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 .
DETAILED ACTION
Disposition of Claims
Claims 1-2, 5, 7, 12, 15, 21, 23-25, 46, 48, 50-52, 68, 88-95, 97, 99, and 106-111 were pending. Claims 3-4, 6, 8-11, 13-14, 16-20, 22, 26-45, 47, 49, 53-87, 96, 98, and 100-105 are cancelled. Amendments to claims 1-2, 7, 12, 15, 23-24, 97, 99, and 106-111 are acknowledged and entered. Claims 1-2, 5, 7, 12, 15, 21, 23-25, 46, 48, 50-52, 88-95, 97, 99, and 106-111 will be examined on their merits.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US2020/0164008A1, Published 05/28/2020.
Response to Arguments
Applicant's arguments filed 04/07/2026 regarding the previous Office action dated 10/07/2025 have been fully considered. If they have been found to be persuasive, the objection/rejection has been withdrawn below. Likewise, if a rejection/objection has not been recited, said rejection/objection has been withdrawn. If the arguments have not been found to be persuasive, or if there are arguments presented over art that has been utilized in withdrawn rejections but utilized in new rejections, the arguments will be addressed fully with the objection/rejection below.
Claim Objections
Claim 23 is objected to because of the following informalities: “elected” at line 1 should be “selected”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b); Second Paragraph
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claims 97 and 99 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claims 1 and 2 and dependent claims 5, 7, 12, 15, 21, 23-25, 46, 48, 50-52, 68, 88-95, 97, 99, and 106-111 thereof rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claims.
(New rejection – necessitated by amendment.) Claim 7 is 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 the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 7 was amended to recite four conditions labeled (i)-(iv). However, after option (ii) and before option (iii), the conjunction “or” is used, but then after option (iii) and before option (iv), the conjunction “and” is used. From the wording of the claim, it is unclear if items (i)-(iv) are alternate embodiments, or if items (iii) and (iv) are somehow supposed to be considered together.
As the metes and bounds of the claim are unclear, claim 7 is rejected on the grounds of being indefinite.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to a method of administering a recombinant adeno-associated viral (rAAV) vector to a human, wherein said rAAV vector comprises:
(A) a capsid, and
(B) a rAAV recombinant nucleic acid comprising a heterologous polynucleotide that either (i) encodes for a first protein: or (ii) transcribes a nucleic acid that inhibits, decreases or reduces expression of a second protein,
said method comprising:
(a) removing a pre-apheresis blood product from said human,
(b) passing said pre-apheresis blood product through a sterile AAV binding antibody affinity matrix comprising an empty capsid comprising said capsid in the absence of said heterologous polynucleotide, and said capsid has a serotype of either AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV 11, AAV12, Rh10, Rh74, or AAV-2i8; or comprises a VP1 of SEQ ID NO: 1 or a VP1 of SEQ ID NO:2 to produce a post-apheresis blood product comprising a reduced amount of antibodies binding said rAAV vector compared to said pre-apheresis blood product;
(c) infusing said post-apheresis blood product to said human; and
(d) administering said rAAV vector to said human.
Claim 2 is drawn to a method of administering a recombinant adeno-associated viral (rAAV) vector to a human, wherein said rAAV vector comprises:
(A) a capsid, and
(B) a rAAV recombinant nucleic acid comprising a heterologous polynucleotide that either
(i) encodes for a first protein; or
(ii) transcribes a nucleic acid that inhibits, decreases or reduces expression of a second protein,
said method comprising:
(a) removing a pre-apheresis blood product from said human,
(b) passing said pre-apheresis blood product through a sterile AAV binding antibody affinity matrix comprising an empty capsid comprising said capsid in the absence of said heterologous polynucleotide, and said capsid has a serotype of either AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV 11, AAV12, Rh10, Rh74, or AAV-2i8; or comprises a VP1 of SEQ ID NO: 1 or a VP1 of SEQ ID NO:2 to produce a post-apheresis blood product comprising a reduced amount of antibodies binding said rAAV vector compared to said pre-apheresis blood product;
(c) infusing said post-apheresis blood product to said human and
(d) administering said rAAV vector to said human, wherein either:
(i) said pre-apheresis blood product has an IgG titer for said capsid of about 1:1000 and said step (d) administering is about 1 hour after said step (c);
(ii) said pre-apheresis blood product has an IgG titer for said capsid of about 1:300 and said step (d) administering is about 3 hour after said step (c);
(iii) said pre-apheresis blood product has an IgG titer for said capsid of about 1:100 and said step (d) administering is about 12 hours after said step (c); or
(iv) said pre-apheresis blood product has an IgG titer for said capsid of about 1:30 and said step (d) administering is about 24 hours after said step (c).
