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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This Action is in response to the papers filed on 09/19/2025.
Claims 78-101 are currently pending. Claims 97-99 have been amended by Applicant’s amendment filed on 09/19/2025.
No claims were added or canceled by Applicants’ amendment filed on 09/19/2025. Claims 78, 92 and 96 are independent claims.
Therefore, claims 78-101 are currently under examination to which the following grounds of rejection are applicable.
Priority
This application is a CON of 17/224,367 filed 04/07/2021 (now ABN) which is a CON of 17/050,911 filed 10/27/2020 (now ABN) which is a 371 of PCT/EP2019/069280 filed July 17, 2019.
Applicant’s claim for the benefit of a prior-filed parent provisional application 62/768,731, filed on November 16, 2018 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Additionally, Applicant’s claim for foreign priority to EUROPEAN PATENT OFFICE (EPO) 18305971.6 filed on July 17, 2018 is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/18/2025 and 04/21/2025 were received. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements were considered by the examiner.
Statement on Claim Interpretation
The examiner notes that administration to a human of an effective amount of an IdeS polypeptide as required in claim 78 would necessarily lead to a reduction of some or all Immunoglobulin G (IgG) including any IgG that have been raised against a recombinant AAV vector which includes neutralizing and non-neutralizing anti-AAV antibodies since IdeS degrades some and all IgG antibodies, which in turn should be reasonably expected to increase cell transduction of the rAAV vector.
Maintained Objections/ Rejections in Response to Applicants’ Arguments or Amendments
Claim Rejections - 35 USC § 112(b)
Claim 97 remains 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 applicant regards as the invention.
Regarding claim 97, the recitation of the phrase “an improvement in the systemic duration of the recombinant AAV vector resulting from IdeS cleavage of neutralizing antibodies”, is vague and renders the claim indefinite. The phrase “an improvement in the systemic duration” is not defined by the claim, and the specification does not provide a standard for ascertaining the ‘‘an improvement in the systemic duration’’ that the applicant is claiming regarding the recited effect. One of ordinary skill in the art would not be reasonably appraised of the scope of the invention. Thus, the metes and bounds of the claim cannot be determined. Does “an improvement in the systemic duration” refer to a specific and measurable benefit? A specific time frame? Will a variance exist depending on which pathology the therapy is used against? Further, the recitation of “an improvement” it is relative insofar as an improvement in systemic duration can only be measured relative to another systemic duration which is not improved and the claim does not set forth such a relationship.
For the sake of compact prosecution, the intended meaning will be interpreted by the examiner to be an expected improvement of the systemic duration of the rAAV-based therapeutic resulting from IdeS cleavage of IgG antibodies. Therefore, this claim is covered by the previous prior art and rationale set forth above.
Claim Rejections - 35 USC § 103
Claims 78-97, 100 and 101 remain rejected under 35 U.S.C. 103 as being unpatentable over Kjellman et al. US 2018/0037962, published 2/8/2018, and claiming priority to GB 1502305.4 filed on Feb. 12, 2015 (hereinafter Kjellman, reference of record) in view of Boutin et al. "Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors." Human gene therapy 21.6 (2010): 704-712 (hereinafter Boutin, reference of record) and Meliani et al. "Determination of anti-adeno-associated virus vector neutralizing antibody titer with an in vitro reporter system." Human gene therapy methods 26.2 (2015): 45-53 (hereinafter Meliani, reference of record).
Kjellman describes a method for treating a disease comprising administering an immunoglobulin G degrading enzyme of S. pyogenes, SEQ ID NO: 2 (IdeS; corresponding to elected SEQ ID NO: 4) The sequence search results shown below detail a 100% match between SEQ ID NO: 2 of Kjellman and SEQ ID NO: 4 of the instant application. The IdeS is administered in a prophylactically or therapeutically effective amount followed by viral vector gene therapy (Kjellman, para 2, 31-34 and claim 11).
