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 .
It is noted that the rejection under 35 USC 103(a) has been withdrawn in view of the specific modification pattern recited.
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.
Claim 29 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 29 depends from a cancelled claim and therefore the metes and bounds of the claim cannot be clearly ascertained. For purposes of the instant examination, the claim is interpreted as depending from claim 21. Appropriate correction is required.
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 21, 25, 30-34, and 36-38 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 specification does not adequately describe the instant genus of dsRNA agents of any length wherein the sense strand comprises the sequence of SEQ ID NO: 853 and the antisense strand comprises the sequence of SEQ ID NO: 1212.
The species of the specification are not representative of the entire claimed genus. The species of the specification are SEQ ID NOs: 853 and 1212 as a duplex. The structure recited encompasses a large genus of dsRNAs that would not likely have the function of inhibiting the expression of XDH. The dsRNA agent can be very long (i.e. 1,000 nucleotides) wherein the sense strand comprises the sequence of SEQ ID NO: 853 and the antisense strand comprises the sequence of SEQ ID NO: 1212.
The MPEP states 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. See 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 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. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
To achieve the desired function, it appears that the structure is required to be of a shorter length than the claimed genus which has no length limitation. With respect to siRNAs, as single species of dsRNA agents, Elbashir et al. (The EMBO Journal, Vol. 20, No. 23, pages 6877-6888, 2001) teaches that duplexes of 21-23 nt RNAs are the sequence specific mediators of RNAi and that even single mismatches between the siRNA duplex and the target mRNA abolish interference (abstract and page 6888).
The claims encompass very long dsRNA, for example, that can trigger RNAi. Such dsRNA with a sense strand comprising the sequence of SEQ ID NO: 853 and the antisense strand comprising the sequence of SEQ ID NO: 1212 would not likely function as claimed. For example, Parrish et al. (Molecular Cell, Vol. 6, 1077–1087, November, 2000) teach that sequences of 1000 bp trigger RNAi (page 1078).
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species for dsRNA agents within the instant enormous genus that are inhibitory of the target as claimed. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Response to Arguments
Applicant argues that the claims have been amended to recite specific nucleotide sequences. However, the claims are not limited to siRNAs, but rather dsRNA agents of any length that comprise the instantly recited sequences, a genus that has not been adequately described by the specification.
Claims 21, 25, 29-34, and 36-38 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 of inhibiting XDH in the liver via subcutaneous injection of a siRNA comprising SEQ ID NOs: 853 (sense strand) and 1212 (antisense strand), does not reasonably provide enablement for delivery of any dsRNA of any length wherein the sense strand comprises SEQ ID NO: 853 and the antisense strand comprises SEQ ID NO: 1212 and the predictable outcome of inhibiting XDH or treating gout. 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/or use the invention commensurate in scope with these claims.
Factors to be considered in a determination of lack of enablement include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The claims are directed to a method of inhibiting XDH or treating gout via delivery of any dsRNA of any length that comprises the instantly recited sequences (21-mers).
The specification demonstrates in vivo delivery via subcutaneous injection to Cynomolgus monkeys of 11 specific XDH specific siRNAs (Example 4) with resultant varying levels of XDH inhibition (page 209, Figures 2 and 3). The specification does not demonstrate treatment of even a single species of diseases that would predictably be treated by the reduction in XDH expression. It is noted that AD-1136091 resulted in the highest level of inhibition from the 11 siRNAs tested.
With regards to XDH inhibition in vivo, the specification demonstrates XDH inhibition via subcutaneous injection of a specific siRNA targeting the instantly recited region, which is not demonstrative of subcutaneous delivery of any dsRNA of any length comprising the instant sequences and the predictable outcome of inhibiting XDH or treating gout.
The claims are not limited to the specific siRNA, but rather dsRNA agents of any length wherein the sense strand comprises SEQ ID ON: 853 and the antisense strand comprises SEQ ID NO: 1212.
