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 .
Status of the Claims
Claims 1, 3-8, 10-14, 32-42 are pending.
Claims 1, 10-13, and 32-35 are newly amended.
Claims 36-42 are newly added.
Due to the amendments of claims 10-13 and 42 which brings the methods within the same scope as claims 1, 3-8, 14, 32-41, upon reconsideration, the species requirement is withdrawn and the claims are rejoined.
Claims 1, 3-8, 10-14, 32-42 have been examined on their merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn.
The rejection of claims 1-3, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Samulski (US20170128528A1, on IDs 01/27/2024) in view of Corti et al. (US20240058477A1, priority to 01/04/2021), Mezo et al. (US20110059889A1, on IDS 01/27/2024), and Delatycki et al. (Neurobiology and Disease, 2019, on IDS 01/27/2024) as evidenced by Buck et al. (International Journal of Molecular Science, 2020) is withdrawn in order to address the claims as amended.
The rejection of claims 4-5 under 35 U.S.C. 103 as being unpatentable over Samulski (US20170128528A1, on IDs 01/27/2024) in view of Corti et al. (US20240058477A1, priority to 01/04/2021), Mezo et al. (US20110059889A1, on IDS 01/27/2024), and Delatycki et al. (Neurobiology and Disease, 2019, on IDS 01/27/2024), as applied to claim 1 above, and further in view of Hordeaux et al. (US20210077553A1, priority to 10/23/2019) is withdrawn in order to address the claims as amended
The rejection of claim 6 under 35 U.S.C. 103 as being unpatentable over Samulski (US20170128528A1, on IDs 01/27/2024) in view of Corti et al. (US20240058477A1, priority to 01/04/2021), Mezo et al. (US20110059889A1, on IDS 01/27/2024), and Delatycki et al. (Neurobiology and Disease, 2019, on IDS 01/27/2024), as applied to claim 1 above, and further in view Nambiar et al. (US20220249705A1, priority to 04/28/2020) is withdrawn in order to address the claims as amended.
The rejection of claims 7-9 under 35 U.S.C. 103 as being unpatentable over Samulski (US20170128528A1, on IDs 01/27/2024) in view of Corti et al. (US20240058477A1, priority to 01/04/2021), Mezo et al. (US20110059889A1, on IDS 01/27/2024), and Delatycki et al. (Neurobiology and Disease, 2019, on IDS 01/27/2024), as applied to claim 1 above, and further in view of and Guclu et al. (J Med Cases, 2014) and Limberis et al. (US20180243416A1) is withdrawn in order to address the claims as amended.
The rejection of claim 14 under 35 U.S.C. 103 as being unpatentable over Samulski (US20170128528A1, on IDs 01/27/2024) in view of Corti et al. (US20240058477A1, priority to 01/04/2021), Mezo et al. (US20110059889A1, on IDS 01/27/2024), and Delatycki et al. (Neurobiology and Disease, 2019, on IDS 01/27/2024), as applied to claim 1 above, and further in view Spiegel et al. (WO2021072269, priority to 10/09/2020) is withdrawn in order to address the claims as amended.
The rejection of claims 33-35 under 35 U.S.C. 103 as being unpatentable over Samulski (US20170128528A1, on IDs 01/27/2024) in view of Corti et al. (US20240058477A1, priority to 01/04/2021), Mezo et al. (US20110059889A1, on IDS 01/27/2024), and Delatycki et al. (Neurobiology and Disease, 2019, on IDS 01/27/2024), as applied to claim 1 above, and further in view Sah et al. (US2016059302) is withdrawn in order to address the claims as amended.
Claim Rejections - 35 USC § 103
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.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 10, 14, 32, 39, and 41-42 are rejected under 35 U.S.C. 103 as being unpatentable over Samulski (US20170128528A1, on IDs 01/27/2024, previously cited) in view of Corti et al. (US20240058477A1, priority to 01/04/2021, previously cited), Mezo et al. (US20110059889A1, on IDS 01/27/2024, previously cited), Delatycki et al. (Neurobiology and Disease, 2019, on IDS 01/27/2024, previously cited), Spiegel et al. (WO2021072269, priority to 10/09/2020, previously cited) as evidenced by Buck et al. (International Journal of Molecular Science, 2020, previously cited) and Kiessling et al. (Science Translational Medicine, 2017).
In regards to claims 1, 14, 39, and 41, Samulski teaches methods for treating patients with Friedrich’s Ataxia (FRDA) (claim 16). Samulski teaches that the method comprises administering a rAAV having a capsid and a vector genome comprising a FXN gene (claims 1, 7, and 9).
Additionally, Samulski teaches that an embodiment of the invention is to avoid neutralizing antibodies in these patients (paragraph [0138]).
Specifically, Samulski teaches, “[T]he rAAV of the invention can be co-administered with empty capsids (i.e., a virus capsid that does not contain a nucleic acid molecule) comprising the same, or a different, capsid protein as the rAAV-FXN vector. This is because one skilled in the art would understand that co-administration of empty capsids may decrease an immune response, e.g., a neutralizing response, the rAAV of the invention. That is, the empty capsid may serve as a decoy allowing the rAAV-FXN vector to avoid a neutralizing antibody (Nab) immune response” (paragraph [0138]).
Thus, in this embodiment, the patients not only have neutralizing antibodies to an rAAV, but they also must also must at least have a neutralizing antibody titer (a concentration of the neutralizing antibody in the blood).
The difference between the method of Samulski and the claimed invention is that the FXN gene of Samukski has a different sequence to the claimed sequences of SEQ ID NOs: 3 or 2, and Samulski does not explicitly teach steps of co-administering a ligand which inhibits binding of FcRn and IgG, wherein the ligand in an anti-FcRn immunoglobulin.