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Kjellman identified IdeS as an extracellular cysteine protease which has an “extraordinarily high” degree of substrate specificity, with its only identified substrate being immunoglobulin (IgG) (Kjellman, para 2). Kjellman describes embodiments wherein the administration of IdeS may serve to improve the efficacy of a viral vector gene therapy by decreasing and neutralizing IgG antibodies that would limit the effectiveness of the viral vector gene therapy (Kjellman, para 31-34). Kjellman states that the amount of IdeS should be administered in an amount “sufficient to cleave substantially all IgG molecules present in the plasma of the subject” wherein the administration of IdeS and the viral vector are separated by a time interval, which is sufficient to cleave substantially all IgG molecules present in the plasma of the subject (Kjellman, para 33 and 34). Kjellman’s description of cleaving “substantially all IgG molecules” reads on the neutralization ranges of anti-AAV antibodies listed in claims 81, 88 and 94 (Kjellman, para 33).
Kjellman states that the time interval between administering the IdeS polypeptide and secondary therapeutic compound may be separated by at least 2 hours and at most 21 days, corresponding to the “within about 72 hours” limitation of independent claims 78, 92, 96, 100 and 101 (Kjellman, para 143). Kjellman describes numerous diseases and their associated antigens for which this enhanced gene therapy can be applied (Kjellman, Table D). In particular, Kjellman identifies Hemophilia, diabetes type 1 among many others as well as their associated antigens like factor VIII (Kjellman, Table D). Kjellman further mentions taking blood from the subject and performing IgG neutralization/fragmentation using IdeS ex vivo in order to determine patient sensitization and treatment efficacy (Kjellman, para 157 and claim 14).
Although Kjellman describes the administration of viral expression vectors in combination with IdeS (para [0031]-[0034] “The invention also provides a method for improving the benefit to a subject of a therapy or therapeutic agent, the method comprising (a) administering to the subject a polypeptide of the invention; and (b) subsequently administering said therapy or said therapeutic agent to the subject; wherein: [0032] said therapy is …. a gene therapy such as a viral vector, a replacement for a defective endogenous factor such as an enzyme, a growth or a clotting factor, or a cell therapy; [0033] the amount of said polypeptide administered is sufficient to cleave substantially all IgG molecules present in the plasma of the subject; and [0034] steps (a) and (b) are separated by a time interval which is sufficient to cleave substantially all IgG molecules present in the plasma of the subject.”), Kjellman does not specifically describe recombinant adeno-associated viral vectors as recited in claim 78 and therefore neutralizing antibodies raised against said vector. Kjellman does not expressly describe the use of AAV vectors comprising VP1, VP2 and/or VP3 capsid proteins as recited in claims 84, 92 and 96. Kjellman does not describe the specific IgG neutralization assay steps in claim 88.
Boutin characterizes the neutralization of various AVV serotypes by IgG antibodies in an attempt to develop new strategies to circumvent AAV acquired immune responses (Boutin, abstract). Boutin examines numerous AAV serotypes (AAV types 1, 2, 5, 6, 8 and 9) and capsid compositions (VP1-VP3) in order to quantify neutralization titers via enzyme-linked immunosorbent assays (Boutin, Prevalence of AAV serum neutralizing factors and Fig 3). Boutin describes the advantages of AAV tropism in achieving high levels of transgene expression in liver tissue (Boutin, discussion para 3).
Moreover, Meliani describes how neutralizing antibodies (NAb; a type of serum IgG antibody) can have a “profoundly” negative impact on the transduction efficiency of AAV vector-mediated gene therapies for hemophilia and other diseases. (Meliani, intro para 1). This is particularly relevant for AAV gene therapies which are administered directly into the bloodstream of a patient, where NAb can block the transduction of AAV vectors even at low titers, thus requiring prescreening before and after vector administration (Meliani, abstract). Meliani presents an in vitro cell based assay for the determination of NAb titer in human serum or plasma samples, which can be administered before and/or after AAV gene therapy. Meliani outlines this in vitro neutralization assay in Fig 1. Meliani describes experimental procedures for determining the neutralization activity of numerous body fluids including plasma, serum, synovial fluid and cerebrospinal fluid (Meliani, Experimental procedure, para 1). Meliani describes serial dilutions ranging from 1:1 to 1:1000 and analyzing the resulting % inhibition or neutralization corresponding to the limitations described in claim 12 (Meliani, Table 1 and first table on pg. 51).
