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 .
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 05/04/2026 is acknowledged. Claims 13,83,84,95 and 97 were cancelled. Claims 3,4,7,14,20 and 66 were amended. Claims 119-123 are new. Claims 3,4,7,14,20,58,59,64,66,75,76,78,114,115,118-123 are pending and under examination.
Applicant elected the species of the antisense strand of SEQ ID NO: 465 which corresponds to positions 3345-3367, and the sense strand of SEQ ID NO: 165 which corresponds to positions 3347-3367 in Table 2 and which is duplex AD-1290122 with traverse in the reply filed on 11/18/2025 and the Examiner withdrew the species election and indicated that the antisense strand of SEQ ID NO: 465 which corresponds to positions 3345-3367, and the sense strand of SEQ ID NO: 165 which corresponds to positions 3347-3367 in Table 2 and which is duplex AD-1290122, as well as the corresponding chemically modified antisense strand sequence for duplex AD-1290122, SEQ ID NO: 1065 and the corresponding chemically modified sense strand sequence for duplex AD-1290122, SEQ ID NO: 765 (See Table 3), as well as the sequences of Duplex AD-1335131 in Table 4 (SEQ ID NOs: 1665 and 1065) will be examined and that the examiner reserves the right to re-introduce the election if amendments re-introduce species which have been removed from the claims.
In consideration of the amendment and in reconsideration of the prior office actions and responses thereto, rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Priority
This application is a 371 of PCT/US2021/037437 filed 06/15/2021, which claims benefit of 63/140,532 filed 01/22/2021 and claims benefit of 63/039,897 filed 06/16/2020.
Withdrawn Objections and Rejections
Applicant’s arguments and amendments, see page 19, filed 05/04/2026, with respect to the objection to the specification for embedded hyperlinks have been fully considered and are persuasive due to the amendments to the specification removing “http://). The objection to the specification has been withdrawn.
Applicant’s arguments and amendments, see pages 19-20, filed 05/04/2026, with respect to the objections to claims 3,14,20 and 97 for reciting “ALK” have been fully considered and are persuasive due to the amendments to the above claims correcting the typos and issues. The objections to claims 3,14,20 and 97 have been withdrawn.
Applicant’s arguments and amendments, see page 20, filed 05/04/2026, with respect to the 35 U.S.C. 112(b) rejection of claims 7,14,20,66,84,97 and 118 have been fully considered and are persuasive due to the cancelation of claims 84 and 97 and the amendments to claims 7,14,20 and 66 correcting the issues. In addition, applicant’s arguments have been found persuasive regarding “Ghd” being a well-established abbreviation for 2’-O-hexadecyl linked G, and therefore the rejection of claim 118 has been withdrawn. The 35 U.S.C. 112(b) rejection of claims 7,14,20,66,84,97 and 118 have been withdrawn.
The 35 U.S.C. 112(a) rejection of claims 83,84,95 and 97 has been withdrawn due to the cancelation of those claims and the rejection is moot.
Applicant’s arguments and amendments, see page 21, filed 05/04/2026, with respect to the 35 U.S.C. 102(a)(1) rejection of claims 3 and 4 as anticipated by McSwiggen, and claims 13,14,20,66,75,76,78,93,114 and 115 rejected under 35 U.S.C. 102(a)(1) or in the alternative under 35 U.S.C. 103 as unpatentable over McSwiggen have been fully considered and are persuasive due to the amendments to claims 3 and 4 requiring at least 18 contiguous nucleotides differing by no more than 2 nucleotides from the antisense nucleotide sequence set forth as SEQ ID NO: 465, which McSwiggen does not teach, as well as the amendment of wherein the dsRNA agent comprises at least one modified nucleotide and at least one phosphorothioate internucleotide linkage, and removing subparts (a) and (b) from claim 4. Therefore, the rejections have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amendments to the claims. See the new 35 U.S.C. 103 rejections below.
Applicant’s arguments and amendments, see pages 22-25, filed 05/04/2026, with respect to the 35 U.S.C. 103 rejection of claims 13,14,20,66,75,76,78,93,114 and 115 as unpatentable over McSwiggen; claims 7,58,59 and 64 as unpatentable over McSwiggen in view of Bettencourt et al., claims 3 and 118 as unpatentable over Haack et al. in view of NCBI Access. No. NM_004304, Bettencourt and Maier et al. have been fully considered and are persuasive due to the amendments to claim 3 requiring at least 18 contiguous nucleotides differing by no more than 2 nucleotides from the antisense nucleotide sequence set forth as SEQ ID NO: 465, wherein the dsRNA agent comprises at least one modified nucleotide and at least one phosphorothioate internucleotide linkage. However, upon further consideration, a new ground(s) of rejection is made in view of the amendments to the claims. See the new 35 U.S.C. 103 rejections below.
Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Interpretation: The examiner has included the elected sequences from Tables 3 and 4 below for reference. Abbreviations are found on instant pages 143-144.. The examiner is interpretating ‘Ghd’ to mean 2’-O-hexadecyl-guanosine-3’-phosphate.
