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 .
Continued Examination Under 37 CFR 1.114
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03 February 2026 has been entered.
Status of the Application
1. Claims 14-29 and 31-34 are pending and subject to examination on the merits.
Priority
2. Acknowledgement is made of applicant’s claim for foreign priority based on an application filed in EP EP19175767.3 on 21 May 2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on 03 February 2026 has been considered by the examiner. See initialed and signed PTO/SB/08’s.
Maintained/Modified Rejections
Claim Rejections - 35 USC § 103
4. 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.
5. 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.
6. Claims 14-27, 29, and 31-34 are rejected under 35 U.S.C. 103 as being unpatentable over Caboche et al. (Caboche et al., 2015, US9132173B2—cited on the Information Disclosure Statement dated 06 February 2024) and Scheer and Justice (Scheer and Justice, 2016, US20160193231A1—cited previously).
Regarding claim 14, drawn to a method of treating Rett Syndrome by providing a vector comprising a cholesterol 24-hydroxylase (CYP46A1) encoding nucleic acid and delivering said vector to the brain or spinal cord, where said vector transduces cells in the brain to express cholesterol 24-hydroxylase at a therapeutically effective level, Caboche et al. teaches a method of treating Huntington’s disease (HD) with a vector comprising a cholesterol 24-hydroxylase encoding nucleic acid and delivering said vector to the central nervous system of the subject, where said vector transduces cells in the CNS to express cholesterol 24-hydroxylase at therapeutically effective levels (Column 5, lines 46-54). Caboche et al. teach (See Summary): The inventors observed that CYP46A1, an enzyme responsible of the degradation of cholesterol in the central nervous system, is neuroprotective in a cellular model of HD. Regarding claim 18, drawn to a vector comprising the nucleic acid sequence of SEQ ID NO: 1, Caboche et al. teaches utilizing the nucleic acid SEQ ID NO: 1, which is 99.9% identical to SEQ ID NO: 1 of the instant claim (Column 2, line 25 and ABSS Sequence Alignment 1—cited previously). Regarding claim 17 drawn to the vector comprising a nucleic acid that encodes for the amino acid sequence SEQ ID NO: 2, Caboche et al. teaches utilizing a vector encoding a nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 2 and having 100% sequence identity with instant SEQ ID NO: 2 (ABSS Sequence Alignment 2—cited previously). Regarding claims 19-21, 27 and 33, where the vector is an Adeno-Associated Virus (AAV) vector, specifically an AAV10 vector being the AAVrh.10 vector and is codon optimized for mammalian expression, Caboche et al. teaches using an AAVrh.10 vector with human CYP46A1 cDNA in frame in a mammalian model (Column 13, Example 2, lines 62-64). Regarding claims 22 and 25, drawn to administering the vector intravenously, Caboche et al. teach that the vector may be delivered by intravenous injection (Column 6, line 30). Regarding claims 23-24 and 29, drawn to the administration of the vector to the brain, neurons, and, specifically, striatal neurons, Caboche et al. teaches the injection of mice with the AAVrh.10 vector with human CYP46A1 cDNA in the striatum (striatal neurons) (Column 14, lines 8-11). Regarding claims 26, drawn to a pharmaceutical composition for use in treatment of Rett syndrome comprising the vector at a therapeutically effective amount, Caboche et al. teaches a pharmaceutical composition of the vector encoding the CYP46A1 (Column 1, lines 55-60). Regarding claims 31-32, drawn to the subject being a child, infant, and female, Cabouche et al. teaches the delivering of the vector to any mammal at any stage of development, e.g. infantile or juvenile, where transgenic mice where sex is not explicitly mentioned; however, it would be obvious to choose female, since there are only three available options (male, female, or intersex) (Column 6, lines 37-39). Regarding claim 34, drawn to an AAV vector being a AAV1, 2, 3, 4, 5, 6, 7, or 8, Cabouche et al. teaches that the AAV vector may be AAV1, AAV2, AAV3, AAV4, AAV5, or AAV6 (Column 3, line 60).
Caboche et al. does not teach the utilization of the CYP46A1 containing vector to specifically treat Rett Syndrome, where Rett Syndrome is associated with an autism spectrum disorder or intellectual disability (claims 14-16).
