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 .
Election/Restrictions
Claims 1, 22-28, and 220 are directed to an allowable product. Pursuant to the procedures set forth in MPEP § 821.04(B), claims 225, 230, 233-237, and 244, directed to the process of making or using an allowable product, previously withdrawn from consideration as a result of a restriction requirement, are hereby rejoined and fully examined for patentability under 37 CFR 1.104.
Because all claims previously withdrawn from consideration under 37 CFR 1.142 have been rejoined, the restriction requirement as set forth in the Office action mailed on 6/24/25 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Specification
The use of the term Lipofectamine RNAi max; , which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Please review the entire specification for any other name or mark used in commerce.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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 225, 230, 233-237 and 244 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 method for treating or delaying progression of a nucleotide repeat expansion disorder in a subject in need thereof, the method comprising directly administering to the targeted cells the dsRNA of claim 1, wherein the disorder is selected from Huntington’s disease (HD) and myotonic dystrophy type 1 (MD1), does not reasonably provide enablement for treating, preventing or delaying progression of a nucleotide expansion disorder in a subject in need thereof, the method comprising administering to the subject the dsRNA of claim 1. 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 and use the invention commensurate in scope with these claims.
The claimed invention broadly reads on treating, preventing, delaying the progression of a genus of nucleotide expansion disorder in a subject in need thereof using any administration route to deliver the dsRNA of claim 1 to the subject.
The claimed invention broadly embraces several types of repeat expansion disorders, including polyglutamine (polyQ) disorders, non-poly Q disorders, polyalanine (PA) disorders, or disorders involving tetranucleotide, pentanucleotide, hexanucleotide, and dodecanucleotide repeats.
The prior art does not teach that MSH3 dsRNA can be used to prevent any nucleotide repeat expansion disorder in a subject in need thereof. The specification contemplates the method, but does not provide any working examples for preventing the disorder or teach the method steps for carrying out the claimed method. The specification does not teach how to identify that the method was achieved or that even if the subject was a possible carrier of the MSH3 gene but never developed the disorder. Furthermore, neither the specification nor the prior art of record teach how to identity the subject embraced by the claimed method. The specification and art of record do not teach what phase of the disease in a subject in need thereof before clinical manifestation of the disease. A search of the prior art indicates that there are no known assays for determining that a subject will develop a nucleotide repeat expansion disorder before the disease has already been diagnosed in said subject.
There are more than 40 disorders embraced by the claimed method (See Liu et al. Trends in Biochemical Sciences 2012, Vol 37 pages 167-172, cited on an IDS). The prior art discloses that there is no cure for any of the diseases embraced by the claimed method. Due to the large number of disorders embraced by the claimed invention, the Office cannot in time allotted to discuss every disorder embraced by the claimed method and will discuss several disorders embraced by the claimed method below. The state of the art for several disorders was already discussed on pages 40-43 of the as-filed specification.
There are several DNA repair mechanisms to be involved in trinucleotide repeat expansion, including MSH2-MSH3 complex that binds to and stabilized TNR, thereby promoting TNR expansion (Liu, supra). Age-dependent somatic TNR expansion also appears to be mediated through an alternate pathway DNA repair pathway (Liu, supra). Even if dsRNA MSH3 could reduce TNR expansion in a cell there could be other mechanisms promoting TNR expansion in a disorder resulting in the dsRNA not treating the disorder.
The prior art and pages 40-43 of the specification appear to disclose that several of the disorders recited in instant claims 225, 230, 233-237 and 244 are not associated MSH3 or that MSH3 is not considered a causative agent for the disorder.
For example, a search of the prior art indicates that Fragile XE syndrome (formerly Fragile XE mental retardation), Frederic’s ataxia (FRDA), Spinocerebellar Ataxia (SCA) types 1-3, 6, 7, 8, 12, 13, and 17; FRA2A syndrome; spinal and bulbar muscular atrophy (SBMA), Dentatorubal-Pallidolysian Atrophy (DRPLA) and FRA7A syndrome are not related to MSH3 or caused by MSH3 gene. See Yau et al. Brain 2020, 143, e25, pages 1-4.