Further limitations on the method of claim 1 and/or 2 are wherein the AAV binding antibody affinity matrix is disposed within a column, apparatus, chamber, device, filter, cartridge, tube having an inlet and an outlet for extracorporeal or intracorporeal removal or depletion of rAAV vector binding antibodies from the pre-apheresis blood product upon contact with the AAV binding antibody affinity matrix (claim 5), wherein, either:
(i) said pre-apheresis blood product has an IgG titer for said capsid up to 1:1000 and said step (d) administering is up to 1 hour after said step (c);
(ii) said pre-apheresis blood product has an IgG titer for said capsid up to 1:300 and said step (d) administering is up to 3 hour after said step (c); or
(iii) said pre-apheresis blood product has an IgG titer for said capsid up to 1:100 and said step (d) administering is up to 12 hours after said step (c); and
(iv) said pre-apheresis blood product has an IgG titer for said capsid up to 1:30 and said step (d) administering is up to 24 hours after said step (c) (claim 7); wherein the said capsid is selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, Rh10, and Rh74 (claim 12); wherein said capsid is AAV8 (claim 15); wherein the substrate and/or column, apparatus, chamber, device, filter, cartridge, or tube is configured from plastic or glass (claim 21); wherein said capsid is selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, Rh10, and Rh74 (claim 23); wherein said capsid is AAV8 (claim 24); wherein 20% or more of the rAAV vector binding antibodies present in the pre-apheresis blood product are removed (claim 25); further comprising analyzing a sample from the subject taken after step (c) for the amount of rAAV vector binding antibodies present in the sample (claim 46), wherein the blood product is plasma (claim 48); wherein the human has a disease is caused by lost or reduced expression of a gene that encodes the first protein and the heterologous nucleic acid encodes said first protein (claim 50); wherein the disease is a blood clotting disorder (claim 51); wherein the disease is hemophilia A, hemophilia A with inhibitory antibodies, hemophilia B, a deficiency in any coagulation Factor: VII, VIII, IX and X, XI, V, XII, II, von Willebrand factor, or a combined FV/FVIII deficiency, or thalassemia, vitamin K epoxide reductase C1 deficiency or gamma-carboxylase deficiency (claim 52); and wherein step (a) and/or step (c) are performed two or more times (claim 68); and wherein the subject is a human (claim 69), wherein the disease is cystic fibrosis (claim 88); wherein disease is a bleeding disorder that is either hemophilia A with or without inhibitors or hemophilia B with or without inhibitors (claim 89); wherein the disease is anemia (claim 90); wherein the disease is Wilson's or Menkes disease (claim 91); wherein the disease is a glycogen storage disease (claim 92), wherein the glycogen storage disease is Pompe disease (claim 93); wherein the disease is an RPE65 deficiency or choroideremia (claim 94); wherein the disease is a solid organ disease that affects brain, liver, kidney or heart (claim 95); wherein at least one structural protein of said empty capsid comprises the amino acid sequence of SEQ ID NO:1 (claim 97) or of SEQ ID NO: 2 (claim 99); wherein said pre-apheresis blood product has an IgG titer for said capsid of up to 1:1000 and said step (d) administering is up to 1 hour after said step (c)(claim 106); wherein said pre-apheresis blood product has an IgG titer for said capsid of up to 1:300 and said step (d) administering is up to 3 hour after said step (c)(claim 107); wherein said pre-apheresis blood product has an IgG titer for said capsid of up to 1:100 and said step (d) administering is up to 12 hours after said step (c) (claim 108); wherein said pre-apheresis blood product has an IgG titer for said capsid of up to 1:30 and said step (d) administering is up to 24 hours after said step (c)(claim 109); wherein said pre-apheresis blood product has an IgG titer for said capsid of about 1:1000 and said step (d) administering is 1 hour after said step (c)(claim 110); and wherein said pre-apheresis blood product has an IgG titer for said capsid of about 1:300 and said step (d) administering is 3 hour after said step (c)(claim 111).