Scheer and Justice teach new strategies in the treatment of Rett Syndrome, where specifically, “the present invention defines certain components of metabolic pathways, and particularly of lipid and/or cholesterol metabolism (e.g., biosynthesis) pathways… in the brain, as targets useful in the identification and/or characterization of potential Rett Syndrome treatment agents” (Summary, paragraph 0005). Regarding claim 15, drawn to Rett Syndrome associated with autism, Scheer and Justice continue to teach that individuals with Rett Syndrome may have associated forms of autism (paragraph 0081). Regarding claim 16, drawn to Rett Syndrome associated with intellectual disability, Scheer and Justice teach that Rett Syndrome is one of the most common causes of intellectual disability in females (Background, paragraph 0001).
Therefore, it would have been obvious to one skilled in the art prior to the effective filing date of the claimed invention to combine the teachings of Caboche et al. and Scheer and Justice to specifically treat Rett Syndrome by administering an AAV CYP46A1 containing vector to an affected individual because “Cholesterol metabolism has been implicated in neurological diseases such as Alzheimer's, Parkinson's and Huntington's Diseases, as well as in Amyotrophic Lateral Sclerosis and Fragile X Syndrome” and treatment of any or all of these disorders including Rett syndrome as taught by Scheer and Justice (paragraphs 0081-0082). One would be motivated to combine these teachings to arrive at the instant claims because Rett Syndrome is typically caused by a mutation(s) in the MECP2 gene, which is involved in cholesterol metabolism (Scheer and Justice, paragraph 0078-0079), and, further, Scheer and Justice teach that CYP46A1-/- mice demonstrate the identical cholesterol metabolism phenotype as the model Rett Syndrome mice (paragraph 0173). There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Caboche et al. with Scheer and Justice, since Caboche et al. teaches a vector for the expression of CYP46A1 in cells of the central nervous system for treatment and control of cholesterol metabolism (Column 1, lines 55-57) and Scheer and Justice teach the implication of CYP46A1 in Rett Syndrome (paragraph 0173).
7. Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Caboche et al. and Scheer and Justice as applied to claims 14-27, 29 and 31-34 above, and further in view of Dayton et al. (Dayton et al., 2018, Gene Therapy—cited on the Information Disclosure Statement dated 06 February 2024).
The teachings of Caboche et al. and Scheer and Justice are discussed above and incorporated into the instant rejection.
Caboche et al. and Scheer and Justice do not teach the utilization of the specific AAV10 vector, AAVPHP.eB vector. Dayton et al. teaches the utilization of the AAV PHP.EB (AAVPHP.eB) vector in rat CNS to test expression levels and neuronal transduction and further that this vector is one of the most efficient AAV vectors in the field for CNS gene transfer (p. 392, Abstract).
Therefore, it would have been obvious to one skilled in the art prior to the effective filing date of the claimed invention to combine the teachings of Caboche et al. and Scheer and Justice with that of Dayton et al. to utilize the AAVPHP.eB vector to deliver the CYP46A1 to treat Rett Syndrome because Dayton et al. teaches that the AAVPHP.eB vector is one of the most efficient AAV vectors in the field for CNS gene transfer as stated above. One would be motivated to combine these teachings to arrive at the instant claims because the AAVPHP.eB vector is more efficient, and more efficient vectors should provide greater neuronal transduction, the ability to use lower vector doses, which lowers the potential of non-specific side effects as taught by Dayton et al. (p. 392, Introduction, Column 2, lines 16-20). There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Caboche et al. and Scheer and Justice with that of Dayton et al. since engineered recombinant adeno-associated virus vectors have advanced the transduction of neurons in the CNS on an expansive, wide-scale basis, as taught by Dayton et al. (abstract).
APPLICANT’S ARGUMENTS AND EXAMINER’S REBUTTAL
The applicant traverses the previous obviousness rejections of claims 14-27 and 29 over Caboche et al and Scheer and Justice. Additionally, the applicant traverses the obviousness rejection of claim 28 over Cabouche et al. and Scheer and Justice and in further view of Dayton et al. New claims 31-34 have been addressed in the above modified rejections.