In regards to the sequences of the FXN gene, while the FXN gene sequence as taught by Samulski (SEQ ID NO: 3) does not have at least 95% identity with the claimed SEQ ID NO: 3 (instead, it appears to have about 90% identity, see International Search Report on 01/11/2021), sequences with at least 95% identity with the claimed SEQ ID NO: 3 were known in the art before the effective filing date.
Specifically, Corti teaches FXN gene sequence (SEQ ID NO: 2) that has 97.2% identity with the claimed SEQ ID NO 3 (see Search Results on 03/05/2026, 20260304_155654_us-18-260-786a-3.rnpbm, Pending_Patents_NA_Main; Result no. 6).
Additionally, SEQ ID NO: 2, as taught by Corti results in a frataxin protein having a sequence that is 100% to the claimed instant SEQ ID NO: 2.
Applicant should note that that the successful cloning and sequencing of the cDNA encoding a known protein is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the cDNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009).
In the instant case, a person of ordinary skill in the art would have been motivated to utilize the FXN gene sequence as disclosed by Corti because Corti teaches that the specific sequence is useful for use for treating a patient with Friedrich’s Ataxia (FRDA) comprising administering a rAAV having a capsid and a vector genome (polynucleotide) comprising a FXN gene (claims 1 and 28; paragraph [0079]).
Furthermore, because Corti teaches that the FXN nucleic acids can be provided as cDNA (paragraph [0047]) and because Samulski and Corti are in the same technical field of treating FRDA with rAAV vectors comprising a FXN gene, it could have been done with predictable results and a reasonable expectation of success.
As above, Samulski does not explicitly teach a step of administering a ligand which inhibits binding of a human neonatal Fc receptor (FcRn) and immunoglobulin G (IgG) (it is noted that this has been interpreted as meaning binding a FcRN to IgG).
However, methods for administering ligands which inhibit binding of an FcRn and IgG was known in art before the effective filing date.
Specifically, Mezo teaches that administering peptides (ligands) that block the binding of FcRn and IgG are useful for treating inflammatory diseases (Abstract; paragraphs [0009, 0046]; clam 117) and as taught by Delatycki, inflammation is important to the pathogenesis of FRDA and recommends therapies including modulators of inflammation (Abstract, p2; Inflammation in FRDA, p4).
Therefore, a person of ordinary skill in the art would have been motivated to include a step of administering ligands which inhibit binding of an FcRn and IgG in order to address the inflammation associated with the pathogenesis of FRDA. Furthermore, because Delatycki recommends therapies that modulate inflammation, and because Mezo teaches specific methods for administering peptides (ligands) that block the binding of FcRn and IgG for treating inflammatory diseases, it could have been done with predictable results and a reasonable expectation of success.
In regards to a ligand that is an anti-FcRn immunoglobulin, such as rozanolixizumab specifically (which as evidenced by Kiessling is a well-known humanized monoclonal antibody designed to block FcRn, Title, Abstract, p1), a person of ordinary skill in the art would have been motivated to select rozanolixizumab because Spiegel teaches that rozanolixizumab is suitable known FcRn antagonist (p138, claim 3) to promote or enhance degradation of circulating proteins such as IgG specifically (Abstract; Background of the Disclosure, p1). Furthermore, because rozanolixizumab is a known suitable FcRn antagonist, it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 3, Samulski teaches that the rAAV vector can comprise a 5’ and 3’ ITRs, introns, the FXN gene, and a poly A (claims 1, 7, and 9; paragraphs [0042 and 0089-0091]).
In regards to promoters, Samulski teaches that the promoter can be a CBA promoter or a CBh, which is a promoter derived from the chicken-actin (CBA) gene and cytomegalovirus (CMV) enhancer (paragraphs [0089-0090]). As evidenced by Buck, CB7 is a shortened CMV early enhancer element and a chicken β-actin promoter (p8, second paragraph) and appears to be the same as CBA (“CBA aka CB7”) (p10, Ubiquitous Promoters in rAAV-Vectors) or at least is an art recognized equivalent for the same purpose (see MPEP 2144.06).
In regards to claims 10 and 42, Samulski teaches methods for treating patients with Friedrich’s Ataxia (FRDA) (claim 16). Samulski teaches that the method comprises administering a rAAV having a capsid and a vector genome comprising a FXN gene (claims 1, 7, and 9).
Additionally, Samulski teaches that an embodiment of the invention is to avoid neutralizing antibodies in these patients (paragraph [0138]).
Specifically, Samulski teaches, “[T]he rAAV of the invention can be co-administered with empty capsids (i.e., a virus capsid that does not contain a nucleic acid molecule) comprising the same, or a different, capsid protein as the rAAV-FXN vector. This is because one skilled in the art would understand that co-administration of empty capsids may decrease an immune response, e.g., a neutralizing response, the rAAV of the invention. That is, the empty capsid may serve as a decoy allowing the rAAV-FXN vector to avoid a neutralizing antibody (Nab) immune response” (paragraph [0138]).
Thus, in this embodiment, the patients not only have neutralizing antibodies to an rAAV, but they also must also must at least have a neutralizing antibody titer (a concentration of the neutralizing antibody in the blood).
Samulski teaches that the modified nucleic acid may be administered by at least two routes including both intravenous administration and directly into tissues (paragraphs [0144-0150]).
Additionally, Samulski and identifies the dentate nucleus as a tissue containing frataxin (paragraph [0190-0192]), and therefore, intraparenchymal administration (into the dentate nucleus) would have been an obvious embodiment.
The difference between the method of Samulski and the claimed invention is that the FXN gene of Samukski has a different sequence to the claimed sequences of SEQ ID NOs: 3 or 2, and Samulski does not explicitly teach steps of co-administering a ligand which inhibits binding of FcRn and IgG, wherein the ligand in an anti-FcRn immunoglobulin.
