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
The text of those sections of Title 35, U.S. Code not included in this action can be found
in a prior Office action.
This Action is in response to the papers filed on May 22, 2026. Pursuant to the amendment filed on May 22, 2026, claims 119, 121-122, 124, 126-135, 137-139, 147-151 and 153-156 are currently pending of which claims 119 and 154 have been amended and claims 155 and 156 have been added. A restriction requirement was made FINAL in the Office Action dated August 12, 2024.
The examiner acknowledges receiving the Declaration under 37 C.F.R. § 1.1320 executed by Xiang Cui (herein “Cui Decl.”) that was filed on May 22, 2026.
Therefore, claims 119, 121-122, 124, 126-135, 137-139, 147-151 and 153-156 are currently under examination to which the following grounds of rejection are applicable.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on May 22, 2026 was filed. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Declaration under 37 CFR 1.132
The Affidavit under 37 CFR 1.132 filed by Xiang Cui on May 22, 2026 is insufficient to overcome the rejection of the claims based upon 35 U.S.C. as set forth in the last Office action for the reasons set forth below.
AFFIDAVIT (Cui Decl.) Summary
Scientist, Xiang Cui, who is an employee and Senior Manager of the Manufacturing Science and Technology Lab at Novartis Gene Therapies, is responsible for production of AAV products including Zolgensma, stating, “Zolgensma is an AAV vector-based gene therapy currently approved for the treatment of pediatric patients less than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene. It comprises a recombinant self-complementary AAV9, also referred to as "AVXS-101," containing a transgene encoding the human survival motor neuron (SMN) protein, under the control of a cytomegalovirus enhancer/chicken-β-actin hybrid promoter.” (Bullet 2).
Cui then designed and conducted a study to prepare Zolgensma according to the process detailed in Wright (WO 2011/094198 ("Wright"); the rejection applied herein is based on related application US US-2013/0072548-A1), a modified version of the Wright process to account for AAV9 as opposed to AAV2, in comparison to Process B of WO 2019/094253 which was the process used to “produce phase 3 clinical and commercial batches of Zolgensma.”(hereinafter “’253”). The ‘253 application is similar to the instant application as being assigned to Novartis. Cui then concludes “As explained below, the results of the study showed that while the Wright Process was unsuitable for AAV9 purification, even the Modified Wright Process still failed to produce AAV preparations with empty capsids and hcDNA levels below the maximum thresholds that I understand are claimed in the instant application. By contrast, Process B in the '253 Application produced Zolgensma products with substantially higher genomic AAV titers and substantially lower levels of empty capsids and hcDNA.” (Bullet 4). In summary, the Wright reference would not meet the claimed limitations in relation to the purity standards and vector concentrations as recited in the claims.
Response to Arguments
Maintained Objections/Rejections in response to Applicants’ arguments or amendments:
Claim Rejections - 35 USC § 103
Claims 119, 121, 124, 126, 127, 129-131, 137-139, 153, and 154 remain rejected and claim 156 is newly rejected under 35 U.S.C. 103 as being unpatentable over Kaspar et al. (US-2015/0252384-A1, of record) in view of Wright et al. (US-2013/0072548-A1; of record). This is a modified rejection necessitated by amendment of the claims in the response filed May 22, 2026.
Claim 119 is directed to a method of treating spinal muscular atrophy (SMA) in a human patient in need thereof, comprising administering intrathecally an AAV9 viral vector comprising a polynucleotide encoding a survival motor neuron (SMN) protein, wherein the AAV9 viral vector is administered at a dose of about 1 x 1013 vg - 5 x 1014 vg, wherein the AAV9 viral vector is administered in a pharmaceutical composition comprising at least one of the following:
a) less than about 5% empty capsid,
b) less than about 1.1x105 pg of residual hcDNA per 1.0x1013 vg of the AAV9 viral vector,
and c) less than about 4 ng of rHCP per 1.0x1013 vg of the AAV9 viral vector.
Kaspar teaches a method of treating spinal muscular atrophy (SMA) in a human patient in need thereof, comprising administering intrathecally a recombinant self-complementary AAV9 viral vector (“the invention provides methods of delivering a polynucleotide to the central nervous system of a patient in need thereof comprising intrathecal delivery of rAAV9 … to the patient, wherein the rAAV9 comprises a self-complementary genome including the polynucleotide… In some embodiments, the polynucleotide is a survival motor neuron (SMN) polynucleotide.”; “The neurological disease is, for example, a neurodegenerative disease such as spinal muscular atrophy” (par 0017-18); ““Treatment” comprises the step of administering via the intrathecal route an effective dose, or effective multiple doses, of a composition comprising a rAAV of the invention to an animal (including a human being) in need thereof.” (par 0032)) comprising a modified 5' AAV2 ITR, a chicken beta-actin (CB) promoter, a cytomegalovirus (CMV) immediate/early enhancer, a modified SV40 late 16S intron. a bovine growth hormone (BGH) polyadenylation signal, and an unmodified 3' AAV2 ITR, and a polynucleotide encoding a survival motor neuron (SMN) protein (par 0043 and 0061 describes all the listed elements; Instant SEQ ID NO: 1 is identical to Kaspar SEQ ID NO: 1 as seen below, the full alignment has been provided in the Office Action dated August 1, 2024 (Result #2)). The instant specification describes in paragraph 0061 and with Table 1 that instant SEQ ID NO: 1 contains the aforementioned elements cited in claim 119.
