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 .
Priority
The instant application, filed on 12 January, 2024, is a 371 of PCT/US22/3708 filed on 14 July, 2022, which further claims domestic benefit to US provisional application no. 63/222,141, filed on 15 July, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05 May, 2025 has been considered by the examiner.
Status of Application, Amendments, and/or Claims
The response filed on 03 September, 2024 has been entered in full. These are the amended claims of the original claim set received on 12 January, 2024. In the amendment, claims 1-20 are original and claims 21 and 22 are cancelled. Therefore, claims 1-20 are pending and are the subject of this Office Action.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 102
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 1-4, 11, 12, 13-17 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Fassler and George (WO 2020/003203, of record IDS 05/05/2025).
In regards to claims 1 and 4 Fassler and George anticipate a method of treating an alpha-synucleinopathy by administering an antibody/single chain fragment variable (PMS208) (pg.7, lines 29-33/ claim 53) which target the small molecule oligomers and preformed fibrils (PFFs) of alpha synuclein (pg.16, lines 29-30) with a higher affinity for PFFs (pg.19, lines 22-25). Further the antibody attenuates toxicity induced by both oligomers and PFF to human and murine neuronal cells as well as downregulates a panel of proinflammatory cytokines produced by microglia (pg.16 line 31- pg.17 line 4).
In regards to claim 2 Fassler and George anticipate the subject to be treated is a mammal and preferably a human (pg.40, lines 21-22/ claim 60).
In regards to claim 3 Fassler and George anticipate the synucleinopathy being dementia with Lewy bodies (DLB) (claim 57).
In regards to claim 11 Fassler and George anticipate PMS208 abrogates PFF seeding (endogenous alpha synuclein aggregation) by inhibiting the PFF prion-like mechanism (pg.63, lines 9-18).
In regards to claim 12 Fassler and George anticipate the method used both in vitro and in vivo. Such as attenuating the neuroinflammation in microglia cells exposed to PMS208 in vitro (Example 7), abrogating the spreading and seeding of human PFFs in vitro (Example 13) or attenuating neuroinflammation in vivo in a murine model (Example 9).
In regards to claim 13 Fassler and George anticipate the route administration of the antibody being selected from a group which includes intravenous and intrathecal (claim 55).
In regards to claims 14 and 15 Fassler and George anticipate the antibody is conjugated to secondary agent selected from a group comprising a therapeutic agent, a peptide, or a pharmaceutical agent (claim 26).
In regards to claim 16 Fassler and George anticipate detecting misfolded alpha synuclein by contacting a biological sample (plasma or CSF, (pg.36, lines 9-11)) with an antibody or antigen binding fragment (pg.8 line 28 – pg.9 line 2) and further the antibody or antigen binding fragment can also be used as a therapeutic as outlined above.
In regards to claim 17 Fassler and George anticipates a composition comprising the antibody and a carrier which can be used as a therapeutic composition (Claims 34 and 36).
Claim Rejections - 35 USC § 103
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.
Claims 5-8, 10, 16, 18, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Fassler and George as applied to claims 1 and 4 above, and further in view of Belanger (2019) Single-Domain Antibodies as Therapeutic and Imaging Agents for the Treatment of CNS Disease Antibodies 8(27), and Slavc et al. (2018) Best practices for the use of intracerebroventricular drug delivery devices Molecular Genetics and Metabolism 124; 184-188 and further as evidenced by Baral et al. (2013) Single-Domain Antibodies and Their Utility Current Protocols in Immunology 2.17.1-2.17.57.
Fassler and George teach the method of treating an alpha-synucleinopathy comprising administering to CNS cells an antibody against alpha synuclein PFFs as outlined above for claims 1 and 4.
In regards to claim 8, 10, and 19 Fassler and George further teach administering the antibody by viral vector which encodes the antibody and further wherein the viral vector is an adeno associated viral vector (AAV) (claims 44-48).