In regards to the sequences of the FXN gene, while the FXN gene sequence as taught by Samulski (SEQ ID NO: 3) does not have at least 95% identity with the claimed SEQ ID NO: 3 (instead, it appears to have about 90% identity, see International Search Report on 01/11/2021), sequences with at least 95% identity with the claimed SEQ ID NO: 3 were known in the art before the effective filing date.
Specifically, Corti teaches FXN gene sequence (SEQ ID NO: 2) that has 97.2% identity with the claimed SEQ ID NO 3 (see Search Results on 03/05/2026, 20260304_155654_us-18-260-786a-3.rnpbm, Pending_Patents_NA_Main; Result no. 6).
Additionally, SEQ ID NO: 2, as taught by Corti results in a frataxin protein having a sequence that is 100% to the claimed instant SEQ ID NO: 2.
Applicant should note that that the successful cloning and sequencing of the cDNA encoding a known protein is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the cDNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009).
In the instant case, a person of ordinary skill in the art would have been motivated to utilize the FXN gene sequence as disclosed by Corti because Corti teaches that the specific sequence is useful for use for treating a patient with Friedrich’s Ataxia (FRDA) comprising administering a rAAV having a capsid and a vector genome (polynucleotide) comprising a FXN gene (claims 1 and 28; paragraph [0079]).
Furthermore, because Corti teaches that the FXN nucleic acids can be provided as cDNA (paragraph [0047]) and because Samulski and Corti are in the same technical field of treating FRDA with rAAV vectors comprising a FXN gene, it could have been done with predictable results and a reasonable expectation of success.
As above, Samulski does not explicitly teach a step of administering a ligand which inhibits binding of a human neonatal Fc receptor (FcRn) and immunoglobulin G (IgG) (it is noted that this has been interpreted as meaning binding a FcRN to IgG).
However, methods for administering ligands which inhibit binding of an FcRn and IgG was known in art before the effective filing date.
Specifically, Mezo teaches that administering peptides (ligands) that block the binding of FcRn and IgG are useful for treating inflammatory diseases (Abstract; paragraphs [0009, 0046]; clam 117) and as taught by Delatycki, inflammation is important to the pathogenesis of FRDA and recommends therapies including modulators of inflammation (Abstract, p2; Inflammation in FRDA, p4).
Therefore, a person of ordinary skill in the art would have been motivated to include a step of administering ligands which inhibit binding of an FcRn and IgG in order to address the inflammation associated with the pathogenesis of FRDA. Furthermore, because Delatycki recommends therapies that modulate inflammation, and because Mezo teaches specific methods for administering peptides (ligands) that block the binding of FcRn and IgG for treating inflammatory diseases, it could have been done with predictable results and a reasonable expectation of success.
In regards to a ligand that is an anti-FcRn immunoglobulin, such as rozanolixizumab specifically (which as evidenced by Kiessling is a well-known humanized monoclonal antibody designed to block FcRn, Title, Abstract, p1), a person of ordinary skill in the art would have been motivated to select rozanolixizumab because Spiegel teaches that rozanolixizumab is suitable known FcRn antagonist (p138, claim 3) to promote or enhance degradation of circulating proteins such as IgG specifically (Abstract; Background of the Disclosure, p1). Furthermore, because rozanolixizumab is a known suitable FcRn antagonist, it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 32, Samulski teaches that administration may be intravenous (paragraph [0139]).
Therefore, the combined teachings of Samulski, Corti, Mezo, Delatycki, and Spiegel renders the invention unpatentable as claimed.
Claims 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Samulski (US20170128528A1, on IDs 01/27/2024, previously cited) in view of Corti et al. (US20240058477A1, priority to 01/04/2021), Mezo et al. (US20110059889A1, on IDS 01/27/2024, previously cited), Delatycki et al. (Neurobiology and Disease, 2019, on IDS 01/27/2024, previously cited), and Spiegel et al. (WO2021072269, priority to 10/09/2020, previously cited) as applied to claim 1 above, and further in view of Hordeaux et al. (US20210077553A1, priority to 10/23/2019, previously cited).
In regards to claims 4-5, Corti teaches that FRDA is associated with pathological conditions in the dorsal root ganglia (DRG) (paragraph [0035]).
Corti also teaches that rAAV vectors for treating patients with FRDA (claims 1 and 28; paragraph [0079]) can comprise sequences which facilitate expression of a transgene including silencers (paragraph [0074], miRNAs are a known type of silencer), but is silent about miRNAs specifically.
However, as taught by Hordeaux, delivering AAV vectors to the central nervous system of subjects is associated with DRG toxicity, but that introduced miRNA sequences reduces toxicity (paragraphs [0003-0008]; claims 17 and 29). Hordeaux teaches that the sequences can comprise at least two tandem repeats which may be the same (paragraph [0009-0008]).
Therefore, a person of ordinary skill in the art would have been motivated to include DRG-specific miRNA sequences in a vector genome targeting sequence in order to minimize toxicity in the region of the brain that is being treated.
Furthermore, because Hordeaux teaches that DRG-specific miRNAs can be introduced with AAVs (claims 17 and 29) and because Corti teaches that AAV vectors can comprise sequences which facilitate expression of a transgene including silencers (of which miRNAs are a type), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Samulski, Corti, Mezo, Delatycki, Spiegel, and Hordeaux renders the invention unpatentable as claimed.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Samulski (US20170128528A1, on IDs 01/27/2024, previously cited) in view of Corti et al. (US20240058477A1, priority to 01/04/2021, previously cited), Mezo et al. (US20110059889A1, on IDS 01/27/2024, previously cited), Delatycki et al. (Neurobiology and Disease, 2019, on IDS 01/27/2024, previously cited), and Spiegel et al. (WO2021072269, priority to 10/09/2020, previously cited) as applied to claim 1 above, and further in view Nambiar et al. (US20220249705A1, priority to 04/28/2020, previously cited).
In regards to claims 6, Samulski teaches various AAVrh capsids (claim 9) and broadly teaches that the capsid may be “any other AAV now known or later discovered” (paragraph [0101]), but does not teach an AAVrh91 capsid specifically.