In reference to the dosage, wherein the AAV9 viral vector is administered at a dose of about 1 x 1013 vg - 5 x 1014 vg, Kaspar teaches “These dosages of rAAV may range from about… about 1×1012, about 3×1012, about 1×1013, about 3×1013, about 1×1014, about 3×1014, … or more viral genomes per kilogram body weight.”; “Dosages may also be expressed in units of viral genomes (vg)” (par 0047)).
The instant Specification states, “The highest selected dose is up to 2.4 x 1014 vg delivered intrathecally. Doses up to 1.1 x 1014 vg/kg have been safely administered systemically (intravenously) to children weighing up to 8.4 kg (total dose 9.24 x 1014 vg). In addition, in preclinical studies, the intrathecal administration of scAAV9.CB.SMN was safe and well tolerated up to 14 months post injection in large non-human primates at a dose of 2 x 1013 vg/kg.” (para 0192 of the instant application).
Based on a child that weighs 8.4 kg according to the calculations of para 0192, a dosage of about 1 x 1013 vg - 5 x 1014 vg, as recited in claim 119, equates to 1.19 x 1012 to 5.95 x 1013 vg/kg, a range that is encompassed by Kaspar (par 0047). Moreover, Kaspar teaches the 14 months post injection in large non-human primates at a dose of 2 x 1013 vg/kg.
SEQ ID NO 1 alignment to Kaspar SEQ ID NO: 1:
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In reference to the claimed purity parameters, Kaspar teaches “The rAAV may be purified by methods standard in the art such as by column chromatography or cesium chloride gradients” and furthermore described the taught rAAV composition being comprised in a pharmaceutical composition with an acceptable carrier (par 0046).
Kaspar does not teach wherein the AAV9 viral vector is administered in a pharmaceutical composition comprising at least one of the following: a) less than about 5% empty capsid, b) less than about 1.1x105 pg of residual hcDNA per 1.0x1013 vg, and d) less than about 4 ng of rHCP per 1.0x1013 vg.
Wright teaches the purification of AAV vectors comprising a transgene for use in gene therapies wherein the AAV product is substantially free of AAV empty capsids (abstract; par 0010). Wright also teaches concentration of purified recombinant AAV by ultracentrifugation run, which can handle approximately 400 mL of solution yielding AAV vector particles of 4x1015 vg which is sufficient as a dose for many clinical applications (para 0063). Wright further describes these vectors encompass AAV9 vectors and the preparation as having >95% full capsid in which the purified AAV particles can be used in a pharmaceutical composition (par 0012, 0075; claim 7).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have taught the pharmaceutical composition of Kaspar as having less than about 5% empty capsids in view of Wright teaching such purity threshold for a similar AAV9 composition after purification in order to arrive at the claimed invention. It would have been obvious to have claimed such threshold based on such methods being taught by Wright, and therefore there is a reasonable expectation in obtaining a pharmaceutical composition that comprises AAV9 particles with less than about 5% empty capsids.
In relation dosage, particularly where the dosage is about 1 x 1013 vg - 5 x 1014 vg as recited in claim 119, it would have been obvious for one of ordinary skill in the art to optimize Wright’s highly purified dose of 4x1015 vg as the claimed dosages were known to be clinically effective dosages, and adjustment of the rate of delivery to adenoviruses was known to affect the toxicity of the adenoviral vectors. Therefore, a person of ordinary skill would have been motivated to optimize the amount of AAV9 in order to advantageously reach optimal dose safety. It is not inventive to find optimal workable ranges by routine experimentation. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Additionally, despite Kaspar teaching dosages based on a weight variable, it can be seen that the claimed dosage value which does not employ a weight variable, is encompassed by the teachings of Kaspar as seen in the derivation recited above. It is important to state that Kaspar does state the dosage does not require to be based on weight but rather only the total viral genome (vg) (par 0047). Altogether, it can be seen that the claimed dosage would be obvious in view of Kaspar and Wright.
Regarding claim 121, dependent on claim 119, the combined teachings of Kaspar and Wright render obvious claim 119. Moreover, Kaspar teaches the polynucleotide and corresponding translated polypeptide thereof for SMN in relation to instant SEQ ID NO: 2. This is shown by describing the polynucleotide as matching that of GenBank Accession Number NM-000344.2 which further corresponds to the SMN protein NP_000335.1 (par 0043). The alignment between SEQ ID NO: 2 and NP_000335.1 is 100% as included below (the full alignment has been provided in the Office Action dated August 1, 2024). This is further supported in the instant specification describing these sequence IDs (NM-000344.2, NP_000335.1) in relation to the SMN sequence (par 0069-70). In reference to remaining limitation of the AAV9 viral vector that comprises SEQ ID NO: 1 this is previously rejected above with claim 119.
SEQ ID NO 2 alignment to NP_000335.1:
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Regarding claim 124, dependent on claim 119, Kaspar teaches wherein the AAV9 viral vector is administered in a pharmaceutical composition with about 0.7 mL of a contrast medium comprising iohexol, wherein the total volume administered is less than about 10 ml (par 0017, 0046; Example 14, par 0078). The benefit of a contrast agent is that the transduction of cells is increased when a vector is used in combination with a contrast agent relative to the transduction of a vector used in combination without a contrast agent (par 0051).