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of claims 1-2, 5, 7, 12, 15, 21, 23-25, 46, 48, 50-52, 68, 88-95, and 106-111 under 35 U.S.C. 103 as being unpatentable over Ferreira (US20180169273A1, Pub. 06/21/2018, Priority 12/16/2016; CITED ART OF RECORD; hereafter “Ferreira”), and further in view of Nilsson (US20140284274A1; Pub. 09/25/2014; hereafter “Nilsson”) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claims 97 and 99 under 35 U.S.C. 103 as being unpatentable over Ferreira and Nilsson as applied to claims 1-2, 5, 7, 12, 15, 21, 23-25, 46, 48, 50-52, 68, 88-95, and 106-111 above, and further in view of High et. al. (US20190192693A1, Priority 09/02/2016; CITED ART OF RECORD; hereafter “High”) is withdrawn in light of the amendments to the claims.
(New rejection – necessitated by amendment.) Claims 1-2, 5, 7, 12, 15, 21, 23-25, 46, 48, 50-52, 88-95, and 106-111 are rejected under 35 U.S.C. 103 as being unpatentable over Bertin et. al. (US20200069790A1, Priority 03/02/2017; CITED ART OF RECORD; hereafter “Bertin”);in further view of
Ferreira (US20180169273A1, Pub. 06/21/2018, Priority 12/16/2016; CITED ART OF RECORD; hereafter “Ferreira”),
Nilsson (US20140284274A1; Pub. 09/25/2014; CITED ART OF RECORD; hereafter “Nilsson”), and
McNeil (US20140074007A1; Pub. 03/13/2014, CITED ART OF RECORD; hereafter “McNeil”).
The Prior Art
Bertin teaches methods for removing undesired anti-AAV antibodies, preferably anti-AAV neutralizing antibodies, from a blood-derived composition (entire document; see abstract), wherein the method for removing anti-AAV antibodies from a blood-derived composition comprises contacting said blood-derived composition with at least one support onto which is grafted one or more affinity ligand(s) that specifically bind to anti-AAV antibodies, wherein said one or more affinity ligand is an AAV particle of one or more serotypes (reference claim 1), wherein the affinity ligand particle is an empty AAV particle, a full AAV particle, or a combination thereof (reference claim 2). Bertin teaches the support is a support suitable for clinical use; for instance, a support complying with regulatory safety provisions for devices to be used in purification/preparation process of biopharmaceuticals for animal and human use (¶[0052]). Bertin teaches the support may be a POROS™ support or a SEPHAROSE™ support (¶0019]), such as a SEPHAROSE™ support grafted with the affinity ligand via an NHS functional group (¶[0019][0055]). Further, Bertin teaches the method can be used to then allow for the treatment of a human in need thereof with AAV-vectored gene therapy, wherein said therapy can be applied to a variety of diseases, such as proliferative diseases, infectious diseases, genetic diseases, or neurological diseases (¶[0070]). Bertin notes specific examples, such as Pompe disease (¶[0070]; instant claims 92-93), Hepatitis B or C infections (¶[0070]), diabetes, cardiovascular diseases, Alzheimer’s (¶[0070]; instant claim 95), eye diseases, cystic fibrosis (¶[0070]; instant claim 88), and hemophilias (such as hemophilia B, ¶[0132]; instant claims 51-52, 89). Many of these diseases and disorders listed by Bertin are inherently caused by lost or reduced expression of a gene that encodes a protein important in said disorder, such as hemophilias and cystic fibrosis (instant claim 50). Bertin therefore teaches methods of apheresis to remove AAV-binding antibodies from blood products before administration of AAV-vectored gene therapy, wherein said AAV vector encodes a protein that provides or supplements for a function of a lost/underexpressed or overexpressed protein (e.g. cancers or metastatic diseases).