However, Nambiar teaches rAAV capsids, including specifically, an AAVrh91 capsid (AAVrh.91.93) (paragraphs [0004]). A person of ordinary skill in the art would have been motivated to use this rAAV capsid because Nambiar teaches that this capsid has reduced immunogenicity, increased storage stability, and increased transduction of a selected target tissue pampered to prior art AAVs (Abstract; paragraph [0050]).
Furthermore, because Nambiar teaches an AAVrh91 capsid, which can be used to tissues including brain and lung (paragraph [0053]) (well-known sites of FRDA pathology), and because Samulski broadly teaches that any capsid can be used, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Samulski, Corti, Mezo, Delatycki, Spiegel, and Nambiar renders the invention unpatentable as claimed.
Claims 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Samulski (US20170128528A1, on IDs 01/27/2024, previously cited) in view of Corti et al. (US20240058477A1, priority to 01/04/2021, previously cited), Mezo et al. (US20110059889A1, on IDS 01/27/2024, previously cited), Delatycki et al. (Neurobiology and Disease, 2019, on IDS 01/27/2024, previously cited), and Spiegel et al. (WO2021072269, priority to 10/09/2020, previously cited) as applied to claim 1 above, and further in view of and Guclu et al. (J Med Cases, 2014, previously cited) and Limberis et al. (US20180243416A1, previously cited).
In regards to claims 7-8, as above, Samulski broadly teaches that the capsid may be “any other AAV now known or later discovered” (paragraph [0101]), but does not teach a AAVhu68 clade F capsid specifically.
It is well-known in the art that FRDA, in addition to targeting the brain (DRG specifically) also results in lung pathology. Indeed, as taught by Guclu, FRDA causes comorbidities such as restrictive lung disease (Introduction, p232).
In regards to rAAV capsids, Limberis teaches rAAV capsids, including specifically, a clade F AAVhu68 capsid (claim 17; paragraph [0037). A person of ordinary skill in the art would have been motivated to select a clade F AAVhu68 capsid because Limberis teaches that the vector has strong expression in the lung (paragraph [0018]) and therefore, this vector would be efficient for alleviating FRDA lung comorbidities such as restrictive lung disease.
Furthermore, because Limberis teaches a clade F AAVhu68 capsid, and because Samulski broadly teaches that any capsid can be used, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Samulski, Corti, Mezo, Delatycki, Spiegel, Guclu, and Limberis renders the invention unpatentable as claimed.
Claims 11-13 and 33-35 are rejected under 35 U.S.C. 103 as being unpatentable over Samulski (US20170128528A1, on IDs 01/27/2024, previously cited) in view of Corti et al. (US20240058477A1, priority to 01/04/2021, previously cited), Mezo et al. (US20110059889A1, on IDS 01/27/2024, previously cited), Delatycki et al. (Neurobiology and Disease, 2019, on IDS 01/27/2024, previously cited), and Spiegel et al. (WO2021072269, priority to 10/09/2020, previously cited) as applied to claim 1 above, and further in view Sah et al. (WO2016059302, previously cited).
In regards to claims 11-13 and 33-35, as above, Samulski teaches that administration may be intravenous (paragraph [0139]). Additionally, Samulski teaches that administration may be done directly into tissues (paragraph [0139]) and identifies the dentate nucleus as a tissue containing frataxin (paragraph [0190-0192]), and therefore, intraparenchymal administration (into the dentate nucleus) would have been an obvious embodiment.
Specifically, a person of ordinary skill in the art would have been motivated to administer into the dentate nucleus in order to treat FRDA at that specific site of frataxin dysregulation. Furthermore, Sah teaches AAV vectors can be administered to at least one site (unilaterally) or bilaterally (claim 10; paragraph [00282]), to the dentate nucleus (paragraph [00507]), and as above, Samulski teaches that administration can be done directly into tissues, it could have been done with predictable results and a reasonable expectation of success.
In regards to the timing of sequentially administering the rAAV within a 24hr period, Sah teaches that AAV particles can be co-administered with lapses of less than 24 hours (paragraph [00010]). A person of ordinary skill in the art would have been motivated to sequentially administer rAVV vectors in order to reduce patient stress.
Additionally, Applicant should note that according to MPEP 2144(IV)(C), the selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946); see also In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious).
Therefore, the combined teachings of Samulski, Corti, Mezo, Delatycki, Spiegel, and Sah renders the invention unpatentable as claimed.
Claim 36-38 are rejected under 35 U.S.C. 103 as being unpatentable over Samulski (US20170128528A1, on IDs 01/27/2024, previously cited) in view of Corti et al. (US20240058477A1, priority to 01/04/2021, previously cited), Mezo et al. (US20110059889A1, on IDS 01/27/2024, previously cited), Delatycki et al. (Neurobiology and Disease, 2019, on IDS 01/27/2024, previously cited), and Spiegel et al. (WO2021072269, priority to 10/09/2020, previously cited) as applied to claim 1 above, and further in view Calcedo et al. (J Infect Dis, 2009, on IDS 01/27/2024).
In regards to claims 36-38, while Samulski teaches that the patients have a neutralizing antibodies titer, Samulski is silent as to the measurement. However, in in vitro assays, Calcedo teaches that subpopulations can have neutralizing antibody titers of 1L20 to 1:80 (Statistical informatics and analysis, p3; Fig. 1, p11) which overlaps with the claimed ranges of greater than 1:5, 1:15, or 1:20 as in claims 36-38 respectively. A person of ordinary skill in the art would have been motivated to target these titer ratios in order to treat these subpopulations of patients. Furthermore, because as taught by Calcedo these are known subpopulations of patients whose neutralizing antibody titers can be measured, it could have been done with predicable results and a reasonable expectation of success.