Kaspar does not teach wherein the contrast medium is at a volume of 1.0-2.0 mL; however, it should be noted the value taught is based on a working example in one year old cynomolgus monkeys wherein the injection contains 0.7 mL iohexol (300 mg/ml formulation) mixed with 2.1 mL of virus (2.8 ml total) (par 0078). Secondly, Example 3 describes the contrast agent with AAV9 encoding SMN showed improved mortality outcomes in mice when employed as opposed to being absent, and increasing viral dosage improved this observed outcome. Therefore, depending on the subject and the amount of viral vector being used it could be understood that the amount of contrast agent can be optimized accordingly for optimal transduction efficiency. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have optimized the amount of contrast agent employed by Kaspar as to improve the transduction efficiency based on variables related to viral dosage and subject type, both of which are expected to also impact transduction efficiency.
Regarding claims 126 and 127, dependent on claim 119, the rejection above to claim 119 describes that Kaspar teaches the AAV9 viral vector is administered at a dose of about 1 x 1013 vg - 5 x 1014 vg by teachings a dosage that overlaps with the claimed range. The instant claims are directed to dosages of 1.2 x 1014 and 2.4 x 1014 vg, respectively.
Based on a child that weighs 8.4 kg according to the calculations of instant para 0192, a dosage of about 1.2 x 1014 vg, and 2.4 x 1014 vg, equates to 1.42 x 1013 and 2.86 x 1013 vg/kg, a range that is encompassed by Kaspar (“These dosages of rAAV may range from about… about 1×1012, about 3×1012, about 1×1013, about 3×1013, … or more viral genomes per kilogram body weight.”; “Dosages may also be expressed in units of viral genomes (vg)” (par 0047)). Moreover, the particular dosage employed can be optimized as it is considered a result-effective variable, and therefore it would be obvious to try different dosages to produce the desired outcomes when using the claimed composition for treatments (MPEP 2144.05). Additionally, Wright further teaches the purified AAV9 vector can be obtained at 4 x 1014 vg, wherein this yield can then be used in therapeutic treatments (Wright par 0063).
Regarding claim 129, dependent on claim 119, Kaspar teaches wherein the patient at the time of the AAV9 viral vector administration is one years old (Example 4).
Regarding claim 130, dependent on claim 119, Kaspar teaches the administration of the viral vector for treatment of SMA (abstract), and further describes SMA is caused when all copies of SMN1 are lost, and that disease severity is dependent on SMN2 copy number which is also affected by a mutation in exon 7 (par 0007). Kaspar describes “Therapeutic approaches for SMA have mainly focused on developing drugs for increasing SMN levels or enhancing residual SMN function.” (par 0008). Kaspar does not specifically teach the claimed mutations related to SMN in view of SMA, yet it is clear based on these mutations that they are encompassed by Kaspar’s teaching of treating SMA due to deletion of SMN1 and low copy number of SMN2.
Therefore, it would have been obvious to employ the viral vector in human subjects with the claimed mutations/conditions as they relate to the teachings of SMA severity based on SMN copy number as taught by Kaspar. Furthermore, there would be a reasonable expectation that the viral vector of Kaspar can be used in treating patients with SMA with the claimed characteristics based on Kaspar’s teachings of treating SMA in patients.
Regarding claim 131, dependent on claim 119, Kaspar teaches wherein the patient is placed in the Trendelenburg position during and/or after administration of the AAV9 viral vector (“In some aspects, it is contemplated that the transduction of cells is further increased when a vector of the disclosure is used in combination with a contrast agent and when the patient is put in the Trendelenburg position (head down position)” (par 0052)).
Regarding claim 137, dependent on claim 119, the claim recites a “wherein clause” specifically, “wherein, by about 24 months after administration of the AAV9 viral vector, the patient achieves…”. The MPEP states in reference to these clauses, “ a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
In this case the wherein clause, as recited above, expresses the desired result of the positive step of administering intrathecally the recombinant self-complementary AAV9 viral vector to a patient with SMA as described in claim 119 which has been rejected above in view of Kaspar. Therefore, it is expected that Kaspar’s method of treatment would have the expected outcomes recited in the instant claim. Thus, this “wherein clause” is not given weight and does not further limit the claim scope.
Regarding claim 138, dependent on claim 119, Kaspar teaches wherein the AAV9 viral vector is administered at a dose of about 6 x 1013 vg - 2.4 x 1014 vg (par 0047). The instant Specification states, “The highest selected dose is up to 2.4 x 1014 vg delivered intrathecally. Doses up to 1.1 x 1014 vg/kg have been safely administered systemically (intravenously) to children weighing up to 8.4 kg (total dose 9.24 x 1014 vg). In addition, in preclinical studies, the intrathecal administration of scAAV9.CB.SMN was safe and well tolerated up to 14 months post injection in large non-human primates at a dose of 2 x 1013 vg/kg.” Based on using a child that is 8.4 kg, claim 138 is directed to a dosage of around 7.1 x 1012 vg/kg to around 2.8 x 1013 vg/kg of which Kaspar’s teachings encompass (“the dosages of rAAV may range from about … about 3×1012, about 1×1013, about 3×1013 … or more viral genomes per kilogram body weight.”; “Dosages may also be expressed in units of viral genomes (vg)” (par 0047)). Moreover, the particular dosage employed can be optimized as it is considered a result-effective variable, and therefore it would be obvious to try different dosages to produce the desired outcomes when using the claimed composition for treatments (MPEP 2144.05). Additionally, Wright further teaches the purified AAV9 vector can be obtained at 4 x 1014 vg, wherein this yield can then be used in therapeutic treatments (Wright par 0063).
