CTNF 18/471,280 CTNF 80625 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. DETAILED ACTION Status of the Application Claims 31-51 are pending and are currently under examination. Claim Rejections - 35 USC § 103 Claims 31-39 and 41-51 is/are rejected under 35 U.S.C. 103 as being obvious over Linsley et al. (US 20140303238 of record IDS 02/07/2024), Sandi et al. (Genetics Research International Volume 2013, Article ID 852,080, 12 pages of record IDS 02/07/2024), Miyagishi et al. (Antisense and Nucleic Acid Drug Development, 2003, 13:1-7), Vickers et al. (The Journal of Biological Chemistry, 2003, 278:7108-7118), Dean et al. (Oncogene, 2003, 22:9087-9096), Buehler et al. (20160178610 of record IDS 02/07/2024) and McSwiggen et al . (US Application 20080249040), 07-30-03-h AIA Claim interpretation Claim 31 is drawn to a method of modifying a cell to comprise a double-stranded oligonucleotide, wherein the double-stranded oligonucleotide has a length of from 13 nucleobases to 22 nucleobases and comprises a repeating tri-nucleobase sequence comprising (i) GAA or CUU or (ii) AAG or UUC or (iii) or AGA or UCU wherein modifying treats a disease associated with an expanded GAA repeat. The term “modifying” is not defined in the specification and the broadest reasonable interpretation is administering the double stranded oligonucleotide to a cell treats a disease associated with an expanded GAA repeat. Claims 37 and 51 recite a method of selectively increasing the expression of a Frataxin transcript in the preamble with a single method step of delivering to a cell a double-stranded oligonucleotide has a length of from 13 nucleobases to 22 nucleobases and comprises a repeating tri-nucleobase sequence comprising (i) GAA or CUU or (ii) AAG or UUC or (iii) or AGA or UCU. A preamble is generally not accorded any patentable weight where it merely recites the purpose of a process or the intended use of a structure, and where the body of the claim does not depend on the preamble for completeness but, instead, the process steps or structural limitations are able to stand alone. See In re Hirao , 535 F.2d 67, 190 USPQ 15 (CCPA 1976) and Kropa v. Robie , 187 F.2d 150, 152, 88 USPQ 478, 481 (CCPA 1951). Therefore any rejection teaching the method step would meet the limitation of the claims. Regarding claims 31, 37 and 51, Linsley et al. teach oligonucleotides targeting a repeating tri- nucleobase sequence, such as AAG (see 0169 and Table 1). Linsley et al. teach an oligonucleotide to target FRIEDREICH ATAXIA 1 having an expanded repeat (GAA)n and teach said single stranded oligonucleotide sequences such as SEQ ID No. 11 or SEQ ID No.12 (see Table 1). Linsley et al. teach in paragraph (21) “As used herein, "nucleobase" (Nu), "base pairing moiety" or "base" are used interchangeably to refer to a purine or pyrimidine base found in native DNA or RNA (uracil, thymine, adenine, cytosine, and guanine), as well as analogs of the naturally occurring purines and pyrimidines, that confer improved properties, such as binding affinity to the oligonucleotide”. Thus, Linsley et al. teach a single stranded oligonucleotide with interchangeable bases such as uracil or thymine, such as TTC or UUC which would target FRIEDREICH ATAXIA 1 having an expanded repeat (GAA)n. Linsley et al. do not teach using a double stranded oligonucleotide. Sandi et al. teach Friedreich Ataxia (FRDA) is a rare autosomal recessive neurodegenerative disorder caused by tri-nucleotide repeats and teach drugs that are able to increase frataxin expression to the levels of healthy carriers would be a beneficial therapeutic (see page 1). Sandi et al. teach “RNA interference (RNAi) is a posttranscriptional phenomenon, where sequence-specific gene silencing is achieved by chromatin remodeling which can be triggered by a small pool of double stranded RNAs with approximately 21 to 28 nucleotides in length [129]. Since agRNAs (duplex RNAs) target in a sequence specific manner, it may be possible to modulate agRNAs to activate the gene expression in disease-associated genes where gene activation is essential, as with FRDA. Importantly, agRNAs can target either sense or antisense strands and coding or noncoding RNA transcripts (page 8 3.3). Thus Sandi et al. suggest using RNAi as a therapeutic for Friedreich ataxia. The prior art teach antisense oligonucleotides and siRNA are functionally equivalent. Miyagishi et al. teach that antisense oligonucleotides and siRNAs can be designed to be targeted to the same target sites with a reasonable expectation to observe reduced target expression levels with both molecules. (See siRNAs and antisense oligonucleotides targeted to target sites 3, 4, 5, and 6 in Figure 1, wherein the antisense