Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 1-49 and 54-58 are pending.
Priority
Claims 1-49 and 54-58 have priority to PRO 63/317,155 filed on March 7, 2022.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on November 21, 2023, and on October 10, 2025, were filed before the mailing of the First Office Action on March 28, 2026. The Non-Patent Literature is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
Election/Restriction
Applicant’s election of Claims 1-11, 27-30, 36-40, 42, 50, and 52 of Group I drawn to the polynucleotide sequence of SEQ ID NO: 3 capable of being expressed by means of an expression vector where the expressed polynucleotide sequence is combined with a pharmaceutical acceptable carrier for treating Angelman syndrome, in the reply file on January 6, 2026, is acknowledged with claims 50 and 52 being canceled.
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.
Invention II for claims 12-26, 31-34, 41, 43-49, 51, and 53, Invention III for claim 35, Invention IV for claims 54 and 55, Invention V for claim 56, and Invention VI for claims 57 and 58 are being withdrawn to nonelected groups.
Additionally, since no species election was made for claims 12 and 57 due to these claims not being elected, the election of species requirement is held in abeyance.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the 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 shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the 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 shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 27-30 are rejected under 35 U.S.C. §112(a) or 35 U.S.C. §112(pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most clearly connected, to make and/or use the invention.
The Nature of the Invention:
Claims 27-30, 36-40, and 42 are directed to a therapeutic method comprising administering a polynucleotide encoding SEQ ID NO: 3, a shRNA, for the treatment of Angelman syndrome by inhibiting silencing of the paternal UBE3A gene. The specification generically states “in embodiments, SEQ ID NO: 3 encodes a shRNA capable of inhibiting the silencing of UBE3A” and describes that “compositions and methods described herein are drawn to targeting SNORD115 and UBE3A-ATS to unsilenced the paternal UBE3A allele. Effective inhibition…result in reduction in SNORD115 and UBE3A-ATS expression levels and concomitant increase in the expression levels of the paternal UBE3A” [¶ 0027]. The specification also generically describes delivery via viral vectors, including AAV and lentivirus [¶ 0054, 0074, 0081, and 0082].
Examiner’s note: the same analysis for claims 27-30 is applied to claims 36-40
Breadth of the Claims:
Claims 27-30, 36-40, and 42 recite therapeutic methods of treatment in a patient, including functional outcomes such as reduction of UBE3A-ATS (claim 28), reduction of SNORD115 (claim 29), and increased expression of paternal UBE3A (claim 30). Claim 27 is directed to administering the polynucleotide to treat Angelman syndrome in a patient and include clinical administration, dosing, delivery routes, and therapeutic effects.
Amount of Direction or Guidance in the Application:
The specification provides only generic guidance concerning vectors, e.g. adeno-associated viruses and lentiviruses), virus particles, and promoters. The discussion of vectors is high level, referring to typical components of viral particles and stating that “viral vectors contain structural and/or functional genetic elements that are primarily derived from a virus” [¶ 0054], and that adeno-associated viruses is “a common mode of delivery of DNA…relatively non-toxic” [¶ 0082]. Promoter selection is described as readily accomplished, with examples of polymerase II and III promoters [¶ 0069-0070]. Aside from the generic listing, there is no specific guidance on how to formulate, manufacture, or deliver therapeutic vector constructs into a human patient, how to cross the blood-brain barrier, or how to achieve therapeutic efficacy in vivo. The only working examples provided involve in vitro neuron culture models.
Presence or Absence of Working Examples:
The specification’s working examples are limited to in vitro experiments. While these experiments demonstrate modulation of transcript levels in cultures AS hESC-derived neurons following viral transduction, they do not demonstrate therapeutic administration to a subject. There is no working example showing effective in vivo delivery, dosing, or treatment of Angelman syndrome in a patient or animal model.
Relative Skill in the Art:
It is argued that the relative skill in the art, is that of a scientist with several years’ experience in the field, but the Art itself is a recognition of what is understood by the Artisan, and thus, as seen below, does not make the breadth of the claims more predictable.
The Predictability or Lack thereof in the Art:
The art demonstrates that achieving therapeutic outcomes in patients is not predictable based solely on in vitro gene expression modulation. Prior publications in the field discuss numerous obstacles for clinical translation of central nervous system gene therapy, including immune response, vector tropism, delivery challenges, and biodistribution issues. For example, Puhl et al. highlights that “viral vectors…safety concerns exist with the use of viral vectors for CNS gene delivery” [Abstract, Challenges of gene delivery to the central nervous system and the growing use of biomaterial vectors, Brain Res Bull, 2021]. This illustrates that in vivo therapeutic efficacy in central-nervous system disorders require addressing barriers and methodologies that are not present in the specification.
Quantity of Experimentation Needed:
Substantial optimization beyond routine in vitro studies would be required to practice the claimed treatment methods of claims 27-30, including selection of vector serotypes, engineering vector capsids for central-nervous system tropism, determining the effective dosing regimens, identifying safe and systemic or localized delivery routes, and overcoming immune barriers to name a few. Based on this, the level of experimentation would be undue.
