill in the art would have a reasonable expectation of success to optimize each TPE exchanges to be about 1 to 1.5 plasma volumes.
This is a nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Traversal:
Applicant asserts that the specification and the prior art of Potter (i.e. Exhibit A) discloses that one of the biggest challenges facing gene transfer therapy (GTT), such as rAAV-based GTT, is overcoming the immune response to GTT administration (Remarks, page 9-10).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
It is noted that the specification and the prior art of Potter disclose that one of the biggest challenges facing gene transfer therapy (GTT) is overcoming the immune response (see e.g. Potter page 1). It is also noted that the prior art of Jeune (2013) discloses that it was well-known that pre-existing anti-adeno-associated virus antibodies are a challenge in AAV gene therapy (see e.g. abstract).
Applicant asserts that Chicoine is directed to the presence of pre-existing antibody immunity with AAVrh.74 (Remarks, page 10). Applicants argue that Chicoine teaches AAV antibody titers in subject populations with pre-existing immunity due to natural exposure to wild-type AAV, which are significantly lower than AAV antibody titers resulting from initial rAAV dosing (Remarks, page 10). Applicants argues that Chicoine also provides absolutely no expectation of success in using TPE to reduce the high AAV antibody titer levels acquired from initial rAAV dosing such that a second dose of rAAV may be administered (Remarks, page 11).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants argument, it is noted that Chicoine is directed to the presence of preexisting immunity to AAV (see abstract). However, Chicoine does disclose the comparison of “sero-negative (i.e. naïve) and sero-positive (naturally infected) animals to gene transfer with AAVrh.74., where there was a rapid and robust increase in antibody levels in the two immune-positive groups, whereas the sero-negative group had a modest antibody response following vector delivery” (See page 342). Further, the prior art of Tse discloses that “clinical interventions such as plasmapheresis and pharmacological modulation of the immune system offer promising, alternative solutions to address pre-existing immunity and/or vector re-administration (page 851). Therefore, a person of ordinary skill in the art would understand that the pre-existing immunity (as taught by Chicoine) would apply to patients that need re-administration.
In response to Applicants argument that Chicoine also provides absolutely no expectation of success in using TPE to reduce the high AAV antibody titer levels (Remarks, page 11). Contrary to Applicants assertion, Chicoine teaches different antibody titers for sero-negative (i.e. naïve) and sero-positive (naturally infected) animals to gene transfer with AAVrh.74.. Thus, a person of ordinary skill in the art would already know that optimization to account for the difference in antibody titers would be different. Further, It is noted that the features upon which applicant relies (i.e. AAV antibody titers) are not recited in the rejected claims. In response to applicant's argument that using TPE to reduce the high AAV antibody titer levels, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Applicant argues that the disclosures of Tagawa does not mention GTT or AAV-based therapy, and that Tagawa does not suggest the use of TPE in subject populations that have received a first dose of GTT (e.g., rAAV).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants argument regarding Tagawa, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Tagawa is cited for teaching the number of plasmaphereses sessions to a given patient and is not cited for teaching AAV-based therapy. As discussed above, the prior art of Tse discloses that after six plasma volumes of plasmapheresis (i.e. TPE) over a 2-day period, sero-positive animals had similar transduction efficiencies as sero-negative animals (see e.g. page 849).
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Closest Prior Art
Art made of record but not relied upon for art rejection:
Art cannot be applied to the claims as written without reading limitations into the claims.
Nonetheless, the following prior art reference teaches many of the elements/steps inferred by the disclosure as filed.
The closest prior art of record is Rodino-Klapac et al (WO2019078916A1, U.S. App. No. 16/757,207, Applicant Research Institute at National Children’s Hospital, filed 3/16/2018) (See file .rni, Result #1, Score Alignment Below). Rodino-Klapac et al. teaches SEQ ID NO: 3, which recombinant AAV vector expressing micro-dystrophin
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(see claim 34, see also Spec Figure 1 below).
However, the prior art of Rodino-Klapac does not teach nor reasonably suggest a recombinant adeno associated virus (rAAV) vector, wherein the MHCK7 promoter comprises a substitution, the intron sequence or the micro-dystrophin sequence comprises nucleotides 55-5021 of SEQ ID NO: 3 or SEQ ID NO: 9 of instant Application. See alignment below of SEQ ID NO:3 of Rodino-Klapac (bottom strand) with nucleotides 55-5021 of SEQ ID NO: 3 of instant Application (see SCORE search 12/06/2023, .rni file, result #1).
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717
587
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775
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Accordingly, the closest prior art of Rodino-Klapac et al does not teach the instant nucleotide sequence that is 100% identical to nucleotides 55-5021 of SEQ ID NO: 3.
Furthermore, see alignment below of SEQ ID NO:3 of Rodino-Klapac (bottom strand) with nucleotides of SEQ ID NO: 9 of instant Application (see SCORE search 12/06/2023, .rni file, result #1).
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886
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Accordingly, the closest prior art of Rodino-Klapac et al does not teach the instant nucleotide sequence that is 100% identical to SEQ ID NO: 9.
Conclusion
SEQ ID Nos: 27-31, 41-43 and 10-19 are free of the prior art (see Search results 10/10/2024 and 10/11/2024).
No claim is allowed.
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JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/ Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631