Fassler and George fail to teach the anti alpha-synuclein PFF antibody being a nanobody of claims 5, 8, 10, 18, and 19, the nanobody not comprising a disulfide bond of claim 6, the fibril specific nanobody of claim 7, and the intracerebroventricular administration of claim 10.
Belanger, however, in regards to claims 5, 8, 10, 18, and 19 teaches that single-domain antibodies (nanobodies) are beneficial to treat central nervous system diseases because their small size, low non-specific interactions with tissues expressing high levels of Fc receptors, remarkable stability against harsh conditions, and low immunogenicity make them advantageous as a transvascular brain delivery vector compared to conventional antibodies (pg.5, lines 14-17). Further Belanger teaches that NbSyn87 is an anti-alpha synuclein nanobody which can bind to the fibril form of alpha synuclein associated with early onset Parkinson disease without structural consequences (pg.8 line 46 – pg.9 line 1). Further Belanger teaches NbSyn87 inhibits the formation of mature fibrils in vitro and induces the conversion of alpha-synuclein from a more stable oligomer to a less stable oligomer reducing cellular toxicity (pg.9 lines 2-5).
In regards to claim 7 Balenger teaches constructing a natural repertoire of single domain antibodies (sdAbs) libraries is a well-established protocol (pg.3, lines 13-14), as evidenced by Baral, which is cited by Balenger and provides methods for immunizing llamas and utilizing phage display to make a library of nanobodies against a specific antigen. Further Balenger teaches the selection or panning of the sdAbs from a library involves selecting for a single property including affinity for the target antigen, wherein the library exposed to an immobilized antigen, eluting bound phage molecules, amplifying them for another round of panning. The process can be repeated until a sufficient number of high affinity sdAbs are obtained (pg.3, lines 22-29).
In regards to claim 10 Balenger teaches a group that used a single domain antibody to treat Huntington’s disease, wherein they removed the disulfide bond to increase the potency of the nanobody and increase the binding affinity by allowing efficient expression of natively folded nanobodies in the cytoplasm (pg.9, lines 26-28). Belanger fails to teach the intracerebroventricular administration of the AAV of claim 10. Slavc, however, teaches the intracerebroventricular administration has been used in the treatment of a broad range of central nervous system disorders because it circumvents the need to cross the blood brain barrier and allows drug to achieve their full therapeutic effect (abstract).
Thus, Fassler and George discloses a method of treating an alpha synucleinopathy by administering an antibody against alpha-synuclein preformed fibrils to inhibit them, Belanger teaches nanobodies are a more effective option for a vehicle because they can cross the blood brain barrier, are less immunogenic, and can survive harsh conditions, NbSyn87 is a nanobody which binds to alpha-synuclein preformed fibrils, and removing the disulfide bond in a nanobody can increase its potency. Further Belanger teaches obtaining and selecting for high affinity nanobodies is well known in the field. Slavc teaches that it is effective to bypass the blood brain barrier during administration by intracerebroventricular administration to achieve full therapeutic effect. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Fassler and George with the teachings of Belanger to substitute the antibody of Fassler and George with the nanobody NbSyn87 of Belanger or further use the suggestions of Balenger to obtain a fibril specific nanobody, and to try the teachings of intracerebroventricular administration of Slavc with a reasonable expectation of success to develop a method of treating an alpha-synucleinopathy which has the increased ability to cross the blood brain barrier and or circumvent it completely for a more effective therapeutic to inhibit alpha synuclein preformed fibrils.
Allowable Subject Matter
Claims 9 and 20 are objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claims 9 and 20 refer to SEQ ID NOs: 1 and 2, which could not be found in the prior art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DASIA A ALDARONDO whose telephone number is (571)272-1977. The examiner can normally be reached on Monday – Friday from 8:30 am to 4:30 pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at telephone number (571)272-2911. The fax phone number for the organization where this application or proceeding is assigned is (571)273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center to authorized users only. Should you have questions about access to the USPTO patent electronic filing system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Examiner interviews are available via a variety of formats. See MPEP § 713.01. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/InterviewPractice.
/D.A.A/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
Prosecution Insights