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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
Applicant is reminded that in order for a patent issuing on the instant application to obtain priority under 35 U.S.C. 119(a)-(d) or (f), 365(a) or (b), or 386(a) or (b), based on priority papers filed in a parent or related Application No. 16464482(to which the present application claims the benefit under 35 U.S.C. 120, 121, 365(c), or 386(c) or is a reissue application of a patent issued on the related application), a claim for such foreign priority must be timely made in this application. To satisfy the requirement of 37 CFR 1.55 for a certified copy of the foreign application, applicant may simply identify the parent nonprovisional application or patent for which reissue is sought containing the certified copy.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings were received on 4/2/24. These drawings are acceptable.
Specification
The amendment to the specification filed on 4/2/24 has been entered.
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 1 and 2 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.
New matter:
New claims 1 and 2 are not supported by the as-filed specification. Applicant has not pointed out where the new claims are supported, nor does there appear to be a written description of the new claim in the application as filed. See MPEP § 2163.06. Olson (US 20140221464) disclose that X-linked myotubular myopathy is caused by mutations in the myotubularin gene (MTM1) and the classical autosomal dominant form is caused by mutations in the dynamin 2 gene (paragraph 4). The art further discloses: Autosomal centronuclear myopathies are relatively mild forms of centronuclear myopathy, a group of inherited myopathies that causes problems with the tone and contraction of skeletal muscles. They are called autosomal in reference to their inheritance pattern. The genetic mutations that underlie these myopathies are not on the X or Y (sex) chromosomes; they’re on the autosomes, or numbered chromosomes.
Autosomal dominant means only one copy of the flawed gene is enough to cause the disease. Autosomal recessive means two copies, one from each parent, are required for the disease to occur. See Muscular dystrophy association. Centronuclear myopathies, including myotubular myopathy - Types of Congenital Myopathies - Diseases | Muscular Dystrophy Association, retrieved on-line 6/10/26.
In view of what was disclose in art regarding autosomal centronuclear myopathies and that they are not on the X chromosome, the claimed method for ameliorating autosomal dominant centronuclear myopathy could not be treated using an allele specific siRNA (AS-siRNA) that targets a region of a human DNM2 gene transcript comprising an X-linked myotubular myopathy causing mutation and does not appear to have written support.
Written Description:
Instant claims 1 and 2 embrace a method of ameliorating X-linked myotubular myopathy or autosomal dominant centronuclear myopathy induced by one or more autosomal dominant centronuclear myopathy causing mutations in Dynamin 2 (DNM2) in a subject in need thereof comprising administering an AS-siRNA to the subject, wherein the AS-siRNA targets a region of a human DNM2 gene transcript comprising an X-linked myotubular myopathy causing mutation.
The claimed method embrace treating any subject with an AS-siRNA that targets a human DNM2 gene transcript. Unless the subject has the human gene transcript, it is not apparent if the AS-siRNA can treat the conditions in any subject. Neither the specification nor the prior art disclose an AS-siRNA which targets a region of a human DNM2 gene transcript comprising an X-linked myotubular myopathy causing mutation and silences the expression of only one allele of a heterozygous DNM2 in a cell that is not a human cell. Other than humans, the specification does not appear to describe any other subject having the human DNMA2 gene.
The specification contemplates the method in humans. Pages 18-19 disclose a DNM2 gene which is heterozygous for the presence of the non-pathological polymorphism rs2229920 (C or T) and AS-siRNA targeting either sequence comprising C or the sequence comprising a T.
The working examples in the specification are directed to studying DNM2 mutations in murine and human cells. Pages 27-28 disclose p.R465W DNM2 mutation was used to construct a mouse model.
Pages 34-35 of the specification state:
Here, we have identified several efficient AS-siRNA against the two possible version of the SNP rs2229920 (either the C allele or the T allele). This results highlight for the first time the possibility to target all the dominant DNM2 mutations whatever the resulting disease (CNM, CMT or HSP) and also to decrease, in a controlled manner, the DNM2 expression in diseases associated with an overexpression of this protein (X-linked myotubular myopathy, pancreas and prostate cancers).
With respect to the limitations “a region of a human DNM2 gene transcript comprising an X-linked myotubular myopathy causing mutation”; “DNM2 gene is heterozygous for the presence of a non-pathological polymorphism and/or heterozygous for the presence of the X-linked myotubular causing mutation” in claims 1 and 2, the specification only provides written support for SNP rs2229920 (either the C allele or the T allele) in the human DNM2 gene transcript. The limitation “DNM2 gene is heterozygous for the presence of a non-pathological polymorphism and/or heterozygous for the presence of the X-linked myotubular causing mutation” embraces a gene from a genus of subjects, including humans, primates, mouse, rat, etc.
Centronuclear myopathy (CNM) is an umbrella term for a group of rare genetic muscle disorders, including X-linked myotubular myopathy and a few autosomal forms referred to as centronuclear myopathy. Autosomal refers to genes that are found on autosomes or chromosomes other than the X or Y chromosomes (sex chromosome). CNM is generally used for the autosomal forms of the disorder and myotubular myopathy is generally used for the X-linked form.