Therefore, the combined teachings of Samulski, Corti, Mezo, Delatycki, Spiegel, and Calcedo renders the invention unpatentable as claimed.
Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Samulski (US20170128528A1, on IDs 01/27/2024, previously cited) in view of Corti et al. (US20240058477A1, priority to 01/04/2021, previously cited), Mezo et al. (US20110059889A1, on IDS 01/27/2024, previously cited), Delatycki et al. (Neurobiology and Disease, 2019, on IDS 01/27/2024, previously cited), and Spiegel et al. (WO2021072269, priority to 10/09/2020, previously cited) as applied to claim 1 above, and further in view High et al. (WO2015013313A2).
In regards to claim 40, in regards to determining the patient’s neutralizing antibodies, Samulski teaches that they follow WO2015013313A2 (referring to High, paragraph [0138] of Samulski), who teaches that it is known in the art that neutralizing antibodies are determined in in vitro assays (High at paragraph [0174]). A person of ordinary skill in the art would have been motivated to select this method in order to determine the level of neutralizing antibodies in a patient. Furthermore, because High teaches it is known in the art that neutralizing antibodies can be determined in vitro (paragraph [0174]) and Samulski incorporates High in regards to neutralizing antibodies, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Samulski, Corti, Mezo, Delatycki, Spiegel, and High renders the invention unpatentable as claimed.
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.
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Claims 1, 3-8, 10-14, 32-35, 39, and 42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 12,594,348B2 in view of Mezo et al. (US20110059889A1, on IDS 01/27/2024, previously cited), Delatycki et al. (Neurobiology and Disease, 2019, on IDS 01/27/2024, previously cited), Spiegel et al. (WO2021072269, priority to 10/09/2020, previously cited), Samulski (US20170128528A1, on IDs 01/27/2024, previously cited) and Corti et al. (US20240058477A1, priority to 01/04/2021, previously cited) as evidenced by Kiessling et al. (Science Translational Medicine, 2017).
Claims 36-38 and 40-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 12,594,348B2 in view of Mezo et al. (US20110059889A1, on IDS 01/27/2024, previously cited), Delatycki et al. (Neurobiology and Disease, 2019, on IDS 01/27/2024, previously cited), Spiegel et al. (WO2021072269, priority to 10/09/2020, previously cited), Samulski (US20170128528A1, on IDs 01/27/2024, previously cited), and Corti et al. (US20240058477A1, priority to 01/04/2021, previously cited) as evidenced by Kiessling et al. (Science Translational Medicine, 2017) as applied to claim 1 above, and further in view of Calcedo et al. (J Infect Dis, 2009, on IDS 01/27/2024).
While the instant claims and the claims of the patent not identical, they are not patentable distinct because the claims of both applications are drawn to methods for treating FRDA in a subject with a rAAV comprising an AAV capsid and a FXN gene targeted to human cells wherein the FXN gene comprises sequences with 100% identity SEQ ID NO: 3, claims 52 and 53) that encodes a frataxin protein that is 100% identical to the instant SEQ ID: NO 2 (see claims 1, 8, 17-19 of U.S. Patent No. 12,594,348B2 specifically).
The patent also discloses that the rAAV comprises, AAV2 5′ inverted terminal repeat (ITR), a CB7 promoter, a FXN gene, an intron, the FXN gene, a polyA, and an AAV2 3′ ITR (claim 2); administration of multiple tandem repeats to the DRG (claim 3); multiple same miRNA target sequences (claim 4); an AAVrh91 capsid (claim 5); an AAV clade F capsid (Claim 6); an AAVhu68 capsid (claim 7); unilateral or bilateral administration to the dentate nucleus (claims 12-14); and intravenous administration within 24hrs (claim 15).
The difference between the claims of the instant invention and the patent is that the patent does not specifically require co-administering a ligand which inhibits binding of FcRn and IgG, wherein said ligand is an anti-FcRn immunoglobulin and the patent does not require that the patient have neutralizing antibodies to a rAAV vector, wherein the patient has a neutralizing antibody titer to the AAV capsid.
However, methods for administering ligands which inhibit binding of an FcRn and IgG was known in art before the effective filing date.
Specifically, Mezo teaches that administering peptides (ligands) that block the binding of FcRn and IgG are useful for treating inflammatory diseases (Abstract; paragraphs [0009, 0046]; clam 117) and as taught by Delatycki, inflammation is important to the pathogenesis of FRDA and recommends therapies including modulators of inflammation (Abstract, p2; Inflammation in FRDA, p4).
Therefore, a person of ordinary skill in the art would have been motivated to include a step of administering ligands which inhibit binding of an FcRn and IgG in order to address the inflammation associated with the pathogenesis of FRDA. Furthermore, because Delatycki recommends therapies that modulate inflammation, and because Mezo teaches specific methods for administering peptides (ligands) that block the binding of FcRn and IgG for treating inflammatory diseases, it could have been done with predictable results and a reasonable expectation of success.
In regards to a ligand that is an anti-FcRn immunoglobulin, such as rozanolixizumab specifically (which as evidenced by Kiessling is a well-known humanized monoclonal antibody designed to block FcRn, Title, Abstract, p1), a person of ordinary skill in the art would have been motivated to select rozanolixizumab because Spiegel teaches that rozanolixizumab is suitable known FcRn antagonist (p138, claim 3) to promote or enhance degradation of circulating proteins such as IgG specifically (Abstract; Background of the Disclosure, p1). Furthermore, because rozanolixizumab is a known suitable FcRn antagonist, it could have been done with predictable results and a reasonable expectation of success.
In regards to administering to a patient having FRDA and neutralizing antibodies to a rAAV vector wherein the patient has a neutralizing antibody titer to the AAV capsid, Samulski teaches methods for treating patients with Friedrich’s Ataxia (FRDA) (claim 16). Samulski teaches that the method comprises administering a rAAV having a capsid and a vector genome comprising a FXN gene (claims 1, 7, and 9).