oligonucleotides comprise all first 19 nucleotides of the antisense strand sequence of the siRNAs). Vickers et al. teach, consistent with Miyagishi et al., that target sites between antisense oligonucleotides and siRNAs are shared with reasonable correlation. (See the entire reference). Dean et al. corroborates the teachings of the Vickers et al. reference by stating that “As an example in comparing RNase H-dependent oligonucleotides to siRNA oligonucleotides, we found that they exhibited similar potency, duration of action, target selectivity and efficiency (Vickers et al. , 2003).” (See page 9089, right column). It would have been obvious to one of ordinary skill in the art at the time the invention was made to use a double-stranded oligonucleotide to target FRIEDREICH ATAXIA because making antisense oligonucleotides compounds and double stranded oligonucleotides targeted to the same target sites of a gene was a known methodology in the art as taught by Miyagishi et al., Vickers et al., and Dean et al., and further because substituting art-recognized equivalents known for the same purpose is a well-established rationale in support of an obviousness rejection. See MPEP 2144.06. Regarding claims 32 and 33, Buehler et al. teach FRIEDREICH ATAXIA is characterized by having GAA repeats from about 66 to greater than 1000 (see 0244). Buehler et al. also teach efficient methods of screening for siRNA that can be useful for treatment of FRIEDREICH ATAXIA (see 0263) thus making it further obvious to use a double-stranded oligonucleotide. Regarding claims 34-39 and 41-51, McSwiggen et al. teach using double stranded oligonucleotides to target genes and teach a length of 18 to 22 nucleobases (0255, 0054), teach the double stranded oligonucleotide can comprise mismatches (0006), can comprise lipid moieties (37-39) and have modified sugars and internucleoside linkages (0249, 0046 and 0097). It would have been obvious to incorporate the known modifications taught by McSwiggen to increase the stability and target efficiency of double stranded oligonucleotides. Moreover, it would have been obvious to one of ordinary skill in the art to make double stranded oligonucleotides targeted to a Frataxin gene for modifying a cell and methods of treatment. Moreover MPEP 2145 states: "The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference.... Rather, the test is what the combined teachings of those references would have suggested to those of ordinary skill in the art." In re Keller, 642 F.2d 413, 425, 208 USPQ 871, 881 (CCPA 1981). See also In re Sneed, 710 F.2d 1544, 1550, 218 USPQ 385, 389 (Fed. Cir. 1983) ("[I]t is not necessary that the inventions of the references be physically combinable to render obvious the invention under review."); and In re Nievelt, 482 F.2d 965, 179 USPQ 224, 226 (CCPA 1973) ("Combining the teachings of references does not involve an ability to combine their specific structures."). The teachings of Sandi et al. would have suggested to one of skill in the art that a siRNA targeted to the Frataxin gene may be able to increase the expression from said gene and given Linsley et al. teach specific inhibitor nucleic acid molecules targeted to that gene and it was known in the art that antisense and siRNA are equivalents, one of skill in the art would have tried using a siRNA to target the gene. The Supreme Court decision in KSR International CO. v. TELEFLEX INC., No. 04-1350 (U.S. Apr. 30, 2007), at page 17 expressed “When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.” Additionally, at page 13, the Court stated, “If a person of ordinary skill can implement a predictable variation, §103 likely bars its patentability.” Thus, there was a need to solve the problem of Friedreich Ataxia, which is a rare autosomal recessive neurodegenerative disorder caused by tri-nucleotide repeats, by trying to increase frataxin expression to the levels of healthy carriers. There was a finite number of identified solutions and a person of ordinary skill in the art would have good reason to use a double stranded oligonucleotide to target the gene given McSwiggen describes the requirements such as length, structure, chemical composition to efficiently mediate siRNA activity (0004-0006). Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed. Claim 40 is/are rejected under 35 U.S.C. 103 as being obvious over Linsley et al. (US 20140303238 of record IDS 02/07/2024), Sandi et al. (Genetics Research International Volume 2013, Article ID 852,080, 12 pages of record IDS 02/07/2024), Miyagishi et al. (Antisense and Nucleic Acid Drug Development, 2003, 13:1-7), Vickers et al. (The Journal of Biological Chemistry, 2003, 278:7108-7118), Dean et al. (Oncogene, 2003, 22:9087-9096), Buehler et al. (20160178610 of record IDS 02/07/2024) and Hinkle et al. (US 20130289094). Hinkle et al. teach linking double stranded oligonucleotides to moieties such as dodecandiol residue, undecyl residues, di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-phosphonate to enhance the activity, cellular distribution or cellular uptake (0107). It would have been obvious to one of skill in the art to try using any of these lipids for the purpose of improving the activity, cellular distribution or cellular uptake of the double stranded oligonucleotide in the claimed methods. Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed. Claim Rejections - 35 USC § 112 07-30-01 AIA The following is a quotation 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 35 U.S.C. 112 (pre-AIA), first paragraph: 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. Written Description 07-31-01 AIA Claim s 31-36 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated: To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious" and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood , 107 F.3d at 1572, 41 USPQ2d at 1966; Regents of the University of California v. Eli Lilly & Co. , 43 USPQ2d 1398. The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc ., 935 F.2d at 1563-64, 19 USPQ2d at 1117. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial Structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed structure, and v. Correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. Moreover, the written description requirement for a genus may be satisfied through sufficient description of a representative number of species by “…disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between functional and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed 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. The claims are drawn to a genus of double stranded oligonucleotides targeted to a Frataxin transcript with the function of treating any disease associated with expanded GAA repeats. The prior art describes expanded GAA repeats as being associated with Friedreich Ataxia (FRDA) which is a rare autosomal recessive neurodegenerative disorder caused by tri-nucleotide repeats (see Sandi et al. (Genetics Research International Volume 2013, Article ID 852,080, 12 pages of record IDS 02/07/2024). The prior art does not describe expanded GAA repeats being associated with any number of different diseases as claimed. When determining whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. In the instant case, the specification describes anti-GAA duplex RNAs that are complementary to the GAA repeat with FXN mRNA that was capable of increasing expression of FXN. The specification does not describe any double stranded oligonucleotide targeted to an expanded GAA repeat that is capable of treating any disease associated with the GAA repeat. The specification does not describe treating any other known disease associated with a GAA repeat. It is then determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e. other than nucleotide sequence), specific features and functional attributes that would distinguish different members of the claimed genera. In the instant case, the only identifying characteristic is a decrease in expression of FXN using the anti-GAA duplex RNA. The specification does not describe modifying a cell to treat any other disease associated with an expanded GAA repeat. A review of the specification shows that it provides no description or guidance that would allow one of skill to distinguish the functional species of the duplex RNA genus from the non-functional members without empirical determination. Since the disclosure and the prior art fail to describe the common attributes and characteristics concisely identifying members of the proposed genus, and because the claimed genus is highly variant comprising a vast number of variations comprising repeating tri-nucleobase sequence, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus claimed. "A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus" (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) ( emphasis added ). Further, “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” Ex parte Kubin , 83 USPQ2d 1410, 1417 (Bd. Pat. App. & Int. 2007) citing University of Rochester , 358 F.3d at 927, 69 USPQ2d at 1895. Vas-Cath Inc. v. Mahurkar , 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention . The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed. ” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). The MPEP further states that 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.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. 