Regarding claim 139, dependent on claim 138, the claim recites a “wherein clause” specifically “wherein the administration results in:…” describing intended results. In reference to the wherein clause, refer to the rejections of claim 137 that describes such clause as not further limiting the claim scope.
Regarding claim 153, dependent on claim 119, Kaspar teaches wherein the AAV9 viral vector is administered by lumbar puncture into the L4-L5 interspinous space and into the subarachnoid space (“The injection was performed by lumbar puncture into the subarachnoid space of the lumbar thecal sac” (par 0078)).
Regarding claim 154, dependent on claim 119, Kaspar teaches 119, wherein the AAV viral vector is formulated in a pharmaceutical composition suitable for intrathecal administration, wherein the composition is in a container (“syringe”) and comprises a unit dosage of the AAV9 viral vector of about 6.0 x 1013 vg, about 1.2 x 1014 vg, or about 2.4 x 1014 vg (par 0004, 0020, 0047, 0061); wherein the composition has a genomic titer of about 1.7 x 1013 - 5.3 x 1013 vg/ml (par 0047).
Claim 155, dependent on claim 119, is rejected solely based on dependency to rejected claim 119
Claim 156, dependent on claim 119, the claim 119 rejection above is applied herein, as it describes therein wherein Kaspar teaches the entirety of the claimed limitations.
Claims 119 and 122 remain rejected under 35 U.S.C. 103 as being unpatentable over Kaspar et al. (US-2015/0252384-A1, of record) in view of Wright et al. (US-2013/0072548-A1; of record), as applied to claim 119 above, and further in view of Wilson et al. (US 7,906,111 B2; US Patent Application No. 10/573,600; of record). This is a modified rejection necessitated by amendment of the claims in the response filed May 22, 2026.
Regarding claim 119, the disclosure of Kaspar in view of Wright, is applied as in the 103 rejections above, the content of which can be found above.
Regarding claim 122, dependent on claim 119, Kaspar teaches the AAV9 vector as described in the claim 119 rejection, wherein the vector is encapsulated in a capsid that includes AAV9 VP1, VP2, and VP3 (par 0012, 0038). Additionally, the AAV capsid proteins may be modified to enhance delivery of the recombinant vector (par 0038).
Kaspar in view of Wright does not teach the capsid sequence as listed in SEQ ID NO: 3; however, the instant specification does describe that SEQ ID NO: 3 is in relation to VP 1, 2, and 3 (par 0065).
Wilson teaches sequences of novel adeno-associated virus capsids wherein the instant SEQ ID NO: 3 is taught in-depth, in particular the sequence is 100% identical to Wilson SEQ ID NO: 123 as listed below (the full alignment was provided in the Office Action dated August 1, 2024). Wilson describes the following observed benefits: “Vectors constructed with capsid of this huAAV9 have exhibited gene transfer efficacies similar to AAV8 in liver, superior to AAV1 in muscle and 200 fold higher than AAV5 in lung. Further, this novel human AAV serotype shares less than 85% sequence identity to previously described AAV1 through AAV8 and is not cross-neutralized by any of these AAVs. (“Summary of the Invention,” col 1, line 50- col 2, line 11).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the capsid proteins taught by Kaspar as encoding SEQ ID NO: 3, because Wilson teaches the same sequence, i.e. SEQ ID NO: 123, with successful outcomes being observed in regard to gene transfer efficiency and reduced cross-neutralization with AAV9 viral vectors. Therefore, there is clear motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. Secondly, such combination would lead to the predictable outcome that by using this capsid sequence in combination with the remaining viral vector elements described in claim 119 that the SMN protein will be effectively delivered in order to treat SMA in a subject in need thereof.
SEQ ID NO: 3 :: Wilson SEQ ID NO: 123:
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Claims 119, 128, 134-135 remain rejected under 35 U.S.C. 103 as being unpatentable over Kaspar et al. (US-2015/0252384-A1, of record) in view of Wright et al. (US-2013/0072548-A1; of record), as applied to claim 119 above, and further in view of Passini et al. (US 2016/0074474 A1; of record). This is a modified rejection necessitated by amendment of the claims in the response filed May 22, 2026.
Regarding claim 119, the disclosure of Kaspar in view of Wright, is applied as in the 103 rejections above, the content of which can be found above.
Regarding claim 128, dependent on claim 119, Kaspar teaches treatment for SMA with AAV9 viral vectors encoding SMN (par 0043). Moreover, Kaspar describes SMA as an autosomal recessive disorder in which the disorder severity is highly dependent on SMN2 copy number when SMN1 is mutated and absent (par 0006-0008).
Kaspar in view of Wright does not describe which SMA Type is being treated (I, II, or III) within a subject.
Passini teaches methods for treating spinal muscular atrophy using a self-complementary recombinant adeno-associated virus (rAAV) viral particle with AAV9 capsid comprising a transgene expressing SMN (abstract). Passini teaches the various SMA types with corresponding symptoms, life expectancies, and SMN2 copy number in addition to treating SMA type I, II or III (par 0060-0061), wherein SMA type I has the most severe symptoms due to the lowest amount of SMN.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have been motivated to treat various SMA types based on the teachings of Passini of using an AAV9 viral vector to treat SMA type II and III patients by delivering a SMN transgene, by doing so the treatment can be expanded to patients of all ages with varying levels of disorder severity. Furthermore, both references explain SMA types are largely based on SMN2 copy number, and therefore it would be obvious to employ the AAV vector and treatment method of Kaspar to treat various SMA types by optimizing the gene delivery in order to adequately restore SMN copy number. Lastly, there would be a reasonable expectation of success in gene delivery treatment for SMA Type II and III based on the higher lifespan in subjects in comparison to type I patients that experience the most severe symptoms (~ 1 year for type I, <30-40 years for type II, and >60 years for type III).