Additionally, Samulski teaches that an embodiment of the invention is to avoid neutralizing antibodies in these patients (paragraph [0138]).
Specifically, Samulski teaches, “[T]he rAAV of the invention can be co-administered with empty capsids (i.e., a virus capsid that does not contain a nucleic acid molecule) comprising the same, or a different, capsid protein as the rAAV-FXN vector. This is because one skilled in the art would understand that co-administration of empty capsids may decrease an immune response, e.g., a neutralizing response, the rAAV of the invention. That is, the empty capsid may serve as a decoy allowing the rAAV-FXN vector to avoid a neutralizing antibody (Nab) immune response” (paragraph [0138]).
Thus, in this embodiment, the patients not only have neutralizing antibodies to an rAAV, but they also must also must at least have a neutralizing antibody titer (a concentration of the neutralizing antibody in the blood).
A person of ordinary skill in the art would have been motivated to administer the rAAV vector to a patient with a neutralizing antibody titer in order to treat this known patient population. Furthermore, because Samulski teaches that FRDA patients with neutralizing antibody titers can be treated with rAAVs, it could have been done with predictable results and a reasonable expectation of success.
In regards to the concentrations of the neutralizing antibody titers, Samulski is silent as to the measurement. However, in in vitro assays, Calcedo teaches that subpopulations can have neutralizing antibody titers of 1L20 to 1:80 (Statistical informatics and analysis, p3; Fig. 1, p11) which overlaps with the claimed ranges of greater than 1:5, 1:15, or 1:20 as in claims 36-38 respectively. A person of ordinary skill in the art would have been motivated to target these titer ratios in order to treat these subpopulations of patients. Furthermore, because as taught by Calcedo these are known subpopulations of patients whose neutralizing antibody titers can be measured in vitro, it could have been done with predicable results and a reasonable expectation of success.
Response to Arguments
Applicant argues that combined references do not suggest the claims when considered as a whole (Remarks, p3).
Specifically, Applicant argues that Samulski does not suggest a method for treating patients having neutralizing antibodies (Remarks, p9). Instead, Applicant argues that the method of Samulski avoids neutralizing antibodies (Remarks, p9). Applicant argues that while Samulski refers to the problem of neutralizing antibodies in the context of rAAV gene delivery in paragraph [0138]), it suggests administration of empty decoy capsids (Remarks, p9). Therefore, Applicant argues that Samulski teaches away from the claimed invention (Remarks, p9).
Applicant’s arguments filed 06/24/2026 have been fully considered but are not found persuasive.
In regards to Applicant’s assertions regarding Samulski’s teachings on neutralizing antibodies, as discussed above, as explicitly taught by Samulski, “[T]he rAAV of the invention can be co-administered with empty capsids (i.e., a virus capsid that does not contain a nucleic acid molecule) comprising the same, or a different, capsid protein as the rAAV-FXN vector. This is because one skilled in the art would understand that co-administration of empty capsids may decrease an immune response, e.g., a neutralizing response, the rAAV of the invention. That is, the empty capsid may serve as a decoy allowing the rAAV-FXN vector to avoid a neutralizing antibody (Nab) immune response” (paragraph [0138]).
Thus, a “[T]he rAAV of the invention can be co-administered with . . . the same . . . capsid protein as the rAAV-FXN vector” is specifically an embodiment for treating “an immune response, e.g., a neutralizing response, the rAAV of the invention” as envisioned by Samulski. Therefore, Samulski does not teaches away from the claimed method as argued by Applicant.
Furthermore, in regards to empty capsids, Applicant’s arguments are not germane because not only is using the rAAV-FXN vector for treating a patient with neutralizing antibodies an embodiment of Samulski, but also the claims are drawn to a method “comprising” the steps as in claim 1 and therefore, are open ended and allow for steps such as using empty capsids.
In regards to the consideration of the claims as a whole, the limitations of the claims were prima facie obvious as discussed above.
As discussed above, Samulski teaches methods for treating patients with Friedrich’s Ataxia (FRDA) (claim 16). Samulski teaches that the method comprises administering a rAAV having a capsid and a vector genome comprising a FXN gene (claims 1, 7, and 9).
Additionally, Samulski teaches that an embodiment of the invention is to avoid neutralizing antibodies in these patients (paragraph [0138]).
Specifically, Samulski teaches, “[T]he rAAV of the invention can be co-administered with empty capsids (i.e., a virus capsid that does not contain a nucleic acid molecule) comprising the same, or a different, capsid protein as the rAAV-FXN vector. This is because one skilled in the art would understand that co-administration of empty capsids may decrease an immune response, e.g., a neutralizing response, the rAAV of the invention. That is, the empty capsid may serve as a decoy allowing the rAAV-FXN vector to avoid a neutralizing antibody (Nab) immune response” (paragraph [0138]).
Thus, in this embodiment, the patients not only have neutralizing antibodies to an rAAV, but they also must also must at least have a neutralizing antibody titer (a concentration of the neutralizing antibody in the blood).
The difference between the method of Samulski and the claimed invention is that the FXN gene of Samukski has a different sequence to the claimed sequences of SEQ ID NOs: 3 or 2, and Samulski does not explicitly teach steps of co-administering a ligand which inhibits binding of FcRn and IgG, wherein the ligand in an anti-FcRn immunoglobulin.
In regards to the sequences of the FXN gene, while the FXN gene sequence as taught by Samulski (SEQ ID NO: 3) does not have at least 95% identity with the claimed SEQ ID NO: 3 (instead, it appears to have about 90% identity, see International Search Report on 01/11/2021), sequences with at least 95% identity with the claimed SEQ ID NO: 3 were known in the art before the effective filing date.
Specifically, Corti teaches FXN gene sequence (SEQ ID NO: 2) that has 97.2% identity with the claimed SEQ ID NO 3 (see Search Results on 03/05/2026, 20260304_155654_us-18-260-786a-3.rnpbm, Pending_Patents_NA_Main; Result no. 6).