In relation to claim 97, in view of the benefit of administering an IdeS and subsequently administering a gene therapy such as a viral vector to cleave substantially all IgG molecules present in the plasma of a subject , it would have been prima facie obvious to one of ordinary skill in the art to select the recombinant AAV vectors described by Boutin and Meliani as the type of viral vector in the treatment methods described by Kjellman employing IdeS administration followed by vector administration, particularly because Boutin characterizes the neutralization of various AAV serotypes by serum IgG antibodies and Meliani teaches AAV gene therapies which are administered directly into the bloodstream of a patient, where neutralizing antibodies (NAb) can block the transduction of AAV vectors even at low titers.
One would have a reasonable expectation of success given that IdeS administration prior to AAV administration would cleave substantially all IgG, leading to further enhancements in cell transduction by neutralizing Ab that can block the transduction of AAV vectors using AAV vector-based gene therapies.
Moreover, in relation to claim 84, Boutin found that neutralizing factor titers to AAV8 and AAV9 vector serotypes were typically lower when compared to other vector types (Boutin, Intro para 5). Boutin also mentions AAV8 as a robust vector for achieving high levels of transgene expression in liver tissue (Boutin, discussion para 3). Thus, one would have been motivated to use recombinant AAV vectors such as AAV8 given their relatively low neutralizing factor seroprevalences and high transgene expression in liver tissue as shown by Boutin.
Furthermore, it would have been prima facie obvious to one of ordinary skill in the art to use the IgG neutralization screening assays described by both Boutin and Meliani in order to determine patient IgG sensitization and determine an effective amount of IdeS to administer to a human in need thereof to treat a disease with AAV-based gene therapy as rendered obvious by the combined teachings of Kjellman, Boutin and Meliani. It would have been a matter of combining known prior art elements according to known methods to yield predictable results since both Boutin and Meliani present these assays as an effective way to pre-screen patients before vector administration in order to circumvent AAV immune responses and improve AAV transduction efficiencies. Thus, one would have been motivated to make this combination in order to determine patient IgG sensitization and determine an effective amount of IdeS to administer in order to improve AAV vector-mediated transduction efficiencies. One would have a reasonable expectation of success given the well-established assay protocols outlined by Boutin and Meliani.
Furthermore, the exact quantity of IdeS one would administer to the patient, the number of times/interval one would administer IdeS to the patient and the repetitive order of AAV administration following IdeS administration are considered result effective variables that would have been determined through routine experimentation using the neutralization screening assays described by both Boutin and Meliani. In particular, Kjellman states that the amount of IdeS should be administered in an amount “sufficient to cleave substantially all IgG molecules present in the plasma of the subject” (para [0031][0142][0143]), wherein the administration of IdeS and the viral vector are separated by a time interval which is sufficient to cleave substantially all IgG molecules present in the plasma of the subject (Kjellman, para 33 and 34). Therefore, Kjellman has a clear appreciation that these are result-effective variables which could readily be optimized using techniques such as the neutralization screening assay described by both Boutin and Meliani, see MPEP 2144.05. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
Response to Applicants’ Arguments as they apply to rejection of claims 78-97, 100 and 101 under 35 USC § 103
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At pages 13-15 of the remarks filed on 09/19/2025, Applicants essentially argue that it would not have been obvious in view of the cited references to treat a subject with IdeS peptide and then administering a recombinant AAV within about 72 hours. Applicant’s entire argument is provided below: Applicants’ arguments have been fully considered, but have not been found persuasive.
These references do not teach that F(ab')2 fragments generated by administration of IdeS levels are sufficient in vivo to neutralize therapeutic AAV doses equivalent to intact IgG. A person of ordinary skill in the art would consider whether net neutralizing activity would be reduced enough to show an improvement of in transduction.