It is known in the field of siRNA design that such lack of specificity would not be enabled. For example, Elbashir et al. (The EMBO Journal, Vol. 20, No. 23, pages 6877-6888, 2001) teaches that duplexes of 21-23 nt RNAs are the sequence specific mediators of RNAi and that even single mismatches between the siRNA duplex and the target mRNA abolish interference (abstract and page 6888).
Kulkarni et al. (NATURE METHODS, VOL.3, NO.10, 2006, 833-838) teach that their analysis predicts that dsRNAs containing greater than or equal to 19-nucleotide perfect matches identified in silico to unintended targets may contribute to a significant false positive error rate arising from off-target effects. We confirmed experimentally that such sequences in dsRNAs lead to false positives and to efficient knockdown of across-hybridizing transcript, raising a cautionary note about interpreting results based on the use of a single ds RNA per gene (abstract). The instant claims encompass dsRNAs 5000 nt in length, for example, that have as little as 21 contiguous nucleotides complementary or identical to the target and therefore encompass thousands of possible nucleotides that are complementary to other target sequences. The specification does not draw an adequate nexus between delivery of the instant genus of dsRNA agents and each of the recited outcomes.
Even with regards to the specific siRNA AD-1136091, the specification does not draw an adequate nexus between delivery of the siRNA and the predictable outcome of treating gout. Applicant has not drawn an adequate nexus between inhibition of XDH alone and the predictable outcome of treating gout.
The references cited herein illustrate the state of the art for therapeutic in vivo applications using dsRNA.
Fujita et al. (Int. J. Mol. Sci. 2015, 16, 5254-5270) teach that two types of small RNA molecules, small interfering RNAs (siRNAs) and microRNAs (miRNAs), have a central function in RNAi technology. The success of RNAi-based therapeutic delivery may be dependent upon uncovering a delivery route, sophisticated delivery carriers, and nucleic acid modifications (page 5254). Fujita et al. teach that the success of an RNAi-based therapy in clinical trials rests on careful selection of target genes and miRNAs. Moreover, we suggest that a delivery route, sophisticated delivery carriers, chemical modification, and modified RNAi platforms are needed to enhance RNAi effects in cancer cells (pages 5262-5263).
As outlined above, it is well known that there is a high level of unpredictability in the RNAi art for therapeutic in vivo applications. The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention, namely a broad method of treating gout or inhibiting XDH in vivo therapeutic effects.
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of
the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed
invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27
USPQ2d 1510, 1513 (Fed. Cir. 1993).
Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether introduction of the dsRNA in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful RNA interference and treatment of gout. To practice the claimed invention, one of skill in the art would have to de novo determine; the stability of the dsRNA molecule in vivo, delivery of the dsRNA molecule to the whole organism, specificity to the target tissue in vivo, dosage and toxicity in vivo, and entry of the molecule into the cell in vivo and the effective action therein. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
Response to Arguments
Applicant argues that the specification teaches how to make the claimed dsRNA agents, or salts thereof (see, e.g., page 27, lines 10-21 of the specification), methods to determine whether a subject has hyperuricemia and gout (see, e.g., page 22, line 21, through page 23, line 2 of the specification), as well as suitable methods for administration of the dsRNA agents, or salts thereof, and suitable doses of the dsRNA agents, or salts thereof (see, e.g., page 107, lines 31-36 of the specification).
The specification is not commensurate in scope with the claims, which encompass dsRNA agents of any length that comprise the instantly recited 21-mer sense and antisense sequences. The specification does not demonstrate that dsRNAs 5000 nt in length, for example, that comprise the 21-mers would predictably inhibit XDH. Even the species that would (siRNAs) inhibit XDH would not necessarily treat gout. Methods of determining if an individual has gout are not enabling for methods of predictably treating the condition.