Additionally, SEQ ID NO: 2, as taught by Corti results in a frataxin protein having a sequence that is 100% to the claimed instant SEQ ID NO: 2.
Applicant should note that that the successful cloning and sequencing of the cDNA encoding a known protein is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the cDNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009).
In the instant case, a person of ordinary skill in the art would have been motivated to utilize the FXN gene sequence as disclosed by Corti because Corti teaches that the specific sequence is useful for use for treating a patient with Friedrich’s Ataxia (FRDA) comprising administering a rAAV having a capsid and a vector genome (polynucleotide) comprising a FXN gene (claims 1 and 28; paragraph [0079]).
Furthermore, because Corti teaches that the FXN nucleic acids can be provided as cDNA (paragraph [0047]) and because Samulski and Corti are in the same technical field of treating FRDA with rAAV vectors comprising a FXN gene, it could have been done with predictable results and a reasonable expectation of success.
As above, Samulski does not explicitly teach a step of administering a ligand which inhibits binding of a human neonatal Fc receptor (FcRn) and immunoglobulin G (IgG) (it is noted that this has been interpreted as meaning binding a FcRN to IgG).
However, methods for administering ligands which inhibit binding of an FcRn and IgG was known in art before the effective filing date.
Specifically, Mezo teaches that administering peptides (ligands) that block the binding of FcRn and IgG are useful for treating inflammatory diseases (Abstract; paragraphs [0009, 0046]; clam 117) and as taught by Delatycki, inflammation is important to the pathogenesis of FRDA and recommends therapies including modulators of inflammation (Abstract, p2; Inflammation in FRDA, p4).
Therefore, a person of ordinary skill in the art would have been motivated to include a step of administering ligands which inhibit binding of an FcRn and IgG in order to address the inflammation associated with the pathogenesis of FRDA. Furthermore, because Delatycki recommends therapies that modulate inflammation, and because Mezo teaches specific methods for administering peptides (ligands) that block the binding of FcRn and IgG for treating inflammatory diseases, it could have been done with predictable results and a reasonable expectation of success.
In regards to a ligand that is an anti-FcRn immunoglobulin, such as rozanolixizumab specifically (which as evidenced by Kiessling is a well-known humanized monoclonal antibody designed to block FcRn, Title, Abstract, p1), a person of ordinary skill in the art would have been motivated to select rozanolixizumab because Spiegel teaches that rozanolixizumab is suitable known FcRn antagonist (p138, claim 3) to promote or enhance degradation of circulating proteins such as IgG specifically (Abstract; Background of the Disclosure, p1). Furthermore, because rozanolixizumab is a known suitable FcRn antagonist, it could have been done with predictable results and a reasonable expectation of success.
Applicant argues that Mezo is not even concerned with treatment of FRDA and there is no disclosure of an anti-FcRN as a ligand in Mezo (Remarks, p10).
Applicant argues that Buck does not relate to the treatment of FRDA, but of ocular gene therapy, and there is no disclosure of an anti-FcRN ligand in this reference (Remarks, p10).
Applicant’s arguments filed 06/24/2026 have been fully considered but are not found persuasive.
In response to applicant's arguments against the references individually, 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).
As discussed above, while Samulski does not explicitly teach a step of administering a ligand which inhibits binding of a human neonatal Fc receptor (FcRn) and immunoglobulin G (IgG) (it is noted that this has been interpreted as meaning binding a FcRN to IgG), methods for administering ligands which inhibit binding of an FcRn and IgG was known in art before the effective filing date.
Specifically, Mezo teaches that administering peptides (ligands) that block the binding of FcRn and IgG are useful for treating inflammatory diseases (Abstract; paragraphs [0009, 0046]; clam 117) and as taught by Delatycki, inflammation is important to the pathogenesis of FRDA and recommends therapies including modulators of inflammation (Abstract, p2; Inflammation in FRDA, p4).
Therefore, a person of ordinary skill in the art would have been motivated to include a step of administering ligands which inhibit binding of an FcRn and IgG in order to address the inflammation associated with the pathogenesis of FRDA. Furthermore, because Delatycki recommends therapies that modulate inflammation, and because Mezo teaches specific methods for administering peptides (ligands) that block the binding of FcRn and IgG for treating inflammatory diseases, it could have been done with predictable results and a reasonable expectation of success.
In regards to a ligand that is an anti-FcRn immunoglobulin, such as rozanolixizumab specifically (which as evidenced by Kiessling is a well-known humanized monoclonal antibody designed to block FcRn, Title, Abstract, p1), a person of ordinary skill in the art would have been motivated to select rozanolixizumab because Spiegel teaches that rozanolixizumab is suitable known FcRn antagonist (p138, claim 3) to promote or enhance degradation of circulating proteins such as IgG specifically (Abstract; Background of the Disclosure, p1). Furthermore, because rozanolixizumab is a known suitable FcRn antagonist, it could have been done with predictable results and a reasonable expectation of success.
Applicant argues that none of Hordeaux, Nambiar, Guclu, Limberis, Speigel, Sah cure the deficiencies of Samulski (Remarks, p10-16).
Applicant’s arguments filed 06/24/2026 have been fully considered but are not found persuasive because Samulski is not deficient as discussed above.
Applicant argues that the instant claims and the claims of U.S. Patent no. 12,594,348 are patentably distinct (Remarks, p14-16). Specifically, Applicant argues that the claims of the patent do not contain claims directed to the method of treatment of therapeutic regimen as claimed (Remarks, p15-16). Additionally, argues that no part of the reference patent may be used as if it were prior art (Remarks, p15); that that the Examiner may only rely on a specification of a reference in specific contexts that are not met (Remarks, p15); and therefore, concludes that the Examiner’s relying on the specification is improper (Remarks, p15-16).
