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 .
DETAILED ACTION
Status of the Application
Claims 31-54 are pending and are currently under examination.
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 applicant regards as his invention.
Claims 36-39, 41, 43, 45, 46, 49, 50 and 51, 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 pre-AIA the applicant regards as the invention.
Claim 36 is indefinite because it lacks antecedent basis. The claim recites “wherein the one or more chemically-modified nucleobases…” and depends from claim 33 that does not recite chemically-modified nucleobases.
Claim 37 is indefinite because it lacks antecedent basis. The claim recites “wherein the nuclease-resistant modification…” and depends from claim 34 that does not recite a nuclease-resistant modification.
Claim 38 is indefinite because it lacks antecedent basis. The claim recites “wherein the modified sugar…” and depends from claim 35 that does not recite a modified sugar.
Claim 39 is indefinite because it lacks antecedent basis. The claim recites “wherein the modified sugar…” and depends from claim 35 that does not recite a modified sugar.
Claim 41 is indefinite because it lacks antecedent basis. The claim recites “wherein the modified sugar…” and depends from claim 35 that does not recite a modified sugar.
Claim 43 is indefinite because it lacks antecedent basis. The claim recites “wherein the 2’-O(CH2)2OCH3 (MOE) modified sugar…” and depends from claim 44 that does not recite a modified sugar.
Claim 45 is indefinite because it lacks antecedent basis. The claim recites “wherein the one or more internucleoside linkage…” and depends from claim 43 that does not recite an internucleoside linkage.
Claim 46 is indefinite because it lacks antecedent basis. The claim recites “wherein the at least one of the phosphate internucleoside linkages…” and depends from claim 44 that does not recite a phosphate internucleoside linkage.
Claims 49-51 are indefinite because they lacks antecedent basis. The claims recite “the method of claim 47…” however claim 47 is not a method claim. For purposes of examination, this claim in interpreted as depending from claim 48 drawn to a method.
Claim Rejections - 35 USC § 103
Claims 31, 35-51 and 54 is/are rejected under 35 U.S.C. 103 as being obvious over Donnelly, Christopher J., et al. ("RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention." Neuron 80.2 (2013): 415-428), DeJesus-Hernandez, Mariely, et al. ("Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS." Neuron 72.2 (2011): 245-256), Mori, Kohji, et al. ("Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins." Acta neuropathologica 126.6 (2013): 881-893), Liu, Jing, et al. ("RNA duplexes with abasic substitutions are potent and allele-selective inhibitors of huntingtin and ataxin-3 expression." Nucleic Acids Research 41.18 (2013): 8788-8801), 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) and Quay et al. (US Application 20110236972).
Regarding claims 31, 48, 50 and 51, Donnelly et al. teach that a hexanucleotide GGGGCC repeat expansion in the noncoding region of the C9ORF72 gene is the most common genetic abnormality in familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (abstract). Donnelly et al. teach administering to cells antisense oligonucleotides (ASOs) that target the GGGGCCexp RNA sequence, but do not lower C9ORF72 RNA levels, mitigate all toxic phenotypes in cells (see page 416 first para and page 422). Donnelly et al. teach reducing C9orf72 in cells having a GGGGCC repeat region wherein the cell is from a subject having ALS (see page 416). The results of Donnelly et al. further indicates that using an inhibitory molecule targeted to a GGGGCC expanded region can be used as a therapeutic. Donnelly et al. do not teach using a double stranded oligonucleotide of 16 to 22 nucleotides wherein the double stranded oligonucleotide comprises 2-5 central mismatches with a target sequence within bases 9-14 and do not teach the expanded GGGGCC repeat region contains 500 or more repeats.
Regarding claim 49, DeJesus-Hernandez et al. teach there are over 700 repeat regions found in ALS/FTD patients (see page 252 para 2).
Regarding claim 54, Mori et al. teach the GGGGCC repeat expansion in the first intron of the gene C9orf72 is the most commonly known cause of familial frontotemporal lobar degeneration (FTD) and amyotrophic lateral sclerosis (ALS) and it would have been obvious to target the GGGGCC repeat expansion in the first intron of the gene.
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 a GGGGCC expanded repeat 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 also 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.
Miyagishi et al., Vickers et al., and Dean et al. do not teach double stranded oligonucleotide comprise mismatches to the target sequence.