Applicant argues that they have demonstrated in the specification that dsRNA agents, “like those claimed”, e.g., AD-1136091, potently inhibit XDH mRNA expression in vitro (see, e.g., Tables 4, 5, 8, and 9). Applicant has further demonstrated in the specification that dsRNA agents, like those claimed, potently and durably inhibit XDH mRNA expression and XDH protein production in vivo in non-human primates, (see, e.g.. Example 4, Figures 2 and 3). The siRNA of the specification is not enabling for dsRNA agents of any length comprising the instant 21-mer sense and antisense sequences. The specification is enabling for inhibition of XDH comprising subcutaneous injection of a dsRNA agent consisting of the instantly recited sequences (instant claim 35).
Applicant argues that the data presented in the Examples fully supports the therapeutic uses of the claimed invention. In order to meet the enablement requirement, it is not necessary that a patent specification include specific examples of every different embodiment encompassed by the claims. Indeed, working examples are not required. However, in this case, Applicant has provided working examples which demonstrate that the claimed dsRNA agents, or salts thereof, inhibit XDH mRNA and protein- the enzyme directly involved in chronic elevated serum uric acid (chronic hyperuricemia), e.g., gout. Furthermore, it is the enzyme XDH that is inhibited by the current therapeutics Allopurinol and febuxostat (Uloric®) for hyperuricemia, e.g., gout.
Contrary to applicant’s argument, an individual that has hyperuricemia does not necessarily develop gout. Although high uric acid levels are a risk factor for gout, inhibiting XDH or treating hyperuricemia would not necessarily predictably treat gout and the specification does not demonstrate otherwise.
As taught by Gotloib (J. Interven. Nephro. 2024 7(6), 351-353), hyperuricemia, characterized by elevated levels of uric acid in the blood, is a condition that can lead to the development of gout (page 351). Although gout occurs when uric acid levels in the blood exceed the solubility threshold, an individual with chronic hyperuricemia does not necessarily have gout and treatment of hyperuricemia does not necessarily treat gout.’
Additionally, normouricemic gout occurs in individuals with normal uric acid levels due to genetic predisposition and diet, as taught by Zhang (Biomolecules 2021, 11, 280, 1-11). Zhang teaches that gout seems to be a multifactorial metabolic disease and its pathogenesis should not rely solely on hyperuricemia or monosodium urate (MSU) crystals (page 1).
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. 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 re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined 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 § 2146 et seq. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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 www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 21, 25, and 29-38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of U.S. Patent No. 11,326,166 B1. It is noted that the instant application is a continuation of application 17505732, US patent No. 11,326,166 B1. Although the claims at issue are not identical, they are not patentably distinct from each other because US ‘166 B1 recites the same dsRNA as instantly recited (SEQ ID NOs:853 and 1212, claim 28). Additionally, claims 13-29 of US ‘166 B1 recite the identical compound as instantly claimed. It would have been obvious to utilize the patented compound in a method of inhibiting XDH, which is the purpose of an XDH dsRNA, or a method of treating a subject having gout because that is the disclosed use of the patented compound. Both applications have identical specifications to define the compound and its uses, doses, and modes of administration (instant claims 2-8 and 22-28). The claims of US ‘166 B1 recite the intended use of inhibition of XDH (claims 1, 12, 13, 26, 27, and 29). Both claim sets recite the same ligands, modifications, and pharmaceutical compositions.