Bertin teaches the matrix may be within a column (¶[0017]; instant claims 5), and notes the different types of particles may comprise one or more of VP1, VP2, or VP3 from a number of AAV serotypes, such as AAV1, AAV2, AAV3, AAV4, AAVS, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, Rh10, Rh74, AAV-2i8, AAV2G9, -LK3, -DJ, and Anc80, (¶[0046]; instant claims 1, 2, 12, 15, 23-24). Bertin teaches the removal of the antibodies, wherein prior to removal there were more than 1:1000 anti-AAV antibodies and the reduction of antibodies was anywhere from 160x to 16,000x (Table 2; instant claims 25, 46). Bertin teaches in vivo evaluation of anti-AAV8 antibody positive human plasma after treatment with an AAV8 immunoaffinity column (¶[0185-0188]; Tables 3-4; instant claims 48). Bertin teaches the blood-derived composition is loaded several times onto the same support (reference claims 24, 26; ¶[0017]).
Bertin therefore teaches or suggests an AAV binding antibody affinity matrix attached to or immobilized on a substrate, wherein the affinity matrix comprises AAV particles, including empty AAV particles, for selectively removing anti-AAV antibodies from a blood-derived composition prior to AAV-mediated gene therapy. Bertin teaches that the support is suitable for clinical use, namely a support complying with regulatory safety provisions for devices to be used in purification/preparation process of biopharmaceuticals for animal and human use (¶[0052]). However, Bertin does not expressly teach that the AAV affinity matrix is sterile, nor does Bertin teach all of the diseases that may be treated by the subsequent AAV vectored therapy. Bertin teaches apheresis systems, but does not explicitly state that the matrix configured from plastic or glass. However, such limitations for said system would be obvious given the prior art, as taught by Ferreira, Nilsson, and McNeil.
Ferreira teaches the depletion of AAV-specific immunoglobulins from the blood (plasma) and subsequent treatment with rAAV vectors (entire document; see abstract.) Ferreira teaches a method of administering a recombinant adeno-associated virus (rAAV) to a subject, such as a human (¶[0037]), comprising depleting a subject's circulating immunoglobulins using immunoadsorption and subsequently administering a rAAV to the subject (reference claim 1) wherein the method utilizes a binding moiety attached to a matrix (¶[0051-0053]) wherein the binding moiety may be AAV epitopes, AAV proteins such as VP1, VP2, or VP3, or AAV empty capsids known to bind to anti-AAV antibodies (¶[0054], instant claims 1-2). Ferreira teaches the chromatography resin may be one that is commercially available that has AAV capsids from serotypes 1, 2, 3, or 5 (¶[0054]; instant claims 5, 12). Ferreira teaches these columns would be useful in methods where recombinant AAV (rAAV) comprises a therapeutic gene and is used for gene therapy in humans, wherein the gene therapy is to repair a gene defect by replacing or correcting deficiency, to treat an epigenetic disorder or disease, or to treat a condition associated with dysregulation of a gene product (¶[0003][0077]; instant claim 50). Said gene therapy methods can treat cystic fibrosis, hypercholesterolemia, Duchenne muscular dystrophy, hemophilia A or B, or the like, and would preferably encode such genes as factor IX, factor VIII, LPL, or AGXT (¶[0077]; instant claims 50-52, 88-89). Ferreira teaches further diseases in which this method could be used, such as cystic fibrosis (¶[0077]; instant claim 88), anemia (¶[0078]; instant claim 90); glycogen storage diseases such as Pompe disease (¶[0078]; instant claims 92-93), retinal degenerative diseases such as RPE65 deficiency or choroideremia (¶[0078; instant claim 94), copper or iron accumulation disorders such as Wilson’s or Menkes disease (¶[0078]; instant claim 91); and congestive heart failure (¶[0078]; instant claim 95). Ferreira teaches the blood may be treated to one or more cycles of processing within the columns (¶[0085]). Ferreira teaches the reduction of anti-AAV antibodies may be at least four fold up to at least 1000-fold, but may be even larger, and the levels of antibodies are measured in blood serum or plasma before and after apheresis (¶[0046]; Fig. 2; instant claims 46, 48). Ferreira teaches the use of known commercial apheresis units, such as LIFE 18™ Apheresis unit, which, absent evidence to the contrary, is made from plastic, has parts which are glass or plastic, and utilizes plastic, glass, or other clinically relevant consumables in the unit (¶[0052]; instant claim 21). Ferreira teaches performing the apheresis no more than 24 hours prior to the administration of a booster of the rAAV5 vaccine (¶[0089]).
