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 .
Election/Restrictions
Applicant’s election of Group I (Claims 1-5, 7-19, and 28; drawn to a method for treating Fragile X Syndrome) in the reply filed on February 9, 2026, is acknowledged.
Claims 29, 34, and 38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Groups II and III), there being no allowable generic or linking claim.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant further elected the following species:
a. A non-standard AAV vector encompassing a self-complementary AAV but not standard AAV vectors (this was confirmed in a call with Applicant’s representative, Robert M. Joynes, on March 12, 2026)
b. A promoter that is a hybrid of a chicken β-actin promoter and a CMV promoter
In light of the Applicant’s elected species, claims 3, 5, and claims 10-12 (each of which are drawn to standard AAV vectors) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
DETAILED ACTION
The amended claims filed on July 24, 2023, have been acknowledged. Claims 6, 20-27, 30-33, 35-37, and 39-47 were cancelled. Claim 7 was amended. In light of the Applicant’s elected invention and species, claims 3, 5, 10-12, 29, 34, and 38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-2, 4, 7-9, 13-19, and 28 are pending and examined on the merits.
Priority
The applicant claims domestic priority from U.S. provisional application No. 63/053,461, filed on July 17, 2020. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1-2, 4, 7-9, 13-19, and 28 receive domestic benefit from U.S. provisional application No. 63/053,461, filed on July 17, 2020.
Information Disclosure Statement
The information disclosure statements (IDS) filed on April 13, 2023, and October 9, 2024, have been considered.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 7, 9, and 16-18 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by World Intellectual Property Organization Patent Application No. 2019227219 (Hampson; referenced in IDS).
Regarding claims 1 and 17-18, Hampson teaches a method of treating Fragile X syndrome comprising administering a therapeutically effective amount of an AAV9-FMRP vector to the CNS of the subject by direct injection into the cerebral spinal fluid via intra-cerebroventricular injection, intracistema magna injection, and/or intrathecal injections. The AAV-FMRP vector comprises a polynucleotide sequence encoding a Group C human FMRP isoform (i.e. a wild type isoform) and has the AAV9 serotype. Examples of human Group C FMRP isoforms include isoforms 7, 17, 8, 18, 9 and 19. The AAV genome can be in single-stranded form. The AAV9-FMRP vector also includes a promoter sequence operably linked to the polynucleotide sequence encoding the Group C FMRP isoform allowing for the expression of the Group C FMRP isoform transgene in vitro or in vivo. An effective amount of a vector is administered to the subject to infect a sufficient number of target neuronal cells (paragraphs 0009-0012, 0028, 0037-0057, 0060, 0070-0077, and 0083-0087).
Regarding claim 2, Hampson teaches that self-complementary AAVs can be used (paragraphs 0037-0057).
Regarding claims 7 and 9, Hampson teaches that the vector may or may not contain a WPRE sequence (paragraph 0096).
Regarding claim 16, Hampson teaches that examples of human Group C FMRP isoforms include isoforms 7, 17, 8, 18, 9 and 19. Each of these isoforms is missing exon 12. Isoforms 7, 8 and 9 differ from one another by alternative splicing in exon 15. Isoforms 7 and 17 differ from one another by alternative splicing in exon 17. Similarly, isoforms 8 and 18, and 9 and 19, differ from one another, respectively, by alternative splicing in exon 17 (paragraph 0060). As exon 12 begins beyond amino acid residue 297, Group C isoforms would maintain the wild type FMRP residues from 1-297.
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.
Claims 1 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over World Intellectual Property Organization Patent Application No. 2019227219 (Hampson) as applied to claim 1 above, and further in view of Zeier et al. (Gene Therapy 16: 1122–1129. 2009; referenced in IDS).
The teachings of Hampson are as discussed above. Hampson teaches that any suitable promoter may be used. The promoter sequence may be constitutively active i.e., operational in any host cell background (paragraph 0072).
Hampson does not teach wherein the promoter is a hybrid of chicken β-actin and CMV.
However, Zeier teaches viral AAV vector encoding a major isoform of FMRP to treat Fragile X syndrome (FXS) and found that that expression of the major CNS isoform of FMRP alone is sufficient to rescue a phenotype of the disease. This suggests that post-developmental protein replacement may have the potential to improve cognitive function in FXS (abstract, page 1123, column 1, paragraph 2-column 2, paragraph 3, and Figure 1). As can be seen in Figure 1, the vector of Zeier uses the chicken β-actin hybrid promoter (CBA) with regulatory elements including an enhancer from the cytomegalovirus (CMV), an exon (chicken b-actin), and a hybrid intron (chicken b-actin/rabbit b-globin).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the chicken β-actin hybrid promoter (CBA) of Zeier in the AAV vector of Hampson to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use the CBA promoter with a reasonable expectation of success because Hampson identifies that constitutive promoters can be used with their vector and Zeier successfully reduces to practice that the CBA promoter can drive expression of a fmrp isoform as part of an AAV vector and successfully treat Fragile X syndrome. Therefore, it would have been obvious that this promoter could also be used in the vector of Hampson. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1, 7-8, and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over World Intellectual Property Organization Patent Application No. 2019227219 (Hampson) as applied to claims 1, 7, and 18 above, and further in view of United States Patent Application No. 20180021364 (Stewart).