The claims of US ‘166 B1 are as follows:
1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of xanthine dehydrogenase (XDH) in a cell, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises at least 19 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of nucleotides 2691-2722 of SEQ ID NO: 1, and the antisense strand comprises a nucleotide sequence selected from the group consisting of 5′-AAAUACTCUGAGAGAGAUCCUGG-3′(SEQ ID NO:485); 5′-AUAATACUCUGAGAGAGAUCCUG-3′(SEQ ID NO:486); 5′-AAUAAUACUCUGAGAGAGAUCCU-3′(SEQ ID NO:487); 5′-ACAUAAUACUCUGAGAGAGAUCC-3′(SEQ ID NO:488); 5′-ACCAUAAUACUCUGAGAGAGAUC-3′(SEQ ID NO:489); 5′-AUCCAUAAUACUCUGAGAGAGAU-3′(SEQ ID NO:490); 5′-AUUCCAUAAUACUCUGAGAGAGA-3′(SEQ ID NO:491); 5′-AGUUCCAUAAUACUCUGAGAGAG-3′(SEQ ID NO:492); 5′-ACGUUCCAUAAUACUCUGAGAGA-3′(SEQ ID NO:493); 5′-ACUCGUUCCAUAAUACUCUGAGA-3′(SEQ ID NO:494); and 5′-AGCUCGUUCCAUAAUACUCUGAG-3′(SEQ ID NO:495), wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides, wherein the sense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus, and wherein the antisense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus and two phosphorothioate internucleotide linkages at the 3′-terminus (instant claims 1, 16, and 17).
2. The dsRNA agent of claim 1, wherein at least one of the modified nucleotides is selected from the group consisting of a deoxy-nucleotide, a 3′-terminal deoxythimidine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5′-phosphate, a nucleotide comprising a 5′-phosphate mimic, a nucleotide comprising a 2′-phosphate, a thermally destabilizing nucleotide, a glycol modified nucleotide (GNA), and a 2-O—(N-methylacetamide) modified nucleotide; and combinations thereof (instant claim 9).
3. The dsRNA agent of claim 1, wherein the sense strand and the antisense strand are each independently 19-25 nucleotides in length (instant claim 10).
4. The dsRNA agent of claim 1, wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide.
5. The dsRNA agent of claim 1, further comprising a ligand (instant claims 11 and 19).
6. The dsRNA agent of claim 5, wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent (instant claim 12).
7. The dsRNA agent of claim 6, wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative (instant claim 13).
8. The dsRNA agent of claim 7, wherein the ligand is ##STR00039## (instant claims 14 and 20).
9. The dsRNA agent of claim 8, wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic ##STR00040## and, wherein X is O or S (instant claims 15 and 21).
10. The dsRNA agent of claim 1, wherein the sense strand and the antisense strand comprise nucleotide sequences selected from the group consisting of 5′-AGGAUCUCUCUCAGAGUAUUU-3′(SEQ ID NO:126) and 5′-AAAUACTCUGAGAGAGAUCCUGG-3′(SEQ ID NO:485); 5′-GGAUCUCUCUCAGAGUAUUAU-3′(SEQ ID NO:127) and 5′-AUAATACUCUGAGAGAGAUCCUG-3′(SEQ ID NO:486); 5′-GAUCUCUCUCAGAGUAUUAUU-3′(SEQ ID NO:128) and 5′-AAUAAUACUCUGAGAGAGAUCCU-3′(SEQ ID NO:487); 5′-AUCUCUCUCAGAGUAUUAUGU-3′(SEQ ID NO:129) and 5′-ACAUAAUACUCUGAGAGAGAUCC-3′(SEQ ID NO:488); 5′-UCUCUCUCAGAGUAUUAUGGU-3′(SEQ ID NO:130) and 5′-ACCAUAAUACUCUGAGAGAGAUC-3′(SEQ ID NO:489); 5′-CUCUCUCAGAGUAUUAUGGAU-3′(SEQ ID NO:131) and 5′-AUCCAUAAUACUCUGAGAGAGAU-3′(SEQ ID NO:490); 5′-UCUCUCAGAGUAUUAUGGAAU-3′(SEQ ID NO:132) and 5′-AUUCCAUAAUACUCUGAGAGAGA-3′(SEQ ID NO:491); 5′-CUCUCAGAGUAUUAUGGAACU-3′(SEQ ID NO:133) and 5′-AGUUCCAUAAUACUCUGAGAGAG-3′(SEQ ID NO:492); 5′-UCUCAGAGUAUUAUGGAACGU-3′(SEQ ID NO:134) and 5′-ACGUUCCAUAAUACUCUGAGAGA-3′(SEQ ID NO:493); 5′-UCAGAGUAUUAUGGAACGAGU-3′(SEQ ID NO:135) and 5′-ACUCGUUCCAUAAUACUCUGAGA-3′(SEQ ID NO:494); and 5′-CAGAGUAUUAUGGAACGAGCU-3′(SEQ ID NO:136) and 5′-AGCUCGUUCCAUAAUACUCUGAG-3′(SEQ ID NO:495) (instant claims 16 and 17).
