DETAILED ACTION
Claims 1-20 are pending.
The amendment filed on 11/27/2024 amending the Specification, Sequence Listing and Drawings is acknowledged.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is a CON of PCT/US2023/063719 and claims priority to 63/316,547 filed on 03/04/2022.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. Hyperlinks can be found on pages 19 and 21.
Claim Rejections - 35 USC § 112(a) Written Description
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 1-16 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.
As stated in MPEP 2111.01, during examination, the claims must be interpreted as
broadly as their terms reasonably allow.
Claim 1 is directed to a composition for treating any neurodegenerative disease comprising at least one component (one or more components) that targets at least one (one or more) muscleblind-like protein (MBNL) binding site near exon 10 of microtubule-associated protein tau (MAPT) to block MBNL binding thereto and modulate exon 10 splicing. Claims 2-8 depend directly or indirectly therefrom claim 1.
The specification discloses support for two major MBNL binding sites (denoted site 1 and site 2) in intron 10. For components that target MBNL binding sites, the specification has examples for dCas13gRNA and ASOs and the claim exceeds what is actually described in the specification.
Claim 9 is directed in part to a method of treating any neurodegenerative disease comprising the step of administering to a patient (human) in need thereof an effective dose of a pharmaceutical composition comprising any molecule which targets at least one muscleblind-like protein (MBNL) binding site near exon 10 of microtubule-associated protein tau (MAPT) to block MBNL binding thereto and modulate exon 10 splicing. Claims 10-16 depend directly or indirectly therefrom claim 9.
The specification discloses in vitro splicing modulation data for dCas13gRNA and ASO 1 and ASO 4 reduced exon 10 inclusion in HEK293T cells (Examples 5 & 6). This disclosure shows that the inventors possessed the concept of using dCas13gRNA and ASOs to antagonize MBNL binding and modulate exon 10 splicing in vitro, but it does not reasonably convey possession of all molecules that inhibit MBNL binding to binding sites near exon 10 to treat any neurodegenerative disease.
Claim Rejections - 35 USC § 112(a) Scope of Enablement
Claims 1-8 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a composition comprising dCas13d or ASOs that target MBNL binding sites in , does not reasonably provide enablement for any composition that targets MBNL binding sites near MAPT exon 10 to modulate splicing and treat disease. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are
summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2nd 1400 (Fed. Cir. 1988)) as follows:
1) quantity of experimentation necessary, 2) the amount of direction or guidance presented, 3)
the presence and absence of working examples, 4) the nature of the invention, 5) the state of
prior art, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art,
and 8) the breadth of the claims. The factors which have led the Examiner to conclude that the
specification fails to teach how to make and/or use the claimed invention without undue
experimentation, are addressed in detail below.
The breadth of the claims. Claim 1 broadly encompasses a composition for treating any neurodegenerative disease comprising any component that targets any MBNL site near exon 10. The specification does not enable the full scope of this composition claim set without undue experimentation.
State of the prior art. Goodwin et al. (Cell Reports, 2015) shows MBNL binding near MAPT exon 10. Kalbfuss et al. (Journal of Biological Chemistry, 2001) shows ASOs can alter tau exon 10 splicing. Konermann et al. shows dCas13d can modulate tau splicing.
Working examples. The specification has in vitro HEK293T minigene data for ASOs and dCas13dgRNA that show blocking MBNL binding at two specific sites (Example 5 and 6). Accordingly, the limited working examples weigh against enablement because a person of ordinary skill in the art would need to engage in more than routine experimentation to practice the full scope of the claimed method set.
Quantity of experimentation necessary. A skilled artisan would have to do significant amount of experimentation to cover the full genus of “at least one component” and “at least two” sites. A person of ordinary skill in the art would need to determine which MBNL-binding site or sites near MAPT exon 10 are suitable targets, which component class is effective for a given target site or site combination, and how to optimize sequence, chemistry, dosage and delivery to achieve the claimed result.
Claims 9-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for in vitro systems to study neurodegenerative disease mechanisms , does not reasonably provide enablement for a method of treating a neurodegenerative disease in a patient. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
The breadth of the claims. Claim 9 broadly encompasses any neurodegenerative disease treatment via MBNL-site targeting near MAPT exon 10. The specification does not enable the full scope of this composition claim set without undue experimentation.