Regarding claim 8, the teachings of Hampson are as discussed above. Hampson teaches that the vector may comprise polyadenylation sites (paragraph 0075).
Hampson is silent regarding which polyadenylation sequences may be included in the vector.
However, Stewart teaches methods for treating Fragile X syndrome in humans comprising administering AAVs encoding a therapeutic protein to the subject. Stewart teaches that the AAV payload constructs can include an SV40 polyadenylation sequence (paragraphs 0265-0270, Example 1, and Table 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the SV40 polyadenylation sequence of Stewart in the AAV vector of Hampson to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use the SV40 polyadenylation sequence with a reasonable expectation of success because Hampson identifies that polyadenylation sequences can be used with their vector to express the fmrp isoform in the CNS and Stewart identifies that the SV40 polyadenylation sequence can be used as part of an AAV vector to express a therapeutic protein in the CNS of a subject. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 19, the teachings of Hampson are as discussed above. Hampson, as stated supra, teaches a method of treating Fragile X syndrome comprising administering a therapeutically effective amount of an AAV9-FMRP vector to the CNS of the subject by direct injection into the cerebral spinal fluid via intra-cerebroventricular injection, intracistema magna injection, and/or intrathecal injections.
Hampson does not teach that the AAV vector further comprises microRNA-target sites.
However, Stewart teaches methods for treating Fragile X syndrome in humans comprising administering AAVs encoding a therapeutic protein to the subject. Stewart teaches that AAV9 serotype can produce robust and wide-scale neuronal transduction throughout the CNS after a peripheral, systemic (e.g., intravenous) administration in neonatal subjects and that intrathecal (intra-cisterna magna routes) administration of AAV9 serotypes can also produce widespread spinal expression (paragraphs 0102 and 0265-0270).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted a combination of intra-cerebroventricular administration and intrathecal administration with a combination of a systemic administration of the AAV vector through intravenous administration and an intrathecal administration to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to substitute with a reasonable expectation of success because Hampson teaches that intra-cerebroventricular injection and intrathecal injections can be performed together for delivery of the AAV vector to the subject. However, intra-cerebroventricular administration is direct delivery to the brain and requires special expertise and precise administration and has the risk of causing brain injury if done wrong. On the contrary, intravenous administration is a much simpler method and Stewart has already identified that systemic administration of an AAV9 vector causes robust and wide-scale neuronal transduction throughout the CNS while intrathecal administration leads to widespread spinal expression (i.e. PNS expression). As intravenous administration is safer and still leads to robust and widespread expression of the therapeutic protein in the CNS, it would have been obvious to use this delivery method with intrathecal administration instead of intra-cerebroventricular administration. Therefore, it would have been obvious to use a combination of systemic intravenous administration and intrathecal administration to achieve widespread expression of the therapeutic fmrp isoform in the CNS and PNS.
Claims 1, 13-14, and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over World Intellectual Property Organization Patent Application No. 2019227219 (Hampson) as applied to claims 1 and 18 above, and further in view of United States Patent Application No. 20180021364 (Stewart) and Qiao et al. (Gene Therapy 18: 403–410. 2011; referenced in IDS)
The teachings of Hampson are as discussed above. Hampson, as stated supra, teaches a method of treating Fragile X syndrome comprising administering a therapeutically effective amount of an AAV9-FMRP vector to the CNS of the subject by direct injection into the cerebral spinal fluid via intra-cerebroventricular injection, intracistema magna injection, and/or intrathecal injections.
Hampson does not teach that the AAV vector further comprises microRNA-target sites.
However, Stewart teaches methods for treating Fragile X syndrome in humans comprising administering AAVs encoding a therapeutic protein to the subject. Stewart teaches that AAV9 serotype can produce robust and wide-scale neuronal transduction throughout the CNS after a peripheral, systemic (e.g., intravenous) administration in neonatal subjects and that intrathecal (intra-cisterna magna routes) administration of AAV9 serotypes can also produce widespread spinal expression (paragraphs 0102 and 0265-0270).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted a combination of intra-cerebroventricular administration and intrathecal administration with a combination of a systemic administration of the AAV vector through intravenous administration and an intrathecal administration to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to substitute with a reasonable expectation of success because Hampson teaches that intra-cerebroventricular injection and intrathecal injections can be performed together for delivery of the AAV vector to the subject. However, intra-cerebroventricular administration is direct delivery to the brain and requires special expertise and precise administration and has the risk of causing brain injury if done wrong. On the contrary, intravenous administration is a much simpler method and Stewart has already identified that systemic administration of an AAV9 vector causes robust and wide-scale neuronal transduction throughout the CNS while intrathecal administration leads to widespread spinal expression (i.e. PNS expression). As intravenous administration is safer and still leads to robust and widespread expression of the therapeutic protein in the CNS, it would have been obvious to use this delivery method with intrathecal administration instead of intra-cerebroventricular administration. Therefore, it would have been obvious to use a combination of systemic intravenous administration and intrathecal administration to achieve widespread expression of the therapeutic fmrp isoform in the CNS and PNS.