11. The dsRNA agent of claim 10, wherein the sense strand and the antisense strand comprise nucleotide sequences selected from the group consisting of 5′-asgsgaucUfcUfCfUfcagaguauuu-3′(SEQ ID NO:844) and 5′-asAfsaudAc(Tgn)cugagaGfaGfauccusgsg-3′(SEQ ID NO:1203); 5′-gsgsaucuCfuCfUfCfagaguauuau-3′(SEQ ID NO:845) and 5′-asUfsaadTa(C2p)ucugagAfgAfgauccsusg-3 ‘(SEQ ID NO:1204); 5’-gsasucucUfcUfCfAfgaguauuauu-3′(SEQ ID NO:846) and 5′-asAfsuaaUfacucugaGfaGfagaucscsu-3 ‘(SEQ ID NO:1205); 5’-asuscucuCfuCfAfGfaguauuaugu-3′(SEQ ID NO:847) and 5′-asCfsauaAfuacucugAfgAfgagauscsc-3′(SEQ ID NO:1206); 5′-uscsucucUfcAfGfAfguauuauggu-3′(SEQ ID NO:848) and 5′-asCfscauAfauacucuGfaGfagagasusc-3 ‘(SEQ ID NO:1207); 5’-csuscucuCfaGfAfGfuauuauggau-3′(SEQ ID NO:849) and 5′-asUfsccaUfaauacucUfgAfgagagsasu-3′(SEQ ID NO:1208); 5′-uscsucucAfgAfGfUfauuauggaau-3′(SEQ ID NO:850) and 5′-asUfsuccAfuaauacuCfuGfagagasgsa-3′(SEQ ID NO:1209); 5′-csuscucaGfaGfUfAfuuauggaacu-3′(SEQ ID NO:851) and 5′-asGfsuudCc(Agn)uaauacUfcUfgagagsasg-3′(SEQ ID NO:1210); 5′-uscsucagAfgUfAfUfuauggaacgu-3′(SEQ ID NO:852); and 5′-asCfsguuCfcauaauaCfuCfugagasgsa-3′(SEQ ID NO:1211); 5′-uscsagagUfaUfUfAfuggaacgagu-3′(SEQ ID NO:853) and 5′-asCfsucgUfuccauaaUfaCfucugasgsa-3′(SEQ ID NO:1212); and 5′-csasgaguAfuUfAfUfggaacgagcu-3′(SEQ ID NO:854) and 5′-asGfscucGfuuccauaAfuAfcucugsasg-3′(SEQ ID NO:1213); wherein a, g, c, and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; s is a phosphorothioate linkage; dA is 2′-deoxyadenosine-3′-phosphate; (Tgn) is a thymidine-glycol nucleic acid (GNA)S-Isomer; dT is 2′-deoxythimidine-3′-phosphate; (C2p) is cytidine-2′-phosphate; and (Agn) is an adenosine-glycol nucleic acid (GNA)S-Isomer (instant claims 18 and 29).
12. A pharmaceutical composition for inhibiting expression of a gene encoding xanthine dehydrogenase (XDH) comprising the dsRNA agent of claim 1 (instant claim 30).
13. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of xanthine dehydrogenase (XDH) in a cell, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises at least 19 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of nucleotides 2701-2721 of SEQ ID NO: 1, and the antisense strand comprises at least 19 contiguous nucleotides from the corresponding nucleotide sequence of SEQ ID NO: 2, wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides, wherein the sense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus, and wherein the antisense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus and two phosphorothioate internucleotide linkages at the 3′-terminus (instant claims 1, 16, and 17).
