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. Claims 1-19, of record 12/21/2023, are pending and subject to prosecution. Priority The instant application is a national stage entry of PCT/JP2022/020224 (filed 5/13/2022). Acknowledgement is made of the applicant’s claim for foreign priority to Japanese application 2021-081389 (filed 5/13/2021). Drawings The drawings are objected to because view number must be preceded by the abbreviation “FIG.” See 37 CFR 1.84(u). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance. Specification The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in ¶0026 of the instant specification . 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. The use of the term s StemFit , iMatrix , NucleoBond , Lipofectamine, Amicon , PureLink , SuperScript , DNeasy , SYBR , CFX Connect, NEBNext , Ultra, and HiSeq , which are trade name s or mark s used in commerce, has been noted in this application. The term s should be accompanied by the generic terminology; furthermore , the term s should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term s . 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 Objections Claim 9 is objected to because of the following informalities: In claim 9, “one or more selected from the group consisting of” should be deleted, and “nucleotides” should be made singular. Appropriate correction is required. 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 appl icant regards as his invention. Claim 14 is 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 14 recites the limitation "the antisense oligomers or the pharmaceutically acceptable salts thereof" in line 2-3. There is insufficient antecedent basis for this limitation in the claim. Claim Rejections - 35 USC § 112 (a) 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. Claim s 1-19 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. The analysis for adequate written description considers the breadth of the pending claims and their claimed result against teachings from the specification including (a) disclosure of drawings or structural chemical formulas of claimed species; (b) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties with functional characteristics, sufficient to establish a structure-function relationship; (c) actual reduction to practice; and/or (d) a representative number of species; and/or whether the complete/partial structure or physical and/or chemical properties and the functional characteristics are known in the prior art. For a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. (Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.) If a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” See MPEP 2163. The MPEP does state that for a generic claim , the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli , the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus . See In re Gostelli , 872, F.2d at 1012, 10 USPQ2d at 1618. Thus, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. Whether the representative number of species disclose satisfies the written description requirement is an inverse function of the skill and knowledge in the art; it depends on whether one of skill in the art would recognize necessary common attributes or features possessed by the members of the genus; and generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus . S ee Enzo Biochem , Inc. v. Gen-Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997). For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. For example, disclosure of only a method of making the invention and the function may not be sufficient to support a product claim other than a product-by-process claim. See, e.g., Fiers v. Revel, 984 F.2d at 1169, 25 USPQ2d at 1605; Amgen, 927 F.2d at 1206, 18 USPQ2d at 1021. Where the process has actually been used to produce the product, the written description requirement for a product-by-process claim is clearly satisfied; however, the requirement may not be satisfied where it is not clear that the acts set forth in the specification can be performed, or that the product is produced by that process. If the application as filed does not disclose the complete structure (or acts of a process) of the claimed invention as a whole, it must be determined whether the specification discloses other relevant identifying characteristics sufficient to describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that the inventor was in possession of the claimed invention. For example, in the biotech nology art, if a strong correlation has been established between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function. Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function. Conversely , without such a correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. In this latter case, disclosure of function alone is little more than a wish for possession; it does not satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing "a result that one might achieve if one made that invention"); In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming a rejection for lack of written description because the specification does "little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate"). Independent claim 1 is directed to an antisense oligomer or a pharmaceutically acceptable salt thereof which consists of a base sequence complementary to a contiguous base sequence of 15 or more bases in the base sequence shown in SEQ ID NO 1 or a contiguous base sequence of 15 or more bases in the base sequence shown in SEQ ID NO 1, having deletion, substitution, or insertion of one or more bases , and which is capable of causing skipping of the 27 th exon in a human WRN gene . The claim is thus drawn to an antisense oligomer complementary to 15 or more contiguous bases of SEQ ID NO 1, with or without deletion, substitution, or insertion of one or more bases, wherein the oligomer must predictably yield skipping of the 27 th exon in a human WRN gene. The genus of antisense nucleotides (and salts thereof) encompassed by the instant claim is very large, as SEQ ID NO 1 comprises an 116 nt -stretch of the human WRN gene. The instant claim do es not limit the number of bases that can be mutated, deleted, or inserted within a starting sequence derived from SEQ ID NO 1 that must be at least 15 contiguous bases long and can be up to 116 bases long . The