Regarding claims 134 and 135, both dependent on claim 119, Kaspar teaches a viral vector can be administered with a contrast agent to improve patients’ outcomes with SMA (abstract) and that the AAV can be used in combination therapies (par 0033).
Kaspar in view of Wright does not teach administering a second therapeutic agent to the patient concomitantly or consecutively with the administration of the AAV9 viral vector. Moreover, Kaspar in view of Wright does not teach the second therapeutic agent comprises an antisense oligonucleotide targeting SMN1 and/or SMN2, a muscle enhancer, and/or a neuroprotector.
Passini teaches providing an AAV viral particle comprising an AAV genome, wherein the rAAV genome comprises a first heterologous polynucleotide sequence (e.g., an SMN1 coding strand) and a second heterologous polynucleotide sequence (e.g., an SMN1 noncoding or antisense strand). Passini describes the first heterologous polynucleotide sequence and a second heterologous polynucleotide sequence are linked by a sequence that facilitates intrastrand base pairing; e.g., a hairpin DNA structure, in particular an siRNA molecule (par 0085). Furthermore, Passini teaches the AAV viral vectors can be used in combination with one or more therapeutic agents for the treatment of SMA (par 0075).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teaching of a second therapeutic agent described by Passini based on Kaspar teaching the AAV viral vector being used in combination therapies, therefore there would be predictable outcome of treating subjects with SMA more effectively. In particular, it would have been obvious to incorporate the second agent with Kaspar in view of Wright’s AAV9 vector based on Passini’s teachings of an AAV9 vector with a first and second therapeutic agent for treating SMA.
Claims 119, 126, 130, 132, 133, 147, 149, and 150 remain rejected under 35 U.S.C. 103 as being unpatentable over Kaspar et al. (US-2015/0252384-A1, of record) in view of Wright et al. (US-2013/0072548-A1; of record), as applied to claims 119, 126, and 130 above, and further in view of Mendell et al. (N Engl J Med 2017;377:1713-1722; of record). This is a modified rejection necessitated by amendment of the claims in the response filed May 22, 2026.
Regarding claims 119, 126, and 130, the disclosure of Kaspar in view of Wright, is applied as in the 103 rejections above, the content of which can be found above.
Regarding claim 132 and 133, both dependent on claim 119, Kaspar teaches the administration of a AAV9 viral vector to a patient to treat SMA as described in the claim 119 rejection above, but does not teach the wherein the patient is administered an oral steroid at least about 1-48 hours prior to being administered the AAV9 viral vector. Additionally, Kaspar does not teach wherein the oral steroid is prednisolone.
Mendell teaches a single dose gene replacement therapy for spinal muscular atrophy wherein an oral steroid (prednisolone) is administered 24 hours prior to administering the gene vector (p 1715, col 2, par 4). The supplemental section describes the adjustment of the prednisolone was done to optimize the management of the patients. The protocol was amended to include a steroid due to a T-cell response that occurred during administration of the viral vector against the AAV9 capsid. Immunosuppression via steroids was conducted to mitigate the T-cell response and related enzymes (serum aminotransferase levels) (Supp. page 2-3; p 1717, col 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have been motivated to use steroids, particularly prednisolone, based on the work by Mendell showing it was vital in reducing immunosuppression that occurred with select patients after administration of the viral vector. By the using a steroid, there would be the predictable outcome of an improved gene delivery due to a reduction in negative reactions to the capsid proteins.
Regarding claim 147, dependent on claim 119, the rejections above to claims 132 and 133 make obvious the use of an oral steroid to be used in treatments for SMA. In reference to the limitations of claim 147, Kaspar does not teach wherein the patient is administered an oral steroid at a dose about 1 mg/kg once daily for at least 30 days after the AAV9 viral vector administration.
Mendell teaches oral prednisolone at a dose of 1 mg per kg daily for at least 30 days after administration of the viral vector to reduce immunosuppression (p 1715, col 1, par 4; Supp. p 2, par 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have been motivated to have the employed the steroid dosage regime taught by Mendell based on the outcome observed taught therein reducing immunosuppression. By doing so, there would be a reasonable expectation of an improved gene therapy method based on the outcomes of observed by Mendell in SMA patients treated with the claimed steroid regime.
Regarding claim 149, dependent on claim 130, Kaspar teaches the administration of an AAV9 viral vector to treat patients with SMA.
Kaspar does not teach wherein at the time of the AAV9 viral vector administration, the patient: a) has one or more of gamma-glutamyl transferase levels less than about 3 times upper limit of normal, bilirubin levels less than about 3.0 mg/dL, creatinine levels less than about 1.0 mg/dL, Hgb levels between about 8 - 18 g/dL, and/or white blood cell counts of less than about 20000 per mm3;b) has platelet counts above about 67,000 cells/ml, or above about 100,000 cells/ml, or above about 150,000 cells/ml; c) has normal hepatic function; and/or d) has hepatic transaminase levels less than about 8 - 40 U/L.