Conclusion:
Given this, the specification fails to provide sufficient disclosure to allow one of ordinary skill in the art to make and use the claimed invention without undue experimentation.
Claims 27-30, 36-40, and 42 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 27 uses the generic phrase “a method of treating Angelman syndrome” as it relates to administering the polynucleotide found in SEQ ID NO: 3. The same generic scope of the “method of treating Angelman syndrome” is present in each of the dependent claims, i.e. Claims 28-30.
Claim 36 uses the generic phrase “inhibiting the silencing of a paternal UBE3A gene by an RNA antisense transcript…administering to a patient in need thereof…the polynucleotide of claim 1”. The same generic scope of “inhibiting the silencing of a paternal UBE3A gene by an RNA antisense transcript…administering to a patient in need thereof…the polynucleotide of claim 1” is present in each of the dependent claims, i.e. 37-40 and 42.
The specification provides antecedent basis for both generic phrases in claim 27 and claim 36 [¶ 0010 and 0012].
Applicant’s specification states “a method of treating Angelman syndrome including administering to a patient in need thereof the polynucleotide of SEQ ID NO: 3 [¶ 0010]. The specification further states “the polynucleotide of SEQ ID NO: 3 encodes a shRNA which causes a reduction of expression of paternal SNORD115 and UBE3A-ATS [Id.]. In ¶ [0012], the specification states the polynucleotide, i.e. SEQ ID NO: 3, is capable of inhibiting the silencing of paternal UBE3A. However, the specification only provides in vitro data showing that AS hESC-derived neurons transduced with lentiviral particles expressing shRNAs targeting SNORD115 and UBE3A-ATS exhibit changes in transcript levels [¶ 00100]. There is no disclosure demonstrating that the methods are effective in a patient or even animal model given there is no guidance for in vivo administration, delivery or dosing. The specification only contains generic statements regarding viral vectors, including adeno-associated viruses and lentiviruses [¶ 0054, 0074, and 0082], and promoters such as RNA polymerase II and III, as well as other promoters [¶ 0069, 0070, and 0074]. Given the unpredictability of gene therapy and viral vectors, let alone gene therapy that has to cross the blood-brain barrier as, as discussed in Puhl et al., a person of ordinary skill would have difficulty quantifying the numerous combinations of promoters, viral vectors, and the disclosed polynucleotide, i.e. shRNA, that would be effective in treating Angelman syndrome where it results in the silencing of a paternal UBE3A gene given there are no working examples in vivo experiments other than a brief description of an in vitro experiment carried out with AS-hESC-derived neurons that were transduced with lentiviral particles to express the selected shRNA sequences targeting SNHG14 long non-coding RNA.
Given the generic phrases “a method of treating Angelman syndrome” of claim 27 and “inhibiting the silencing of a paternal UBE3A gene by an RNA antisense transcript…administering to a patient in need thereof…the polynucleotide of claim 1” of claim 36, as they both relate to treating Angelman syndrome and the absence of teachings that include any evidence of success in vivo, the Artisan would not understand Applicant to be in possession of the generic scope of a method of treating Angelman syndrome by administering the polynucleotide by silencing of the paternal UBE3A gene given only in vitro examples were provided.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5, 36-40, and 42 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 5 recites the limitation "neuron specific promoter" in Line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 36 recites “inhibiting the silencing of a paternal UBE3A gene by an RNA antisense transcript encoded by SEQ ID NO: 2”. A person of ordinary skill would not understand specifically what SEQ ID NO is responsible for silencing the inhibition of the paternal UBE3A gene. A person of ordinary skill would understand that reducing or inhibiting the levels of UBE3A-ATS would lead to the suppression or silencing of the inhibition of UBE3A, therefore allowing the UBE3A gene to be expressed. Here, the claim seems to be attributing the inhibition of UBE3A silencing to SEQ ID NO: 2 which based on the sequence listing provided is a nucleotide sequence for SNORD115. Given the language, a person of ordinary skill would not understand with reasonable certainty the functional scope of the claim or which RNA is actually responsible for inhibiting silence.
Claim 36 recites “effective to cut the RNA antisense transcript”. The term “cut” is unclear. shRNAs are transcribed in the nucleus by RNA polymerase II or III depending on promoter and then becomes a short guide RNA that joins a cellular protein complex called RISC. This guide RNA then directs the complex to a matching messenger RNA from the target gene. This complex then cleaves or blocks the mRNA from being used. However, the shRNA itself does not “cut” or cleave itself. Because of this, a person of ordinary skill would not be able to understand what is meant by “encoding a shRNA effective to cut the RNA antisense transcript”.
Claims Free of the Art
Claims 1-4 and 6-11 are free of the art. The art does not teach or disclose the polynucleotide construct of claim 1.
Claims 2-4 and 6-11 are free of the art based on dependency to claim 1.
Claim 5 stands rejected under 35 U.S.C. §112(b).
Conclusion
Claims 1-4 and 6-11 are allowed.
Claims 5, 27-30, 36-40, and 42 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN DAVID MOORE whose telephone number is (703)756-1887. The examiner can normally be reached M-F 8-5.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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