Working examples. The specification appears to provide only in vitro HEK293T/minigene data and predictive statements about possible clinical use, without in vivo efficacy data, human clinical data, dosing guidance, route-of-administration guidance, or other disclosure sufficient to teach a person of ordinary skill in the art how to practice the claimed treatment without undue experimentation.
Quantity of experimentation necessary. A person of ordinary skill in the art would need to determine whether the disclosed compositions are effective in disease-relevant tissue, whether they achieve adequate brain delivery or target engagement, what dose constitutes an “effective dose”, and whether the method is safe and effective across the full scope of “neurodegenerative disease” recited in the claims. The specification does not provide sufficient direction or working examples for these issues, and the claimed therapeutic scope is therefore broader than the enabled disclosure.
Claim Rejections - 35 USC § 112(b)
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 1-3, 6-9 and 11-14 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 1 is indefinite in the recitation of “near exon 10” for the following reason. The claim does not provide an objective boundary for what constitutes an MBNL binding site “near” exon 10. Read in light of the specification, the term leaves the metes and bounds of the claim uncertain. Correction is required.
Claim 6 is indefinite in the recitation of “useful” for the following reason. It is unclear what aspect/property of treating FTD is useful. Correction is required.
Claims 7-8 are indefinite in the recitation of “ASO 1” and “ASO 4” for the following reason. It is unclear what antisense nucleotides (ASO) are considered as ASO “1” and ASO “4”. Correction is required.
Claim 9 is indefinite in the recitation of “effective dose” and “targets at least one muscleblind-like protein (MBNL) binding site near exon 10… block MBNL binding” for the following reasons. The claim does not state what amount of composition is “effective”, what level of binding inhibition is sufficient to “block” MBNL binding. Correction is required.
Claim 9 is indefinite in the recitation of “near exon 10” for the following reason. The claim does not provide an objective boundary for what constitutes an MBNL binding site “near” exon 10. Read in light of the specification, the term leaves the metes and bounds of the claim uncertain. Correction is required.
Claims 11-14 are indefinite in the recitation of “MBNL binding site near exon 10” for the following reason. The claim does not provide an objective boundary for what constitutes an MBNL binding site “near” exon 10. Read in light of the specification, the term leaves the metes and bounds of the claim uncertain. Correction is required.
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.
Claims 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over Furling et al. (US2017/0035841A1, published 02/09/2017), in view of Goodwin et al. (Cell Reports, Vol. 12, Issue 7, pg. 1159-1168, published on 08/18/2015).
Furling et al. teaches a pharmaceutical composition comprising a modified MBNL polypeptide (ΔCT3) that has almost no splicing activity (see paragraphs [0034] - [0036]). Furling et al. teaches that ΔCT3 targets pathogenic CUG repeats and blocks access to endogenous MBNL1 (see paragraph [0075]). Furling et al. teaches that ΔCT3 proteins correct both alternative splicing misregulation and myotonia in Myotonic Dystrophy 1 (DM1) mice (see paragraph [0073]). Furling et al. teaches ΔCT3 construct restores DM1 deregulated splicing of Tau exon2/3 minigene (see Figure 3). Furling et al. teaches that the modified MBNL protein maintains its YGCY binding property (see paragraph [0007]).
Furling et al. does not teach a composition that targets a MBNL binding site near exon 10.
Goodwin et al. teaches in dCLIP and crosslinked induced mutation site analysis of MBNL2 binding in hippocampus revealed MBNL protein bind primarily to YGCY clusters within intron 10 (see Aberrant Tau Processing in DM1 and Mbnl Compound Knockouts). Goodwin et al. teaches a major Mbnl2 binding peak was detectable in Mapt Intron 9 upstream of the exon 10 3’ ss (see Figure 5B). Goodwin et al. teaches double knockout of MBNL1 and MBNL2 triggers a strong change towards exclusion, suggesting that both MBNL1 and MBNL2 synergize to control MAPT exon 10 splicing (see Aberrant Tau Processing in DM1 and Mbnl1 Compound Knockouts).