Olson (US 20140221464) disclose that X-linked myotubular myopathy is caused by mutations in the myotubularin gene (MTM1) and the classical autosomal dominant form is caused by mutations in the dynamin 2 gene (paragraph 4).
In view of the what was taught in the prior art, with respect to claim 2, if the subject in need thereof has an autosomal dominant CNM, then the subject would probably not have a DNM2 gene that is heterozygous for the presence of the X-linked myotubular myopathy causing mutation.
The claims encompass any sort of gene alteration that may occur in the encompassed DNM2 gene regions, including but not limited to single or multiple nucleotide insertions, deletions, or substitutions, or larger gene arrangements, translocations, copy number variations, repeat expansions and the encompassed structural variations can be in any area of a large genomic locus, where the variation can result in gene alterations of coding regions of exons, or in non-coding introns and splice sites, gene promoters, or upstream or downstream regulatory elements while the claims encompass any of a wide variety of variations, the specification only provides a limited description of the disease-causing mutations in a human DNM2 gene transcript.
The claims embrace an enormous genus of DNM2 gene transcripts structural variations. Neither the specification nor the prior art disclose a representative number of disease-causing mutation associated with X-linked myopathy or centronuclear myopathy (CNM). 15 different CNM-related mutations have been reported in 40 families (Bohm et al., Human Mutation 33, 949-959, 2012). See also page 12 of the as-filed specification. Page 956 of Bohm discloses a variability in DNM2 mutations genotype-phenotype. Laporte et al. disclose that 198 mutations in the MTM1 gene have been identified in unrelated families (Human Mutation 15:393-409, 2008).
Other than the limited disease causing mutations in the specification (page 12) for CNM or non-pathological polymorphism rs2229920 (C or T) or rs 12461992 (A or T), the instant disclosure does not have written support for a genus of a human DNM2 gene transcript comprising an X-linked myotubular myopathy causing mutation or a DNM2 gene is heterozygous for the presence of a non-pathological polymorphism and/or heterozygous for the presence of the X-linked myotubular causing mutation.
Note that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See Enzo Biochem., 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)(“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). See also MPEP §2163.
In view of the foregoing, it is clear that the specification of the instant disclosure fails to convey to the skilled artisan that the applicant had possession of the claimed genus of subjects or regions of a human DNM2 gene transcript comprising an X-linked myotubular myopathy causing mutation; a DNM2 gene is heterozygous for the presence of a non-pathological polymorphism and/or heterozygous for the presence of the X-linked myotubular causing mutation in instant claims 1-2 as of the effective filing date.
Conclusion
See attached PTO-326 for disposition of claims.
Claim 12 of U.S. Patent No. 10947540 recites using an allele specific siRNA (AS-siRNA) to treat autosomal dominant centronuclear myopathy or myotubular myopathy in a subject in need thereof, comprising administering to the subject a therapeutic amount of a AS-siRNA that comprises a sequence mismatch and is able to silence the expression of only one allele of a heterozygous DNM2 gene in a cell, wherein the DNM2 gene is heterozygous for the presence of a non-pathological polymorphism, wherein the non-pathological polymorphism is rs2229920 (C or T) or rs12461992 (A or T), and wherein the AS-siRNA targets a region of the allele comprising said non-pathological polymorphism.
Claims 8 and 9 of U.S. Patent No. 11926829 embrace using an AS-siRNA to ameliorate X-linked myotubular myopathy or autosomal dominant centronuclear myopathy in a subject in need thereof comprising administering a AS-siRNA that comprises a sequence mismatch and is able to silence the expression of only one allele of a heterozygous DNM2 gene in a cell, wherein the DNM2 gene is heterozygous for the presence of a disease-causing mutation, wherein said AS-siRNA targets a region of a human DNM2 gene transcript comprising said disease-causing mutation, wherein the disease-causing mutation is 1393C>T; c.1105C>T, c.1106G>A, c.1856C>T or c.1948G>A, and wherein the AS-siRNA comprises a sense strand and an antisense strand and the antisense strand only contains bases selected from the group consisting of guanine, cytosine, adenine, uracil, and deoxythymidine.
However, neither the claims of ‘829 nor ‘540 embrace using a AS-siRNA which targets a region of a human DNM2 gene transcript comprising an X-linked myotubular myopathy causing mutation.
The art made of record and not relied upon is considered pertinent to applicant's disclosure. WO 2024033467 (filed and published after the effective filing date of the instant application) disclose work (allele specific siRNA for dynamin-2 related disorders from co-inventors of the instant application.
Trochet (Current Gene Therapy 15, 503-510, 2015) teaches the state of the art for using AS-siRNA to treat dominant inherited diseases. However, X-linked myotubular myopathy is not considered a dominant inherited disease.
WO2015055859 is the closest prior art to the claimed invention, but ‘859 does not teach or suggest using AS-siRNA that targets a human DNM2 gene transcript comprising an X-linked myopathy causing mutation to ameliorate X-linked myotubular myopathy or autosomal domain CNM in a subject in need thereof. ‘859 teaches MTM1 mutations associated with X-linked myotubular myopathy in laborer retrievers.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636
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