McNeil teaches a method and apparatus for the isolation, modification and re-administration of a molecule or biomolecule, or a class of biomolecules, from the body fluid of a mammal via an extracorporeal closed circuit device (entire document; see abstract), namely for apheresis or plasmapheresis methods, including immunoadsorption for removal of immunoglobulins from plasma (¶[0004][0013][0026]). McNeil teaches the apparatus and methods may be used to capture and potentially modify a previously introduced foreign entity, for example, an immunogen or vaccine (¶[0067]). McNeil teaches extracorporeal closed-circuit devices for processing body fluid, including blood or plasma, wherein a body fluid is conducted through an inlet to a sequestering chamber containing a capture support capable of binding or reacting with a targeted component, and then returned to the subject through an outlet (¶[0013][0090-0091]; reference claims 1-41). McNeil teaches wherein the substrate and/or column, apparatus, chamber, device, filter, cartridge, or tube is configured from plastic or glass (¶[0163][0171][0174][0177][0209]; instant claim 21). McNeil teaches the capture support of the claimed device comprises a matrix material which may be porous or nonporous (reference claim 16; ¶[0011][0154][0185]). McNeil teaches the apparatus itself can be sterilized, in whole or in part, e.g., using irradiation or ethylene oxide, prior to use. Alternatively, various parts of the apparatus may be separately sterilized or prepared using aseptic technique, for later assembly using sterile connections or aseptic techniques (¶[0015][0048][0063][0166][0171-0172][0180][0198]; reference claim 15). Therefore, as McNeil teaches an apparatus for performing the plasmapheresis methods of Bertin and Ferreira, and teaches that the entire apparatus or individual parts or components thereof may be sterile or aseptic, and teaches that at least one part of the apparatus is a capture support which comprises an affinity matrix which may be coated with capture antigen molecules for depleting the host of antibodies (¶[0026]).
Nilsson teaches adsorbent and adsorbent systems for reducing or eliminating target components from blood or plasma by contacting the blood with a solid matrix having a ligand bound thereto (entire document; see abstract; ¶[0031]). Nilsson teaches the matrix may comprise agarose, cross-linked agarose, cellulose, dextran, silica, or synthetic organic polymers, and that the ligand may be covalently bound to the matrix, including by use of activated matrix chemistries such as NHS groups (¶[0008][0031][0063][0071]; reference claim 6). Nilsson further teaches that the adsorbent may be provided in a column, cartridge, filter, or other blood/plasma-containing device configuration, and that sterile blood or plasma filters, plastic linings, tubing, connectors, and other sterile fluid path components may be used in connection with the adsorbent system (¶[0015][0034]). Nilsson also teaches that production of the adsorbent having covalently bound ligand may be performed completely or partly according to good manufacturing practices (GMP) in clean rooms, and that the adsorbent or device may be sterilized, including by autocleaning or steam sterilization, with sterilization parameters selected and validated for the particular adsorbent and device (¶[0034]
Nilsson teaches that depending on the starting antibody titer that would be against the product or organ being delivered (in one example, Nilsson uses the amount of anti-A or anti-B antibody titers when a subject is receiving a blood group incompatible transplantation), the plasma volume of the patient, the filter (i.e. normally for an adult a plasma filter for treatment of an adult), and the quantity of adsorbent with ligands which the antibody desired for removal would bind, the expert could adjust the apheresis parameters, such as the flow rate of the blood line to ensure that more antibodies were removed from the blood product (¶[0036-0037][0080-0082]). Therefore, if the antibody titer/concentration in the patient against the product being delivered to the patient is high, then the flow rate would be lowered, to ensure the most amount of antibodies are cleared prior to delivery of the rAAV (¶[0015][0026][0029-0030][0042-0045]).
Given the teachings of Bertin and Ferreira, one of skill in the art would be aware of methods to perform anti-AAV plasmapheresis prior to recombinant AAV treatment. It would have been obvious to one of ordinary skill in the art to modify the methods taught by Bertin and Ferreira in order to sterilize the system utilized to perform apheresis, thereby ensuring the filtered blood product returned to the subject was sterile and safe, especially in light of the teachings of Nilsson and McNeil. One would have been motivated specifically to sterilize all of the system or parts of the system, such as the capture matrix, given the suggestion by McNeil that the apparatus for the apheresis could be entirely aseptic or one or more parts could be specifically sterilized, and given the teachings of Nilsson that components, such as the adsorbent matrix, could be autoclaved or otherwise sterilized.