First, the applicant argues that the Scheer disclosure does not demonstrate a correlation of Cyp46a levels during disease progression. However, the examiner respectfully disagrees. Scheer et al. does teach an increase in Cyp46a1 in early, asymptomatic early disease, where specifically Scheer et al teaches: “When Mecp2tm1.1Bird/Y mice display minimal symptoms, Cyp46a1 expression is already increased (38-fold over wild type; p>0. 05) in the null brain, indicating a heightened need for cholesterol turnover in early stages of disease. Further, Fig. 2b demonstrates a critical turning point of Cyp46a1 between the P28 and P56 mice, where the P56 mice demonstrate a sharp decrease (38 fold lower than wild type). Therefore, this is a correlation between protein levels and disease progression (paragraph 0172).
Second, the applicant argues that Scheer et al. teaches against the addition of Cyp46a1 as a therapeutic in disease because one would want to reduce cholesterol levels and would do so by the administration of statins. The examiner respectfully disagrees. Since there is a marked uptick and subsequent downtick of the expression level of the protein during disease progression, this makes the protein an attractive target for therapeutics. Additionally, the applicant contends that lowering cholesterol is the goal in treatment. The examiner understands this position; however, Scheer et al. states that the upregulation in Cyp46a1 during early disease is indicative of the need for cholesterol turnover (paragraph 0172). Additionally, the reason to combine the teachings of the reference need not be the same as that of the applicant. MPEP § 2144.
Third, the applicant argues that Scheer teaches the reduction of cholesterol in the brain to treat Rett syndrome. However, the examiner disagrees with this interpretation. Scheer et al. teaches that the “trait amelioration occurs by modifying the abnormal synthesis and deposition of lipids in the brain and liver of MECP2 male and female mice, and thereby establishes that such abnormal synthesis and deposition causes some or all of the metabolic defects associated with RTT. The present Example thus establishes that statin drugs can be used to alleviate the abnormal lipid deposition and improve motor symptoms in male and female mice. Thus, Scheer et al. does not teach cholesterol reduction via statins but rather the decrease in abnormal lipid deposition.
It does not matter if the Scheer et al. does not teach the same things as claimed in the claims here as long as the steps followed and the components used in the treatment methods are very similar. Whatever applicant observed is perhaps inherent to the treatment steps even though the reference may not identify the same.
Fourth, the applicant argues that the Examiner’s response in the advisory reaction was conclusory and needs to utilize official notice. However, the examiner disagrees because this argument/response was not utilized in the teachings or rationales in the obviousness type rejections above.
Fifth, the applicant continues to argue that Cyp46a1 does not reduce cholesterol levels and thus would not be utilized as a therapeutic. Again, the reduction of cholesterol was not the intent of Scheer et al; again, it was the deposition of lipids. The applicant continues to argue that Scheer et al. does not teach the reduction of cholesterol but merely mentions that the modulation of certain pathways may be useful in the treatment of Rett Syndrome absent any indication of the directionality of said modulation. The examiner agrees with this assertion insofar that modulation could go either way, up or down. However, the standard of obviousness is not absolute expectation of success, it merely has to be a reasonable expectation of success, and given the teachings of Scheer et al. demonstrate a change in protein expression level and suggest the modulation of cholesterol controlling pathways; there would be a reasonable expectation of success that the addition of Cyp46a1 to a Cyp46a1 deficient individual could result in a therapeutic effect.
Sixth, the applicant continues to argue that Cyp46a1 is overexpressed, and therefore, a skilled artisan would not administer further Cyp46a1 to a subject with Rett Syndrome. However, as discussed above, there is an overexpression of the Cyp46a1 protein early in disease when symptoms are absent; however, later in the disease Cyp46a1 is markedly decreased (as discussed in detail above).
Seventh, the applicant argues that Caboche does not teach the utilization of Cyp46a1 as a therapeutic in Rett Syndrome. The examiner utilized this reference to teach the utilization of a Cyp46a1 containing vector in neurons of subjects not in the disease of Rett Syndrome.
Eighth, the applicant argues that the rejection to claim 28 is traversed for the same arguments utilized above (arguments 1-7). The examiner detailed the rebuttals to each of these arguments above.
The examiner does not find the arguments presented by the applicant persuasive, and for these reasons, the rejections of record above apply.
Conclusion
8. All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CIARA A MCKNIGHT whose telephone number is (703)756-4791. The examiner can normally be reached M-F 8:00am-4:30pm.
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/CIARA A MCKNIGHT/Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656
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