The combined teachings of Hampson and Stewart do not teach wherein the AAV vector comprises microRNA-target sites.
However, Qiao teaches that tissue-specific gene expression is often needed to minimize ectopic expression in unintended cells and undesirable consequences. They investigated whether incorporation of target sequences of tissue-specific microRNA (miRNA) into AAV vectors could inhibit ectopic expression in tissues such as the liver. They inserted liver-specific miR-122 target sequences (miR-122T) into the 3’-untranslated region (UTR) of a number of AAV vectors. After intravenous delivery in mice, they found that five copies of the 20mer miR-122T reduced liver expression of luciferase by 50-fold and b-galactosidase (LacZ) by 70-fold. Five copies of miR-122T also reduced mRNA levels of a secretable protein (myostatin propeptide) from the AAV vector plasmid by 23-fold in the liver. However, gene expression in other tissues, including the heart was not inhibited (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the AAV vector of Hampson to incorporate miR-122 microRNA-targeting sites to detarget the vector in the liver, as identified by Qiao, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Hampson is focused on expressing their vector in the nervous system and Qiao teaches that tissue-specific gene expression is often needed to minimize ectopic expression in unintended cells and undesirable consequences. As part of the intravenous administration, multiple other tissues will also receive the AAV vector of Hampson, such as the liver, and can be detargeted in these tissues to minimize ectopic expression. Furthermore, Qiao has successfully reduced to practice that miR-122 target sites incorporated into the vector significantly decreased ectopic expression in the liver. As such, it would have been obvious to incorporate miR-122 targeting sites into the AAV vector to minimize ectopic expression in the liver following intravenous administration of the vector. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over World Intellectual Property Organization Patent Application No. 2019227219 (Hampson) as applied to claim 1 above, and further in view of Ligsay et al. (Journal of Neurodevelopmental Disorders 9: 1-13. 2017).
The teachings of Hampson are as discussed above.
Hampson is silent regarding whether their treatment can be used to treat a human child.
However, Ligsay teaches a method of treating Fragile X syndrome in children aged 6-17 years old by administering ganaxolone as part of a clinical trial (abstract and title).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have treated children with the AAV vector of Hampson to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to treat children with a reasonable expectation of success because Ligsay has successfully reduced to practice a method of treating Fragile X syndrome in children. Although Ligsay focused on treating the children with ganaxolone, it would have been obvious that a similar target population could be treated with other therapeutic compounds, such as the vector of Hampson. Therefore, it would have been obvious that the vector of Hampson could be administered to human children to treat Fragile X syndrome. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1, 7, and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Arsenault et al. (Human Gene Therapy 27: 982-996. 2016).
Arsenault teaches a method of treating Fragile X syndrome in mice comprising administering, via intracerebroventricular administration, a single stranded AAV vector with AAV9 serotype encoding the coding region of Mus musculus FMRP (isoform 1; a wild type protein) under the control of the synapsin promoter, a downstream Woodchuck Hepatitis posttranscriptional regulatory element (WPRE), and a poly adenylation site (abstract and page 982, column 1, paragraph 1-page 984, column 1, paragraph 1). As can be seen in Figure 2, the vector caused expression of the FMRP gene in Fmr1 knockout mice.
Arsenault does not teach administering their vector to a human patient.
However, Arsenault teaches that their study provides encouraging support for the development of AAV-FMRP as a viable human biopharmaceutical therapeutic agent as they demonstrated that their vector fully or partially rescued abnormal behaviors associated with Fragile X syndrome after moderate FMRP expression (page 994, column 1, paragraph 1-page 995, column 2, paragraph 2).
As such, it would have been obvious that one could modify the vector and the method of Arsenault for use in treating Fragile X syndrome in humans. The vector would need to be modified to encode the human isoform 1 FMRP protein instead of the mouse isoform 1 protein for expression in humans. As the mouse isoform 1 protein successfully rescued abnormal behaviors associated with Fragile X syndrome after moderate FMRP expression, it would have been obvious to use the human isoform 1 (i.e. the full length protein) in the vector for treating humans. Arsenault specifically identifies the potential for their results to inform the development of a viable human AAV-FMRP to treat humans. Therefore, it would have been obvious that one could modify the vector of Arsenault to encode a human isoform 1 protein and administer this vector to treat a human as Arsenault showed a similar vector worked in mice to treat Fragile X syndrome.
Regarding claim 16, specifically, as isoform 1 represents the full-length human protein, it would comprise amino acids 1-297 of the wild type sequence.
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631