Given the teachings of Nilsson, one of skill in the art would be apprised as to the mechanisms and parameters that may be adjusted to ensure the greatest amount of anti-AAV antibodies are removed from the subject prior to administering the therapeutic rAAV. According to Nilsson, one of those parameters subject to adjustment is the flow rate, meaning the flow rate can be reduced in order to ensure the most amount of antibodies are removed, and would be adjusted according to the pre-apheresis existing antibody titers. Therefore, where a pre-apheresis blood product contains a higher AAV-antibody titer, one of ordinary skill in the art would have understood that a greater amount of anti-AAV antibody must be bound and removed in order to reach the desired post-treatment titer or predetermined end product, and ti would have been obvious to correspondingly increase the apheresis or filtration treatment duration while adjusting the flow rate and/or adsorbent amount in order to achieve the desired reduction in anti-AAV antibodies. There would have been a reasonable expectation of success, given the knowledge that adjustment of these parameters was known to a skilled artisan, as taught by Ferreira and Nilsson. Therefore, given the combined teachings of Bertin, Ferreira, McNeil, and Nilsson, arriving at the limitations of instant claims 1-2, 7, 21, and 106-111 would be obvious to a skilled artisan.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Bertin in order to utilize plasmapheresis methods which comprised aseptic technique, such as sterile matrices, or to alter the flow rate or timing of the plasmapheresis method depending on the starting anti-AAV antibody titer. One would have been motivated to do so, given the suggestion by McNeil and Nilsson that apheresis methods could be performed using sterilized equipment, including sterilized matrices. There would have been a reasonable expectation of success, given the knowledge that such methods could clear a subject of anti-AAV antibodies prior to treatment for a number of disease wherein the AAV vector introduced heterologous proteins to the subject, as taught by Bertin and Ferreira, and also given the knowledge that depending on the starting AAV antibodies the flow rates could be adjusted accordingly, as taught by Nilsson. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
(New rejection – necessitated by amendment.) Claims 97 and 99 are rejected under 35 U.S.C. 103 as being unpatentable over Bertin, Ferreira, McNeil, and Nilsson as applied to claims 1-2, 5, 7, 12, 15, 21, 23-25, 46, 48, 50-52, 88-95, and 106-111 above, and further in view of High et. al. (US20190192693A1, Priority 09/02/2016; CITED ART OF RECORD; hereafter “High”.)
The Prior Art
The teachings of Bertin, Ferreira, McNeil, and Nilsson have been set forth supra. While Bertin and Ferreira teaches that a variety of serotypes and sequences of AAV capsids and VP1, VP2, and/or VP3 proteins thereof may be used in the apheresis methods, and that said capsids, empty capsids, and/or VP1-3 proteins may be bound to the matrix, Bertin and Ferreira both fail to explicitly teach SEQ ID NOs: 1-2. Nilsson and McNeil fail to cure this deficiency. However, a variety of sequences for AAV, especially rAAV, were known in the art at the time of filing and would be obvious to use in such a method, as evidenced by High.
High teaches methods and uses of treating a disease in a mammal through administration of rAAV comprising heterologous genes (entire document; see abstract; ¶[0049]). High teaches exemplary AAV capsid sequences, including SEQ ID NO: 1 (AAV-LK03 VP1 capsid protein, aligns with 100% identity to instant SEQ ID NO:2) and SEQ ID NO:2 (AAV 401 VP1 capsid protein, aligns with 100% identity to instant SEQ ID NO:1). High teaches these non-natural variants would be useful as their sequences would be distinct from other serotypes, and therefore would be useful for treatment purposes in individuals (¶[0060-0061]). However, it would be obvious to a skilled artisan that after the initial priming delivery/vaccination of the LK03 or 4-1 AAV serotypes, that one would likely need to use apheresis to clear the blood of antibodies which would subsequently be present and prevent the efficacy of subsequent booster administrations of the LK03 or 4-1 rAAV. Additionally, it would be helpful even prior to administration of these engineered rAAV to perform apheresis to ensure that any antibodies present in the patient that had any sort of cross-reactivity to the LK03 and/or 4-1 rAAV would be precleared from the subject to ensure the efficacy of rAAV delivery of the heterologous gene payload to the host. Therefore, given the teachings of Bertin, Ferreira, McNeil, and Nilsson, and High, a skilled artisan would find it obvious to arrive at instant claims 97 and 99.