Mendell teaches a single dose gene replacement therapy for spinal muscular atrophy wherein the patients enrolled in the clinical trial had gamma-glutamyl transferase (GGT) levels less than three times the upper limit of normal, bilirubin levels less than about 3.0 mg/dL, creatinine levels less than about 1.8 mg/dL, Hgb levels between about 8 -18 g/dL, and white blood cell counts of less than about 20,000 per mm3 (Supp. p 2, par 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method taught by Kaspar to include patient screening parameters to better predict outcomes relating to treatment, particularly by using the parameters taught by Mendell for patient enrollment in clinical trials with AAV9 for treating SMA.
Regarding claim 150, dependent on claim 126, Kaspar teaches the administration of an AAV9 viral vector to treat patients with SMA.
Kaspar does not teach wherein at the time of the AAV9 viral vector administration, the patient: a) does not have severe scoliosis (defined as > 500 curvature of spine) evident on X-ray examination; b) is not contraindicated for spinal tap procedure or administration of intrathecal therapy; c) has not previously had a scoliosis repair surgery or procedure; d) does not need the use of invasive ventilatory support or does not need non-invasive ventilatory support for 12 or more hours daily in the two weeks prior to dosing; e) has a pulse oximetry > 95% saturation at screening while at screening while the patient is awake, or for high altitudes > 1000 m, oxygen saturation > 92% while the patient is awake; f) does not have a history of standing or walking independently; g) does not use a gastric feeding tube; h) does not have an active viral infection; i) has not had a severe non-pulmonary and/or respiratory tract infection within four weeks; j) does not have concomitant illness, major renal or hepatic impairment, known seizure disorder, diabetes mellitus, idiopathic hypocalciuria or symptomatic cardiomyopathy; k) does not have a history of bacterial meningitis or brain or spinal cord disease; I) does not have a known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or excipients; m) does not have a known allergy or hypersensitivity to iodine or iodine- containing products; n) is not taking drugs to treat myopathy or neuropathy; o) is not receiving immunosuppressive therapy, plasmapheresis, immunomodulators or adalimumab, within three months; p) has not received an investigational or approved compound product or therapy to treat SMA; and/ or q) has anti-AAV9 antibody titers at or below 1:50 as determined by ELISA.
Mendell teaches a single dose gene replacement therapy for spinal muscular atrophy wherein the enrolled patients that received treatment (d) do not need the use of invasive ventilatory support, (e) has a pulse oximetry ~ 95% saturation at screening, (h) does not have an active viral infection, (j) does not have diabetes mellitus, (l) does not have a known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or excipients; (n) is not taking drugs to treat myopathy or neuropathy, (o) are not receiving immunosuppressive therapy or within 3 months of starting the trial, (p) have participation in a recent SMA treatment clinical trial that may create unnecessary risks for gene transfer, and (q) anti-AAV9 antibody titers at or below 1 :50 as determined by an enzyme-linked immunosorbent assay (ELISA) (Supp. p 1-2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method taught by Kaspar to include patient screening parameters to better predict outcomes relating to treatment, particularly by using the parameters taught by Mendell for patient enrollment in clinical trials with AAV9 for treating SMA.
Claim 119, 132, and 148 remain rejected under 35 U.S.C. 103 as being unpatentable over Kaspar et al. (US-2015/0252384-A1, of record) in view of Wright et al. (US-2013/0072548-A1; of record) and Mendell et al. (N Engl J Med 2017;377:1713-1722; of record), as applied to claims 119 and 132 above, and further in view of Hinderer et al. (US 2020/0147185 A1; of record). This is a modified rejection necessitated by amendment of the claims in the response filed May 22, 2026.
Regarding claims 119 and 132, the disclosure of Kaspar in view of Wright and Mendell, is applied as in the 103 rejections above, the content of which can be found above.
Regarding claim 148, dependent on claim 132, Kaspar teaches the administration of a AAV9 viral vector to a patient to treat SMA as described in the claim 119 rejection above, but does not teach the use of an oral steroid.
Mendell teaches a single dose gene replacement therapy for spinal muscular atrophy wherein an oral steroid (prednisolone) is administered 24 hours prior to administering the gene vector (p 1715, col 2, par 4). The supplemental section describes the adjustment of the prednisolone was done to optimize the management of the patients. The protocol was amended to include a steroid due to a T-cell response that occurred during administration of the viral vector against the AAV9 capsid. Immunosuppression via steroids was conducted to mitigate the T-cell response and related enzymes (serum aminotransferase levels) (Supp. page 2-3; p 1717, col 2). After administration of the viral vector, the oral steroid was started at 2 mg/kg and was maintained for 35 days until T-cell response and serum transaminases were reduced. The criteria for tapering off the steroid was if aspartate aminotransferase and alanine transaminase exceed 120 IU/L, prednisolone would be maintained until enzymes fell below this level while at the same time monitoring T-cell response that had to drop below 100 SFCs per 106 PBMC (Supp. page 2-3).
Mendell does not teach the specific dosage regime as claimed.
Hinderer describes using an oral steroid after administration of a AAV9 viral vector for immunosuppressive therapy wherein oral prednisolone is delivered at 0.5 mg/kg/day after delivery of the vector and then tapering down across 16 weeks (par 0366). Hinderer describes the goal is to discontinue prednisolone by week 12 (par 0370, 0375).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the steroid dosage regime taught by Mendell that involves a higher dosage of steroids across 30 days, in view of Hinderer that describes using a lower concentration that slowly tapers off. Furthermore, Mendell teaches for the outcomes seeking to be obtained with immunosuppression in relation to AST and ALT concentrations, and T-cell response as seen with PBMCs. Therefore, it would have been obvious to optimize the method based on the teachings describing the desired effects and lower steroid dosage regime possible in obtaining such effects.