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, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gosteli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gosteli, 872 F.2d at 1012, 10 USPQ2d at 1618. Thus the specification and claims lack written description because it is clear that Applicant did not have possession of every variation of the double stranded oligonucleotides with the function of treating any disease associated with an expanded GAA repeat. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder , 736 F.2d 1516, 1521,222 USPQ 369,372-372 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventors, at the time the application was filed, had possession of the entire scope of the claimed invention. Double Patenting 08-33 The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the "right to exclude" granted by a patent and to prevent possible harassment by multiple assignees. See In re Goodman , 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi , 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum , 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel , 422 F.2d 438, 164 USPQ 619 (CCPA 1970);and, In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/forms/. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA/25, or PTO/AIA/26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp. Claims 31-51 are rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,795,457 (Patent ‘457). Although the conflicting claims are not identical, they are not patentably distinct from each other because the instant claims and the claims of the patent are drawn to patently indistinguishable subject matter MPEP 804 “A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985). In determining whether a nonstatutory basis exists for a double patenting rejection, the first question to be asked is: Is any invention claimed in the application anticipated by, or an obvious variation of, an invention claimed in the patent? If the answer is yes, then a nonstatutory double patenting rejection may be appropriate.” The instant claims and claims of Patent ‘457 are drawn to methods of modulating and selectively increasing the expression of Frataxin transcript comprising modifying a cell with a double-stranded oligonucleotide that has a length of from 13 nucleobases to 22 nucleobases and comprises a repeating tri-nucleobase sequence comprising (i) GAA or CUU or (ii) AAG or UUC or (iii) or AGA or UCU. Patent ‘457 does not teach the double stranded oligonucleotide comprises modifications as instantly claimed. McSwiggen et al. (cited above) teach using double stranded oligonucleotides to target genes and teach a length of 18 to 22 nucleobases (0255, 0054), teach the double stranded oligonucleotide can comprise mismatches (0006), can comprise lipid moieties (37-39) and have modified sugars and internucleoside linkages (0249, 0046 and 0097). Hinkle et al. (cited above) teach linking double stranded oligonucleotides to moieties such as dodecandiol residue, undecyl residues, di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-phosphonate to enhance the activity, cellular distribution or cellular uptake (0107). It would have been obvious to modify the oligonucleotide to increase stability and enhance targeting efficiency. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kimberly Chong at (571)272-3111 . The examiner can normally be reached Monday thru Friday between M-F 8:00am-4:30pm. If attempts to reach the examiner by telephone are unsuccessful please contact the SPE for 1636 Neil Hammell at 571-272-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. 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For all other customer support, please call the USPTO Call Center (UCC) at 800-786-9199. /KIMBERLY CHONG/ Primary Examiner Art Unit 1636 Application/Control Number: 18/471,280 Page 2 Art Unit: 1636 Application/Control Number: 18/471,280 Page 3 Art Unit: 1636 Application/Control Number: 18/471,280 Page 4 Art Unit: 1636 Application/Control Number: 18/471,280 Page 5 Art Unit: 1636 Application/Control Number: 18/471,280 Page 6 Art Unit: 1636 Application/Control Number: 18/471,280 Page 7 Art Unit: 1636 Application/Control Number: 18/471,280 Page 8 Art Unit: 1636 Application/Control Number: 18/471,280 Page 9 Art Unit: 1636 Application/Control Number: 18/471,280 Page 10 Art Unit: 1636 Application/Control Number: 18/471,280 Page 11 Art Unit: 1636 Application/Control Number: 18/471,280 Page 12 Art Unit: 1636 Application/Control Number: 18/471,280 Page 13 Art Unit: 1636 Application/Control Number: 18/471,280 Page 14 Art Unit: 1636 Application/Control Number: 18/471,280 Page 15 Art Unit: 1636 Application/Control Number: 18/471,280 Page 16 Art Unit: 1636
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