Claims 1-3 are directed in part to a composition for treating any neurodegenerative disease, the composition comprising at least one component that targets at least one muscleblind-like protein (MBNL) binding site near exon 10 of microtubule-associated protein tau (MAPT) to block MBNL binding thereto and modulate exon 10 splicing, wherein the component targets two or more MBNL binding sites or wherein the component targets two MBNL binding sites.
It would have been obvious to one of ordinary skill in the art before the effective filling date of the claimed invention to modify the pharmaceutical composition of Furling et al. to bind YGCY clusters near exon 10 of MAPT to block MBNL binding to treat DM.
A person of ordinary skill in the art is motivated to block MBNL binding near exon 10 because Goodwin et al. teaches both MBNL1 and MBNL2 synergize to control MAPT exon 10 splicing in DM.
One of ordinary skill in the art has a reasonable expectation of success because the proposed modification applies a known splicing modulation strategy to a known disease-relevant tau exon 10 target, and the art shows predictable results from interfering with RNA-splicing interactions. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Furling et al. (US2017/0035841A1, published 02/09/2017), Goodwin et al. (Cell Reports, Vol. 12, Issue 7, pg. 1159-1168, published on 08/18/2015) as applied to claims 1-3 above, and further in view of Konermann et al. (Cell, published 04/19/2018).
The teachings of Furling et al. have been discussed above.
The teachings of Goodwin et al. have been discussed above.
Konermann et al. teaches dCasRx target to MAPT exon 10 could induce exclusion to alleviate dysregulated 4R/3R tau ratios (see Viral Delivery of dCasRx to a Neuronal Model of Frontotemporal Dementia). Konermann et al. teaches RNA-targeting Cas13d/dCas13d systems for transcriptome engineering.
Claim 4 is directed in part to the composition of claim 1, where the component comprises nuclease-inactive dCas13d in complex with one or more guide RNAs.
It would have been obvious to one of ordinary skill in the art before the effective filling date of the claimed invention to use dCas13d in complex with guide RNAs targeted to MAPT exon 10 to block MBNL binding.
A person of ordinary skill in the art is motivated to use dCas13d/gRNA because Konermann et al. shows that Cas13d is a programmable RNA-targeting platform, making it a natural implementation for directing a binding/steric blocking component to the claimed RNA site.
One of ordinary skill in the art has a reasonable expectation of success because Konermann et al. demonstrates that RNA-targeting Cas13d systems can be programmed to bind selected transcripts, so adapting that platform to the MBNL-binding site strategy would have been a routine and predictable substitution. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 5-8 are rejected under 35 U.S.C. 103 as being unpatentable over Furling et al. (US2017/0035841A1, published 02/09/2017), Goodwin et al. (Cell Reports, Vol. 12, Issue 7, pg. 1159-1168, published on 08/18/2015) as applied to claims 1-3 above, and further in view of Kalbfuss et al. (Journal of Biological Chemistry, published 11/16/2001).
The teachings of Furling et al. have been discussed above.
The teachings of Goodwin et al. have been discussed above.
Kalbfuss et al. teaches modified oligonucleotides directed against the tau exon 10 splice junctions suppress inclusion of tau exon 10 and that the alternative splicing defects of tau as found in frontotemporal dementia and Parkinsonism associated with chromosome 17 (FTDP-17) can be corrected by application of antisense oligonucleotides (see abstract).
Claims 5-8 are directed to the composition of claim 1, wherein at least one of the components comprises one or more antisense nucleotides, wherein the composition is useful for treating frontal temporal dementia (FTD), wherein the ASOs comprise one or more of ASO 1 and ASO 4 and wherein ASO1 and ASO4 are useful in treating FTD.
It would have been obvious to one of ordinary skill in the art before the effective filling date of the claimed invention to use ASOs to block MBNL binding near exon 10 in FTD patients.
A person of ordinary skill in the art is motivated to use ASOs because Kalbfuss et al. shows ASO-mediated correction of tau exon 10 splicing in a frontotemporal dementia context, and ASOs are a well-known way to sterically block RNA-protein interactions at a target site.