Claim 151 remains rejected under 35 U.S.C. 103 as being unpatentable over Kaspar et al. (US-2015/0252384-A1, of record) in view of Wright et al. (US-2013/0072548-A1; of record), as applied to claims 119 and 131 above, and further in view of Hinderer et al. (US 2020/0147185 A1; of record). This is a modified rejection necessitated by amendment of the claims in the response filed May 22, 2026.
Regarding claims 119 and 131, the disclosure of Kaspar in view of Wright, is applied as in the 103 rejections above, the content of which can be found above.
Regarding claim 151, dependent on claim 131, Kaspar teaches wherein the patient is placed tilted head-down at about 30° after administration of the AAV9 viral vector (i.e., Trendelenburg position) (par 0052). Kaspar does not teach the patient in this position for about 15 minutes.
Hinderer describes the Trendelenburg position after administration with a viral vector in order to improve cranial distribution of vector in cases of using a large injection volume (par 0729-730). The teaching describes lowering the head 30 degrees for about 10 minutes immediately following injection (par 0734, 0748).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Kaspar’s method using the Trendelenburg position by adding a time component of the position based on the Hinderer employing 10 minutes to effectively increase the injection distribution within the cranium. Furthermore, it would be obvious to optimize the time component based on the injection volume employed which impacts distribution as taught by Hinderer.
Response to Applicants’ Arguments as they apply to rejection of claims 119, 121-122, 124, 126-135, 137-139, 147-151 and 153-154 rejected under 35 USC § 103
Cui Decl. filed on May 22, 2026
The Affidavit under 37 CFR 1.132 filed on May 22, 2026 is insufficient to overcome the rejection of the claims based upon the rejections set forth under 35 U.S.C. 103 of Kaspar in view of Wright as set forth in the last Office action because the Affidavit, and the instant Specification are making incorporations by reference of WO 2019/094253 (hereinafter ‘253), particularly purification methods as described as Process B in relation to the claimed composition recited in the claims. The attempt to incorporate subject matter into this application by reference to WO 2019/094253 is ineffective because it is unclear if the composition(s) claimed are identical to the composition purified, and subsequently obtained in ‘253, and therefore it is not clear if outcomes related to ‘253 are to be expected in the instant application. The Affidavit primarily describes the purification methods of Wright as not being sufficient to arrive at the claimed invention, yet there are no clearly identified purification steps pointed to in the instant application, nor the Affidavit when describing “Process B,” but rather stating the methods of ‘253 would lead to such outcomes. The Applicant should clearly point to essential material in ‘253, such as the particular methods steps for production and purification, and furthermore the composition used in ‘253 that would lead to the claimed composition.
As discussed in 37 CFR 1.57, section (d) :
“(d) “Essential material” may be incorporated by reference, but only by way of an incorporation by reference to a U.S. patent or U.S. patent application publication, which patent or patent application publication does not itself incorporate such essential material by reference. “Essential material” is material that is necessary to:
Provide a written description of the claimed invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and set forth the best mode contemplated by the inventor of carrying out the invention as required by 35 U.S.C. 112(a);
Describe the claimed invention in terms that particularly point out and distinctly claim the invention as required by 35 U.S.C. 112(b); or
Describe the structure, material, or acts that correspond to a claimed means or step for performing a specified function as required by 35 U.S.C. 112(f)…
(f) The examiner may require the applicant to supply a copy of the material incorporated by reference. If the Office requires the applicant to supply a copy of material incorporated by reference, the material must be accompanied by a statement that the copy supplied consists of the same material incorporated by reference in the referencing application.”
The Specification makes incorporations by reference to WO 2019/094253 A1 (Application PCT/US2018/058744) in paragraph 0062, stating “Embodiments of these vector constructs and methods of preparing and purifying them are provided e.g., in PCT/US2018/058744, which is incorporated herein by reference in its entirety.”; and in paragraph 0090, “In addition, exemplary methods for determining the dose, purity and percentage of functional viral vectors of the rAAV viral vectors disclosed herein are also provided in the disclosure of PCT/US2018/058744, which is incorporated herein by reference in its entirety.” However, the “essential material” is not referenced adequately, and furthermore not clear as to obtain the claimed composition.
The incorporation by reference will not be effective until correction is made to comply with 37 CFR 1.57(c), (d), or (e). If the incorporated material is relied upon to meet any outstanding objection, rejection, or other requirement imposed by the Office, the correction must be made within any time period set by the Office for responding to the objection, rejection, or other requirement for the incorporation to be effective. Compliance will not be held in abeyance with respect to responding to the objection, rejection, or other requirement for the incorporation to be effective. In no case may the correction be made later than the close of prosecution as defined in 37 CFR 1.114(b), or abandonment of the application, whichever occurs earlier.
Any correction inserting material by amendment that was previously incorporated by reference must be accompanied by a statement that the material being inserted is the material incorporated by reference and the amendment contains no new matter. 37 CFR 1.57(g).
Starting on page 13 of the remarks filed on May 22, 2026, Applicants essentially argue the following:
In relation to claim 119, the Applicant states “Fixed intrathecal dosages are not taught or suggested by Kaspar or Wright.” Kaspar discusses weight based doses of an AAV vector for intrathecal delivery as opposed to a fixed dose not reliant on weight, but total viral genome (vg).