Applicants cite the prior art of Jarnum et al., (Mol. Cancer Ther. 16: 1887-97 (2017) and Jordan et al., (N. Engl. J. Med. 377:442-53 (2017) to essentially explain that IgG and the F(ab')2 fragments thereof continued to circulate in human subjects within 72 hours after administration of [the] IdeS [polypeptide] and therefore “Therefore, one of ordinary skill in the art starting with the references of Kjellman, Boutin, and Meliani, would expect the IgG F(ab')2 fragments generated by administration of IdeS, which are present in the serum up to 72 hours post-administration, to inhibit the transduction efficiency of AAV vector particles. As a result, there would be no expectation that pre-treatment with IdeS peptide would successfully reduce AA -neutralizing IgG antibodies.” (Remarks at page 14).
The examiner acknowledges that the prior art of Jarnum and Jordan do not explicitly disclose digestion of anti-AAV antibodies. However, as Applicants previously indicated in remarks filed on 9/30/2024 (Applicants’ arguments of record) in subpart iv) of page 18, “page 448 of Jordan reports that "Figure S2 ... shows the dynamics of total IgG, Fc, and F(ab')2 fragments in the serum specimens obtained from Jordan-treated patients ... “. It is evident from this figure that administration of IdeS (a cysteine protease) reduces intact IgG, Fab-containing fragments and Fc-containing fragments (Jordan’s Fig S2). Neutralizing antibodies are a type of IgG antibodies. Therefore, if administration of a therapeutically effective amount of IdeS reduces expression of intact IgG, Fab-containing fragments and Fc-containing fragments in the serum specimens obtained from IdeS-treated patients, administration of a therapeutically effective amount of IdeS should be reasonably expected to digest neutralizing intact anti-AAV IgG antibodies IgG, Fab-containing fragments and Fc-containing fragments in serum specimens obtained from IdeS-treated patients for the for the same reason it digests IgG antibodies– both IgG antibodies IgG and anti-AAV IgG antibodies are proteins/ peptides.
Moreover, as set forth in the paragraphs above, it was known in the art prior to the date the present invention was filed that AAV neutralizing antibodies (NAb) were present following AAV administration, and that such NAbs would significantly impact the AAV transduction efficiency. Meliani teaches “Neutralizing antibodies (NAb) directed against AAV have a profound impact on transduction efficiency when the vector is delivered directly into the bloodstream or in any body compartment where immunoglobulin can be found. This has been demonstrated in several preclinical and clinical studies, in which the presence of apparently low-titer NAb to AAV was associated with lack of efficacy (Pg. 45, Introduction, 2nd Paragraph).
Further, Boutin demonstrated that exposure to AAV types 1, 2, 5, 6, 8, and 9 would result in generation of AAV specific antibody response (Discussion, 2nd Paragraph). Specifically, Boutin teaches that an IgG response to AAV administration was known (Discussion, 2nd Paragraph). Additionally, Boutin teaches cross reactivity between antibodies for AAV serotypes could occur and could further limit administration (and thus therapeutic) use of AAVs (Discussion, final paragraph).
The above teachings of Boutin and Meliani combined with Kjellman's teaching that IdeS polypeptides cleaved essentially ALL IgG, make it apparent that at the time of applicants filing of the invention the following was known: 1) The occurrence of anti-AAV antibodies (IgGs) was known, 2) the potential of anti-AAV antibodies to reduce the efficiency of administered AAVs was known, and 3) the use of IdeS to cleave these Anti-AAV antibodies to maintain efficacy was known. Therefore, applicants’ arguments are not persuasive.
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Applicant also points to the following references of “Gurda et al. (J Vir 86(15):7739-7751 (August 2012)) reference cited in the Armour Declaration shows F(ab')2 binding to AAV8 and Figure 2A of Wobus et al. (J Virol. 2000 Oct;74(19):928 l-93.)” and asserts these references “shows two different F(ab')2 fragments inhibiting the binding of AAV2 particles to cells (figure reproduced below).” As discussed above, while the cited art does show F(ab')2 fragments binding to and inhibiting AAV capsid proteins, they do not demonstrate that the residual F(ab')2 fragments generated by IdeS administration would have the capacity to neutralize AAV vectors to the extent of intact IgG in vivo, nor does it teach that IdeS pretreatment would have been ineffective for improving AAV vector delivery.