It would have been obvious to one of ordinary skill in the art to modify the methods taught by Bertin, Ferreira, McNeil, and Nilsson in order to deliver a variety of genes either lost or upregulated in genetic disorders, thereby providing therapeutic options to treat said disorders, and to utilize apheresis to preclear the subject’s blood of any potential anti-AAV interfering antibodies. One would have been motivated to do so, given the suggestion by High to use AAV gene therapy to treat disorders, and to use rAAV that would have lower seroprevalence in the host. There would have been a reasonable expectation of success, given the knowledge that AAV gene therapy methods could be more successfully employed after removing AAV-specific antibodies prior to the AAV gene therapy vector treatment, as taught by Ferreira, and also given the knowledge that engineering AAV vectors to be less immunogenic and to encode proteins important to treat diseases had been suggested in the art, as taught by High. Thus the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to Arguments
Applicant’s arguments, filed 04/07/2026, with respect to the rejection(s) of the claim(s) under 35 USC 103 in view of Ferreira and Nilsson have been fully considered and are persuasive in light of the amendments to the claims. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Bertin and McNeil. The arguments regarding Ferreira and Nilsson will be addressed as applicable herein.
Applicant argues that the amendments to the claims specifically requiring the use of empty capsids was not taught by Ferreira or Nilsson, and that the benefit of using empty capsids was demonstrated by the third party art Bertin. While the Office notes that Ferreira teaches the use of empty capsids as an option, the referenced teachings of Bertin are a better primary reference as they demonstrate the safety and efficacy of using empty vector as the capture agent for antibody. Therefore, in light of the amendments to the claims, the teachings of Bertin were incorporated into the obviousness rejection to fully support that the use of only empty capsids was supported by the prior art, as evidenced by Bertin.
Applicant then argues that Nilsson includes descriptions of a variety of factors to take account for the flow that are independent of the pre-apheresis IgG capsid antibody titer. Applicant’s argument is not persuasive because the claim limitation merely recites adjusting the apheresis or filtration method based on the pre-apheresis anti-capsid IgG titer, such that higher starting titers require a longer method. Bertin teaches removal of anti-AAV antibodies using an AAV-particle-grafted affinity support. Nilsson teaches that blood/plasma adsorption methods are operated until the concentration of the target component reaches a predetermined value, and that the flow rates, amount of adsorbent, contact time, treatment time, treatment volume, pressure, filter size, and filter type are selected based on the desired treatment effect, patient size, and volume to be treated. A higher starting anti-AAV capsid IgG titer necessarily presents a greater amount of target antibody to be removed to reach the same target endpoint. Accordingly, one of ordinary skill in the art would have found it obvious to increase treatment duration or otherwise adjust flow rate, contact time, and/or processed volume as taught by Nilsson when the pre-apheresis anti-AAV capsid IgG titer is higher, because those parameters were known result-effective variables for achieving the desired antibody reduction. Therefore, this line of argument is not persuasive.
Applicant further argues that High fails to cure the deficiencies of Ferreira and Nilsson. Bertin and McNeil were utilized to cure the deficiencies of Ferreira and Nilsson, and High was utilized to cure the deficiency of none of the references specifically teaching the known AAV sequences in the art. Therefore, this argument is not persuasive to the current rejections.
For at least these reasons, the claims are still determined to be obvious in view of the prior art.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Masat E, et. al. Discov Med. 2013 Jun;15(85):379-89. Teaches repeated cycles of plasmapheresis are effective in lowering anti-AAV Nab with low, but not high, Nab titers. Not utilized as rejection would be redundant to those set forth supra.
Bertin B, et. al. Sci Rep. 2020 Jan 21;10(1):864. Post-filing art related to the instant claims to describe state of the art and provide references.
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 RACHEL B GILL whose telephone number is (571)272-3129. The examiner can normally be reached on M to F 8:00 AM to 5:00 PM Eastern.
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/RACHEL B GILL/Primary Examiner, Art Unit 1671
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