One of ordinary skill in the art has a reasonable expectation of success because the art teaches that Asos can block RNA binding sites by steric hinderance and can successfully alter tau exon 10 splicing in disease-relevant cells, making the claimed ASO implementation a predictable use of known technology. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 9-16 are rejected under 35 U.S.C. 103 as being unpatentable over Furling et al. (US2017/0035841A1, published 02/09/2017), Goodwin et al. (Cell Reports, Vol. 12, Issue 7, pg. 1159-1168, published on 08/18/2015) as applied to claims 1-3 above, and further in view of Konermann et al. (Cell, published 04/19/2018) and Kalbfuss et al. (Journal of Biological Chemistry, published 11/16/2001).
The teachings of Furling et al. have been discussed above.
Furling et al. teaches a method of treating myotonic dystrophy disease or disorders caused by abnormal sequestration of the MBNL protein comprising administering to a subject a modified MBNL polypeptide that binds the MBNL YGCY RNA motif (see claim 17).
The teachings of Goodwin et al. have been discussed above.
The teachings of Konermann et al. have been discussed above.
The teachings of Kalbfuss et al. have been discussed above.
Claims 9-14 are directed in part to a method of treating a neurodegenerative disease comprising the step of administering to a patient in need thereof an effective dose of a pharmaceutical composition which targets at least one muscleblind-like protein (MBNL) binding site near exon 10 of microtubule-associated protein tau (MAPT) to block MBNL binding thereto and modulate exon 10 splicing, wherein the disease is FTD, wherein treating any neurodegenerative disease and has two or more binding sites, wherein treating FTD and has two or more binding sites, wherein treating any neurodegenerative disease has two binding sites and wherein treating FTD has two binding sites.
Claim 15 directed in part to the method of treating a neurodegenerative disease comprising the step of administering to a patient in need thereof an effective dose of a pharmaceutical composition which targets at least one muscleblind-like protein (MBNL) binding site near exon 10 of microtubule-associated protein tau (MAPT) to block MBNL binding thereto and modulate exon 10 splicing of claim 9, where the component comprises nuclease-inactive dCas13d in complex with one or more guide RNAs.
Claim 16 is directed to the method of claim 9, wherein the pharmaceutical composition comprises one or more antisense oligonucleotides.
It would have been obvious to one of ordinary skill in the art before the effective filling date of the claimed invention to modify the method of treating myotonic disease of Furling et al. to a method of treating FTD as both neurodegenerative diseases are caused by abnormal sequestration of MBNL proteins that bind to YGCY RNA motifs.
A person of ordinary skill in the art is motivated to administer the claimed composition or method because Kalbfuss et al. shows that targeting tau exon 10 can correct a disease-relevant splicing defect, and Furling et al. provides the rationale for blocking MBNL-RNA interactions to modulate splicing therapeutically.
One of ordinary skill in the art has a reasonable expectation of success because the combination uses established splicing-interference strategies at a known disease-associated exon 10 target, and the expected outcome is modulation of exon 10 inclusion. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Allowable Subject Matter
Claims 17-20 are allowed.
The following is a statement of reasons for the indication of allowable subject matter:
The prior art does not teach a method of overexpressing MBNL proteins in HEK293T cells or any other human cell lines. While Chamberlain et al. (Human Molecular Genetics, published 07/30/2012) teaches overexpression of MBNL1, it is taught in a transgenic mouse model. Also, Chamberlain et al. teaches that MBNL1 overexpression causes premature fetal-to-adult splicing transition. However, it does not teach anything about adult MAPT expression as a result of overexpression of MBNL1. The prior art does not teach a method of modeling tauopathies by overexpressing MBNL proteins in HEK293T cells or any other human cell lines. Prior art such as Wray (Brain Pathology, published 04/25/2017) teaches modeling of tau pathology in human stem cell derived neurons but does not teach the overexpression of MBNL proteins in the neurons.
Conclusion
Claims 17-20 are in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DALTON KIEFER, PhD whose telephone number is (571)272-1235. The examiner can normally be reached M-F 7:30-5 EST.
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, Robert Mondesi can be reached at 408 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DALTON EDWARD KIEFER/Examiner, Art Unit 1652
/ROBERT B MONDESI/Supervisory Patent Examiner, Art Unit 1652
Prosecution Insights