Applicant also argues that Limberis that the AAV could contain a gene other than the influenza antibodies (Remarks, p15).
Applicant’s arguments filed 06/24/2026 have been fully considered but are not found persuasive.
It is first noted that the Examiner has cited neither the instant specification nor the specification of U.S. Patent no. 12,594,348, and therefore, Applicant’s arguments regarding the use of specifications are not germane to the rejection and therefore, unpersuasive.
In regards to Limberis, the instant rejection does not rely on Limberis for any teaching, and therefore, Applicant’s arguments are moot.
In regards to Applicant’s arguments that the claims of the patent do not contain claims directed to the method of treatment of therapeutic regimen as claimed, Applicant’s arguments are unpersuasive.
As discussed above, while the instant claims and the claims of the patent not identical, they are not patentable distinct because the claims of both applications are drawn to methods for treating FRDA in a subject with a rAAV comprising an AAV capsid and a FXN gene targeted to human cells wherein the FXN gene comprises sequences with 100% identity SEQ ID NO: 3, claims 52 and 53) that encodes a frataxin protein that is 100% identical to the instant SEQ ID: NO 2 (see claims 1, 8, 17-19 of U.S. Patent No. 12,594,348B2 specifically).
The patent also discloses that the rAAV comprises, AAV2 5′ inverted terminal repeat (ITR), a CB7 promoter, a FXN gene, an intron, the FXN gene, a polyA, and an AAV2 3′ ITR (claim 2); administration of multiple tandem repeats to the DRG (claim 3); multiple same miRNA target sequences (claim 4); an AAVrh91 capsid (claim 5); an AAV clade F capsid (Claim 6); an AAVhu68 capsid (claim 7); unilateral or bilateral administration to the dentate nucleus (claims 12-14); and intravenous administration within 24hrs (claim 15).
The difference between the claims of the instant invention and the patent is that the patent does not specifically require co-administering a ligand which inhibits binding of FcRn and IgG, wherein said ligand is an anti-FcRn immunoglobulin and the patent does not require that the patient have neutralizing antibodies to a rAAV vector, wherein the patient has a neutralizing antibody titer to the AAV capsid.
However, methods for administering ligands which inhibit binding of an FcRn and IgG was known in art before the effective filing date.
Specifically, Mezo teaches that administering peptides (ligands) that block the binding of FcRn and IgG are useful for treating inflammatory diseases (Abstract; paragraphs [0009, 0046]; clam 117) and as taught by Delatycki, inflammation is important to the pathogenesis of FRDA and recommends therapies including modulators of inflammation (Abstract, p2; Inflammation in FRDA, p4).
Therefore, a person of ordinary skill in the art would have been motivated to include a step of administering ligands which inhibit binding of an FcRn and IgG in order to address the inflammation associated with the pathogenesis of FRDA. Furthermore, because Delatycki recommends therapies that modulate inflammation, and because Mezo teaches specific methods for administering peptides (ligands) that block the binding of FcRn and IgG for treating inflammatory diseases, it could have been done with predictable results and a reasonable expectation of success.
In regards to a ligand that is an anti-FcRn immunoglobulin, such as rozanolixizumab specifically (which as evidenced by Kiessling is a well-known humanized monoclonal antibody designed to block FcRn, Title, Abstract, p1), a person of ordinary skill in the art would have been motivated to select rozanolixizumab because Spiegel teaches that rozanolixizumab is suitable known FcRn antagonist (p138, claim 3) to promote or enhance degradation of circulating proteins such as IgG specifically (Abstract; Background of the Disclosure, p1). Furthermore, because rozanolixizumab is a known suitable FcRn antagonist, it could have been done with predictable results and a reasonable expectation of success.
In regards to administering to a patient having FRDA and neutralizing antibodies to a rAAV vector wherein the patient has a neutralizing antibody titer to the AAV capsid, Samulski teaches methods for treating patients with Friedrich’s Ataxia (FRDA) (claim 16). Samulski teaches that the method comprises administering a rAAV having a capsid and a vector genome comprising a FXN gene (claims 1, 7, and 9).
Additionally, Samulski teaches that an embodiment of the invention is to avoid neutralizing antibodies in these patients (paragraph [0138]).
Specifically, Samulski teaches, “[T]he rAAV of the invention can be co-administered with empty capsids (i.e., a virus capsid that does not contain a nucleic acid molecule) comprising the same, or a different, capsid protein as the rAAV-FXN vector. This is because one skilled in the art would understand that co-administration of empty capsids may decrease an immune response, e.g., a neutralizing response, the rAAV of the invention. That is, the empty capsid may serve as a decoy allowing the rAAV-FXN vector to avoid a neutralizing antibody (Nab) immune response” (paragraph [0138]).
Thus, in this embodiment, the patients not only have neutralizing antibodies to an rAAV, but they also must also must at least have a neutralizing antibody titer (a concentration of the neutralizing antibody in the blood).
A person of ordinary skill in the art would have been motivated to administer the rAAV vector to a patient with a neutralizing antibody titer in order to treat this known patient population. Furthermore, because Samulski teaches that FRDA patients with neutralizing antibody titers can be treated with rAAVs, it could have been done with predictable results and a reasonable expectation of success.
In regards to the concentrations of the neutralizing antibody titers, Samulski is silent as to the measurement. However, in in vitro assays, Calcedo teaches that subpopulations can have neutralizing antibody titers of 1L20 to 1:80 (Statistical informatics and analysis, p3; Fig. 1, p11) which overlaps with the claimed ranges of greater than 1:5, 1:15, or 1:20 as in claims 36-38 respectively. A person of ordinary skill in the art would have been motivated to target these titer ratios in order to treat these subpopulations of patients. Furthermore, because as taught by Calcedo these are known subpopulations of patients whose neutralizing antibody titers can be measured in vitro, it could have been done with predicable results and a reasonable expectation of success.
Conclusion
No claims are allowed.
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.
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