Liu et al. demonstrates double-stranded oligonucleotides with at least 2-3 mismatches to a target sequence in positions 8-11 of a 22mer efficiently inhibited express of a repeat region of a gene (see Table 2 and page 8794). Liu et al. teach mismatches in the central region by introducing abasic sites provided a more optimal therapeutic agent (see page 8789 col. 1). The instant specification describes mismatches as either abasic or unlocked nucleotides (0009). It would have been obvious to introduce mismatches in the double-stranded oligonucleotide to develop duplexes with optimized potency and selectivity as taught by Liu et al.
Regarding claims 35-47, Quay et al. teach using double stranded oligonucleotides to target genes and teach a length of 15-24 nucleobases (0035), teach the double stranded oligonucleotides have modified sugars, bicyclic sugar moieties, 2’MOE, 2’-Flour modifications, internucleoside linkages (0033, 0038, 0097 and 0110) and lipid moieties such as cholesterol (0182). It would have been obvious to incorporate the known modifications taught by Quay increase the stability and target efficiency of double stranded oligonucleotides.
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.
Claims 32-34 and 52-53 is/are rejected under 35 U.S.C. 103 as being obvious over Donnelly, Christopher J., et al. ("RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention." Neuron 80.2 (2013): 415-428), Liu, Jing, et al. ("RNA duplexes with abasic substitutions are potent and allele-selective inhibitors of huntingtin and ataxin-3 expression." Nucleic Acids Research 41.18 (2013): 8788-8801), 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), Bhat et al. (US Application 20090306178) and McSwiggen et al. (US 20080249040).
Donnelly et al., Liu et al., Miyagishi et al., Vickers et al. and Dean et al. are relied upon as above. These references do not teach lipid moieties such as palmityl, dodecandiol or di-hexadecyl-rac-glycerol conjugated to siRNA.
Regarding claims 32-34, Bhat et al. teach using lipid moieties such as palmityl, dodecandiol or di-hexadecyl-rac-glycerol conjugated to siRNA to enhance the properties of the double stranded oligonucleotide (see 0151). It would have been obvious to conjugate any one of these lipid moieties to the double stranded oligonucleotide taught by Donnelly.
Regarding claims 52-53, it would have been obvious to one of ordinary skill in the art to make double stranded oligonucleotides targeted to a GGGGGCC C9orf72 expansion to treat ALS or FTD given ‘‘GGGGCC’’ repeat’’ expansion in the noncoding region of the C9ORF72 gene has been found in at least 8%ofsporadicALS (sALS) and FTD cases and more than 40% of familial ALS (FALS) and FTD cases as taught by Donnelly found that the generation of toxic RNA plays a major role in C9ORF72 diseases and that specifically targeted inhibitory oligonucleotides can effectively prevent neurotoxicity (see page 416 first para). It would have been obvious to administer the double stranded oligonucleotide to the central nervous system to target ‘‘GGGGCC’’ repeat’’ expansion in the noncoding region of the C9ORF72 gene in neurodegenerative disorders such as ALS and FTD.
One would have been motivated to combine the teachings above to make a double-stranded oligonucleotide with improved optimal targeting using mismatches in the central region as taught by Liu et al. 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 above would have suggested to one of skill in the art that making siRNA targeted to GGGGCC sequence can be used to treat diseases such as ALS and FTD.
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 ALS/FTD C9orf72 expansion by targeting GGGGCC using an inhibitory oligonucleotide. 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 and chemical composition of an siRNA 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.
Double Patenting
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 31-54 are rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 10,538,762. 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.
Claims 31-54 are drawn to a double-stranded oligonucleotide 16-22 nucleotides in length targeted to a GGGGCC expanded repeat of C9orf72 and claims 1-22 of Patent ‘762 are drawn to a double-stranded oligonucleotide 18-22 nucleotides in length targeted to a GGGGCC expanded repeat of C9orf72. Thus both claim sets overlap in scope and are therefore patently indistinguishable subject matter.
Claims 31-54 are rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1-37 of U.S. Patent No. 11,840,690. 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.
Claims 31-54 are drawn to a double-stranded oligonucleotide 16-22 nucleotides in length targeted to a GGGGCC expanded repeat of C9orf72 and methods of treatment and claims 1-37 of Patent ‘690 are drawn to a method of reducing C9orf72 in a cell comprising administering a double-stranded oligonucleotide 18-22 nucleotides in length targeted to a GGGGCC expanded repeat of C9orf72. Thus both claim sets overlap in scope and are therefore patently indistinguishable subject matter.
Conclusion
No claims are allowed.
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/KIMBERLY CHONG/
Primary Examiner Art Unit 1636
Prosecution Insights