Moreover, rapid cleavage of IgG by IdeS as taught by the cited prior art provides a clear motivation to administer AAV vectors within a limited time window following IdeS treatment, during which neutralizing antibody activity will have a net reduction. The time period of “within about 72 hours” represents an obvious optimization of timing based on the known effects of IdeS and does not impart a novel distinction to the claimed method.
Accordingly, the combination of the cited references would have rendered the claimed method obvious to a person of ordinary skill in the art at the time of the application, and applicants’ arguments do not overcome the rejection under 35 U.S.C. 103.
Claim Rejections - 35 USC § 112(a)
Claims 98-99 remains rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter, which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims” and “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112, para. 1, as lacking adequate written description”. According to MPEP § 2163.I.B, “While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure” and “The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117”.
Amended claim 98-99 recite:
Claim 98. “The method of claim 78, wherein: the at least one disease comprises hemophilia A or hemophilia A with inhibitory antibodies; the at least one recombinant AAV vector encodes at least one Factor VIII polypeptide; and the administration of the at least one AAV vector results in expression of the at least one Factor VIII polypeptide in an amount that is greater than 1-3 ng/mL in the plasma of the human.
Claim 99. “The method of claim 78, wherein: the at least one disease comprises hemophilia B or hemophilia B with inhibitory antibodies; the at least one recombinant AAV vector encodes at least one Factor VIII polypeptide; and the administration of the at least one AAV vector results in expression of the at least one Factor VIII polypeptide in an amount that is greater than 1-3 ng/mL in the plasma of the human"
The response dated 09-19-2025 at page 12 indicates support for the new claim as follows:
“These amendments are supported by paragraph [0286] of the specification which states: "FVIII and FIX levels in normal humans are about 150-200 ng/mL plasma, but may be less ( e.g., range of about 100-150 ng/mL) or greater ( e.g., range of about 200-300 ng/mL) and still considered normal, due to functional clotting as determined, for example, by an activated partial thromboplastin time (aPTT) one-stage clotting assay. Thus, a therapeutic effect can be achieved such that the total amount of FVIII or FIX in the subject/human is greater than 1% of the FVIII or FIX present in normal subjects/humans. e.g. 1% of 100-300 ng/mL." (emphasis added)”.
However, this percentage is in the context of a blood coagulation factor concentration that is greater than 1% of total factor concentration found in a normal individual and does not support one Factor VIII polypeptide concentration in an amount that is greater than 1-3 ng/mL occurring following administration of an rAAV in a human subject within about 72 hours after administration of the IdeS polypeptide.
Moreover, with respect to claim 99, a thorough search of the art pertaining to hemophilia B and Factor VIII as a therapeutic provided no evidence that such therapy exists or would be useful. A recent review from Herzog et al. (Herzog RW et al., Mol Ther. 2025) on Hemophilia gene therapy shows that hemophilia B was well characterized in the art as being a disease of Factor FIX deficiency (not associated with FVIII deficiency). Although clinical trials as early as 1999 and multiple studies were performed to investigate the efficacy of AAV vectors encoding FIX or modified FIX treatment for hemophilia B, no studies showing the use of AAV vectors encoding FVIII to treat Hemophilia B were performed, let alone that administering to a human a recombinant AA V vector encoding FVIII within about 72 hours after administration of the IdeS polypeptide treats Hemophilia B (Pg. 2015, Section: Gene Therapy for Hemophilia-Introduction, from 2nd Paragraph).
Considering the lack of predictability provided by the specification and art for the full scope of the claimed limitations in claims 98-99 it is likely that Applicant did not possess the invention as claimed at the time of filing.
Additionally, considering that hemophilia B was characterized as a factor FIX deficiency and subsequent studies with respect to treatment focus on providing increased or modified factor FIX and the lack of predictability and support provided by the specification, it is likely the applicant did not possess the invention as recited in claim 99.
The instant disclosure does set forth any particular direction about how the limitation finds support in the disclosure of any of the priority documents. Thus, the amended claims include impermissible New Matter.
Conclusion
Claims 78-101 are rejected.
THIS ACTION IS MADE FINAL. 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 KODYE LEE ABBOTT whose telephone number is (703)756-1111. The examiner can normally be reached M-F 8-5.
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/KODYE LEE ABBOTT/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634