14. The dsRNA agent of claim 13, wherein at least one of the modified nucleotides is selected from the group consisting of a deoxy-nucleotide, a 3′-terminal deoxythimidine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5′-phosphate, a nucleotide comprising a 5′-phosphate mimic, a nucleotide comprising a 2′-phosphate, a thermally destabilizing nucleotide, a glycol modified nucleotide (GNA), and a 2-O—(N-methylacetamide) modified nucleotide; and combinations thereof (instant claim 9).
15. The dsRNA agent of claim 13, wherein the sense strand and the antisense strand are each independently 19-25 nucleotides in length (instant claim 10).
16. The dsRNA agent of claim 15, further comprising a ligand (instant claims 11 and 19).
17. The dsRNA agent of claim 16, wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent (instant claim 12).
18. The dsRNA agent of claim 17, wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker (instant claim 13).
19. The dsRNA agent of claim 18, wherein the ligand is ##STR00041## (instant claim 14).
20. The dsRNA agent of claim 19, wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic ##STR00042## and, wherein X is O or S (instant claims 15, 20, and 21).
21. The dsRNA agent of claim 13, wherein the antisense strand comprises the nucleotide sequence 5′-ACUCGUUCCAUAAUACUCUGAGA-3′(SEQ ID NO:494) (instant claim 16).
22. The dsRNA agent of claim 21, wherein the sense strand comprises the nucleotide sequence 5′-UCAGAGUAUUAUGGAACGAGU-3′(SEQ ID NO:135) and the antisense strand comprise the nucleotide sequence 5′-ACUCGUUCCAUAAUACUCUGAGA-3′(SEQ ID NO:494) (instant claim 17)..
23. The dsRNA agent of claim 22, wherein the sense strand comprises the nucleotide sequence 5′-uscsagagUfaUfUfAfuggaacgagu-3′(SEQ ID NO:853) and the antisense strand comprises the nucleotide sequence 5′-asCfsucgUfuccauaaUfaCfucugasgsa-3′(SEQ ID NO:1212), wherein a, g, c, and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; and s is a phosphorothioate linkage (instant claims 18 and 29).
24. The dsRNA agent of claim 23, further comprising a ligand (instant claim 12).
25. The dsRNA agent of claim 24, wherein the 3′-end of the sense strand is conjugated to a ligand as shown in the following schematic ##STR00043## wherein X is O (instant claim 14).
26. A pharmaceutical composition for inhibiting expression of a gene encoding xanthine dehydrogenase (XDH) comprising the dsRNA agent of claim 13.
27. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of xanthine dehydrogenase (XDH) in a cell, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises the nucleotide sequence 5′-uscsagagUfaUfUfAfuggaacgagu-3′(SEQ ID NO:853) and the antisense strand comprises the nucleotide sequence 5′-asCfsucgUfuccauaaUfaCfucugasgsa-3′(SEQ ID NO:1212), wherein a, g, c, and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; and s is a phosphorothioate linkage; and wherein the 3′-end of the sense strand is conjugated to a ligand as shown in the following schematic ##STR00044## wherein X is O.
28. The dsRNA agent of claim 27, wherein the sense strand consists of the nucleotide sequence 5′-uscsagagUfaUfUfAfuggaacgagu-3′(SEQ ID NO:853) and the antisense strand consists of the nucleotide sequence 5′-asCfsucgUfuccauaaUfaCfucugasgsa-3′(SEQ ID NO:1212).
29. A pharmaceutical composition for inhibiting expression of a gene encoding xanthine dehydrogenase (XDH) comprising the dsRNA agent of claim 27.
Conclusion
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 Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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, Neil Hammell can be reached at 571-270-5919. 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.
/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
Prosecution Insights