instant claim also does not limit the chemical modifications that can be made to the antisense oligomer. Teachings of the Specification: The specification discloses that the human WRN gene product has 35 exons and that he majority of the Japanese patients with Werner syndrome have a specific point mutation in a splice acceptor sequence of exon 26 that induces skipping of exon 26 to generate a premature stop codon in exon 27 (See ¶ 0056 of the application’s PG Pub ). A truncated WRN protein having exons 26-27 removed by skipping is able to recover some wild-type WRN protein functions (See ¶ 0058). The specification generically discloses that antisense oligomers can be used to effect exon skipping (See ¶ 0012, 0047-0048, 0057, and 0060-0063). The antisense oligomer can be 15-116 bases long, and preferences of 20-40, 23-38, and 25-35 bases are disclosed (See ¶ 0063). Preferences that the target sequence comprise at least a base sequence of the boundary region between intron 26 and exon 27 or at least a base sequence of the boundary region between exon 27 and intron 27 are disclosed (See ¶ 0068) . The number of bases deleted, substituted, or inserted is not limited as long as the antisense oligomer causes exon skipping (See ¶ 0079). However, there is no specific teaching of what property or properties the antisense oligomer must possess in order to yield skipping of exon 27. The specification therefore does not disclose a structure-function relationship for the oligomer that will predictably result in binding to mRNA and exon excision. Working Examples of the Specification: The specification d iscloses working examples that use morpholino antisense oligomers having the sequences of SEQ ID 17-20 , 25-3 4, and 36 (30 nt long) and lentivirus expressing antisense oligonucleotides having the sequences of SEQ ID NO 21-22 (105 nt long) (See ¶ 0163, 0173, and 0178) . All sequences tested were able to cause some level of exon skipping, apart from control sequences (See fig. 11-12). The specification does not explore how modification of length, sequence, or structure would affect the activity of the oligomers. Thus, while the specification discloses some sequences that yield the desired effect, it does not actually disclose a structure-function relationship between an antisense oligomer and targeting of a human WRN gene mRNA to cause skipping of exon 27 . Nor does the specification disclose a representative number of species for the genus encompassed by the independent claim. State of the Art at the Time: At the time of the invention, antisense oligonucleotide-mediated exon skipping technology was unpredictable. Li et al. teach that because factors such as RNA secondary structure and competition between antisense oligonucleotides and trans-acting serine-arginine-rich proteins, heterogenous nuclear RNPs, and/or the spliceosome can affect action, antisense oligonucleotides directed at crucial acceptor or donor splice sites will not always alter splicing (See page 985, full ¶ 3 ). Maruyama et al. also teach that the length of effective splice-switching antisense oligonucleotides depends on their chemistries and that melting temperature versus an RNA strand is an important additional factor (See page 81, ¶ 2 ) , which compounds the unpredictability of how any given antisense oligonucleotide will work . Arechavala-Gomeza et al. teach that, despite the fact that bioinformatic tools can provide optimal targets areas for antisense oligonucleotide binding and help rank sequences according to predicted bioactivity, empirical in vitro analysis is always necessary to confirm the suitability of an antisense sequence (See page 8, col. 1, ¶ 1). The quantity of experimentation needed to make or use the invention: As iterated above, the specification demonstrate s only 17 antisense oligomers that cause skipping of exon 27 . The art at the time of filing acknowledged that antisense oligonucleotide-mediated exon skipping was unpredictable , had multiple parameters to be considered, and required validation and testing. Neither the specification nor the art recognized a discrete structure-function relationship wherein antisense oligomers can be designed so that they predictably yield exon skipping . Thus, the amount of experimentation needed to make or use the invention would have been undue to a skilled artisan. E ach oligomer encompassed by claim 1 (excepting those few tested in the specification) would require trial and error to predictably generate skipping of exon 27 . Even though the applicant’s specification lists each and every element in the claimed invention, the combination as claimed is not supported in the specification sufficiently to meet the burdens of 35 U.S.C. 112(a). In Hyatt v. Dudas , 492 F.3d 1365, 1371, 83 USPQ2d 1373, 1376-1377 (Fed. Cir. 2007), the examiner made a prima facie case by clearly and specifically explaining why the applicant’s specification did not support the particular claimed combination of elements, even though the applicant’s specification listed each and every element in the claimed combination. The court found the "examiner was explicit that while each element may be individually described in the specification, the deficiency was lack of adequate description of their combination" and, thus, "[t]he burden was then properly shifted to [inventor] to cite to the examiner where adequate written description could be found or to make an amendment to address the deficiency." Id.; see also Stored Value Solutions, Inc. v. Card Activation Techs., 499 Fed.App’x 5, 13-14 (Fed. Cir. 2012). Taken together, the person of ordinary skill in the art would not have concluded that the applicant possessed the invention as it is claimed. Claims 2 -19 are included in the rejection because they d o not remedy the written description deficiency . Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT JENNIFER S SPENCE , whose telephone number is FILLIN "Phone number" \* MERGEFORMAT 571-272-8590 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT M-F 8:30-5:30 . 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, FILLIN "SPE Name?" \* MERGEFORMAT Christopher M Babic , can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT 571-272-8507 . 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. /J.S.S./ Examiner, Art Unit 1633 /CHRISTOPHER M BABIC/ Supervisory Patent Examiner, Art Unit 1633