In relation to claim 119, Applicant states, “Neither Kaspar nor Wright suggest the intrathecal administration of a viral vector having the claimed purity parameters.”
In relation to claim 119, Applicant states “Surprising benefits of the claimed intrathecal fixed dose administration and of the claimed purity parameters.”
In response to the arguments, they have been fully considered but is not persuasive due to the following reasons:
Regarding the first presented argument, Kaspar clearly describes the AAV9 viral vector titer “may be expressed in units of viral genomes (vg),” wherein the dosage is not limited by a weight variable. Therefore, it is clear that Kaspar is not limited to a dosage that requires a weight variable. Moreover, Applicant states Kaspar is describing the units for the dosage are by which to measure the viral vectors, rather than the units by which the dosage are used. However, there is no support for this line of reasoning as it is clear that Kaspar is stating the dosage that is used can be expressed in just viral genomes (vg).
Furthermore, despite the units listed in the taught dosage ranges as being “vg/kg” by Kaspar, the claimed value of about 1x1013 vg to 5x1014 vg is still encompassed by the teaching of Kaspar because when a weight variable is included in the teaching of Kaspar the claimed range is encompassed as seen in the derivation described above. Therefore, despite the Applicant stating Kaspar as not teaching a fixed dosage, the dosages of Kaspar encompass the claimed values set forth in claims 119, 126, 127, 138, and 154 when weight is considered for Kaspar.
Lastly, the dosage value is considered a result-effective variable, in that these values are considered outcomes of routine optimization. MPEP 2144.05 (II) (A) states:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.")
It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980).
Since the prior art teaches that the concentration of the viral vector for treatment of SMA can vary, in particular Kaspar states, “Titers of rAAV to be administered in methods of the invention will vary depending, for example, on the particular rAAV, the mode of administration, the treatment goal, the individual, and the cell type(s) being targeted, and may be determined by methods standard in the art… Dosages may also vary based on the timing of the administration to a human.” (par 0047) it would have been obvious for one of ordinary skill to discover the optimum dosages to be used based on the prior art by normal optimization procedures known with clinical trials, specifically during phases I and II.
Regarding the second argument, 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). Regarding the third argument, the Wright reference clearly teaches the AAV9 intrathecal delivery in which the pharmaceutical composition is less than about 5% empty capsid. The rejection above describes the obviousness rationale to claim the high purity based on Wright teaching obtaining such threshold with AAV9 vectors. There is a reasonable expectation that the composition taught by Kaspar can be purified by Wright to obtain a highly purified AAV composition with less than 5% empty capsids.
In respect to the Cui Decl., described above the Cui Decl. is currently insufficient based on the lack of clarity of the incorporations by reference to WO 2019/094253 A1, particularly the necessary steps and compositions that are required to obtain the claimed composition. The Cui Decl. states:
“As explained below, the results of the study showed that while the Wright Process was unsuitable for AAV9 purification, even the Modified Wright Process still failed to produce AAV preparations with empty capsids and hcDNA levels below the maximum thresholds that I understand are claimed in the instant application. By contrast, Process B in the '253 Application produced Zolgensma products with substantially higher genomic AAV titers and substantially lower levels of empty capsids and hcDNA.”
The aforementioned “Process B” is not listed in the instant Specification, nor generally the required steps to obtain the claimed purification standards as described in ‘253. Secondly, it is not clear if the outcomes observed by Cui are to be expected with the currently claimed composition as recited in claim 119 since scope of the claimed composition appear to not be identical as that described as “Zolgensma” in Cui Decl. paragraph 2. Altogether, the incorporations by reference should provide more detail, and furthermore the compositions should be commensurate with the current scope of the claims.
Regarding the third argument about unexpected clinical outcomes, the Applicant describes the higher dosage leading to better therapeutic outcomes; however, this outcome is to be expected as a higher amount of the therapeutic protein is expected to be delivered to target cells/ tissues. Secondly, the particular dosage is considered a routine optimization as described above since the claimed composition is clearly taught by Kaspar in view of Wright.
Secondly, in relation to unexpected results, evidence of unexpected results, used to support nonobviousness, should be commensurate with “the full scope” of the claimed invention to overcome prima facie obviousness. For example, Applicants’ reference to Table 6 in Example 2 of dosages A and B of an AAV9-SMN viral vector composition that were administered intrathecally, were more specifically AVXS-101 that contains a 5' AAV2 ITR, a chicken beta-actin (CB) promoter, a cytomegalovirus (CMV),
immediate/early enhancer, a modified SV40 late 16S intron, a bovine growth hormone (BGH) polyadenylation signaling, and an unmodified 3' AAV ITR. The subjects or patients had 3 copies of the SMN2 gene in addition to biallelic deletion of SMN1 wherein the patient was greater than 6 months and less than 5 years of age. It can be seen that Example 2 is not commensurate with the current claims, and therefore it is not clear if the “unexpected results” observed therein would similarly be expected with the composition recited in the claims when using a similar dosage(s).
Conclusion
It is recommended by the Examiner that the Applicant requests an Interview via an Automated Interview Request (AIR) in order to better advance prosecution of the claims.
Claims 119, 121-122, 124, 126-135, 137-139, 147-151 and 153-156 are rejected. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL A RIGA whose telephone number is (571)270-0984. The examiner can normally be reached Monday-Friday (8AM-6PM).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHAEL ANGELO RIGA/ Examiner, Art Unit 1634
/TERESA E KNIGHT/ Primary Examiner, Art Unit 1634
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