There appears to be ongoing studies to determine if MSH3 is involved in Fragile X syndrome (FXS). See Zhao et al. (Human Molecular Genetics 2015, Vol. 24, 7087-7096). The prior art does not appear to teach that MSH3 dsRNA can be used to treat FXS. Thus, the claimed method is not considered enabled for treating FXS using the claimed method.
In addition, a search of the prior art discloses that MSH3 is rarely associated with early infantile epileptic encephalopathy (EIEE) and there is nothing in the prior art disclosing that the MSH3 dsRNA could be used to treat or delay the progression of the disorder. The prior art appears to indicate that further studies are required to determine if reducing MSH3 expression in a subject in need thereof can treat EIEE.
The prior art, including the teaching in the as-filed specification do not appear to teach that polyalanine (PA) disorders, or disorders involving tetranucleotide, pentanucleotide, hexanucleotide, and dodecanucleotide repeats could be treated using the dsRNA of claim 1.
In view of the art of record and the teaching in the specification (working examples and pages 40-43 of the specification), a skilled artisan would possess the knowledge that DNA repair protein MSH3 drives somatic CAG repeat expansion in the huntingtin gene and contributes to the development of Huntington’s disease (HD). See Driscoll et al. Scientific Reports 14:2061, 2024.
In view of the totality of the prior art of record and teaching in the specification, it appears that HD and MD1 can possibly be treated with MSH3 dsRNA.
The specification provides working examples of studying the dsRNA of clam 1 in several different cell lines. Example 5 beginning on page 144 contemplates mouse studies in several different trinucleotide repeat expansions diseases including HD, FA, DM1.
In view of the totality of the prior art of record, there appears to be a limited number of nucleotide expansion disorders known in the prior art where MSH3 is considered a causative agent and the dsRNA of claim 1 could be used to treat the disorder.
With respect to the claimed method embracing using a genus of administration routes to treat, prevent or delay progression of nucleotide expansion disorder, the claimed invention embraces different types of disorders that involved different cells, tissues, organs of the subject. The only disorders enabled by the specification (HD and MD1) appear to be directed neurodegenerative disorders which are involve neurons or brain tissue. The skilled artisan would possess the knowledge that blood: brain barrier is obstacle for delivering a dsRNA to the targeted cells in the brain. “Currently, clinically proven drugs to treat brain disease are unavailable.” See Lu et al. (Pharmaceuticals Science Advance 2 100041, 2024). See also Driscoll et al. (supra) that disclose, “Clinical safety remains a paramount concern when targeting MSH3 given its integral role in the DNA mismatch repair mechanism (page 9).” “By confining MSH3 knockdown to the CNS via intrathecal administration of di siRNA in humans, we can mitigate potential risks tied to MutSβ activity loss in peripheral tissues, including the colon (page 9).” Other than direct administration to these targeted area of the subject, the specification does not enable using any route of administration to deliver the dsRNA to the subject and treat or delay progression of the disorder. The prior art of record does not teach that a skilled artisan could reasonable extrapolate from direct administration to a genus of administration routes without an undue amount of experimentation.
Furthermore, other than cell line examples and contemplating the claimed methods, the specification of the instant application does not teach how to use the full scope of the claimed invention. See Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 clearly states: "Patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable. See Brenner v. Manson, 383 U.S. 519, 536, 148 USPQ 689, 696 (1966) (stating, in context of the utility requirement, that "a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.") Tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention." Thus, in view of the reasons set forth above, it would take an undue amount of experimentation for one of skill in the art to practice the full scope of the claimed invention.
Allowable Subject Matter
Claims 1, 22-28 and 220 are in condition for allowance. See the reasons for the allowance in the office action mailed on 12/31/25 and incorporated herein.
Conclusion
See attached PTO-326 for disposition of claims.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brian Whiteman whose telephone number is (571)272-0764. The examiner can normally be reached on Monday thru Friday; 6:00 AM to 3:00PM.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636
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