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The above chemical modification motif can be summarized as below:
Sense strand SEQ ID NO: 765: positions 1-5,8,12-21 2’-OMe; positions 7,9-11 2’-F, position 6 Ghd (2’-O-hexadecyl-guanosine-3’-phosphate).
Antisense strand SEQ ID NO: 1065: 5’ vinyl-phosphonate, positions 1,3-5,7,10-13,15,17-23 2’-OMe; positions 2,6,8,9,14,16 2’-F.
Sense strand SEQ ID NO: 1665: positions 1-6,8,12-21 2’-OMe; positions 7,9-11 2’-F.
Regarding claim 114, the preamble “kit” does not add any structure to the claim, as the body of the claim recites the required structure of “the dsRNA agent of claim 3”, and therefore art reading on the dsRNA agent of claim 3 also applies to claim 114.
Claims 3,14,20,75,76,78,114,115 and 123 are rejected under 35 U.S.C. 103 as being unpatentable over Haack et al. (US 20120101108, Published 26 April 2012) in view of Zhang et al. (US 20180223277, Published 9 Aug 2018, EFD 05 May 2016) and Maier et al. (US 20170275626, Published 28 Sept 2017).
Regarding claims 3, 14(c) and (f), 20 and 114, Haack et al. teach the association of ALK as driving proliferation and survival of the subset of kidney cancer in which it is expressed and is not known to be expressed in normal kidney tissue and cells (paragraph 0043), and that a patient whose kidney cancer expresses a polypeptide with ALK activity may respond favorably to administration of an ALK inhibitor (paragraph 0044). Haack et al. teach siRNA compositions which inhibit the activity of ALK through the process of RNA interference may be employed in the methods of the invention, and that RNA interference and the selective silencing of target protein expression by introduction of exogenous small double-stranded RNA molecules comprising sequence complementary to mRNA encoding the target protein has been well described in the art (paragraph 0175). Haack et al. teach that detailed technical manuals on the design, construction, and use of dsRNA for RNAi are available, See e.g., Dharmacon’s “RNAi Technical Reference and Application Guide”; Promega’s “RNAi: A Guide to Gene Silencing”, that that ALK-inhibiting siRNA products are also commercially available and may be employed in the methods of the invention (paragraph 0177). Haack et al. teach that small dsRNA less than 49 nt in length, preferable 19-25 nucleotides comprising at least one sequence that is substantially identical to part of a target mRNA sequence are most effective in mediating RNAi in mammals (paragraph 0178). Haack et al. teach if the sequence of the gene to be targeted in a mammal is known, 21-23 nt RNAs can be produced and tested for their ability to mediate RNAi in a mammalian cell such as a human or other primate cell, and then can be tested in an appropriate animal model to further assess their in vivo effectiveness (paragraph 0179). Haack et al. also teach the sequences of effective dsRNA can be rationally designed/predicated screening the target mRNA of interest for target sites using a computer folding algorithm, and various parameters may be used to determine which sites are the most suitable target sites within the target RNA sequence (paragraphs 0180,0181).
Haack et al. do not teach an antisense strand comprising a region of complementary to an mRNA encoding ALK comprising at least 18 contiguous nucleotides differing by no more than 2 nucleotides from the antisense sequence set forth as SEQ ID NO: 465, wherein the dsRNA agent comprises at least one modified nucleotide and at least one phosphorothioate internucleotide linkage, or wherein the at least one modified nucleotide is a 2’-O-methyl modification or a 2’-fluoro modification.
Before the effective filing date, Zhang et al. taught anti-miRNAs and/or siRNA including ALK siRNA (paragraph 0036). Example 14, Table 17 on page 31 shows siRNA sequences designed for the ALK gene locus shows sense strand sequences of ALK siRNAs, including Sequence number 86.
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Below is the alignment between the instant sense strand sequence of SEQ ID NO: 165 (Qy) and the ALK sense strand sequence of SEQ ID NO: 86 of Zhang et al. (Db), which shows alignment of 18 contiguous nucleotides at 100% identity to those 18 contiguous nucleotides:
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While Zhang et al. do not teach the antisense sequence of the siRNA having the sense strand sequence of SEQ ID NO: 86, one of ordinary skill in the art would be able to use the sense strand sequence of SEQ ID NO: 86 of Zhang et al. to arrive at the corresponding antisense sequence. Alignment is shown below of the antisense sequence of instant SEQ ID NO: 465 (Qy) with the sense sequence of sequence 86 of Zhang et al. (Db) which shows alignment of 19 contiguous nucleotides with no mismatches and just conservative substitutions, and therefore shows that nucleotides 4-22 of the antisense sequence of instant SEQ ID NO: 465 are complementary to nucleotides 19-1 of the sense sequence 86 of Zhang et al.
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Maier et al. taught the need for iRNA duplex agents to improve the gene silencing efficacy of siRNA gene therapeutics (paragraph 0009) and taught dsRNA agents with effective nucleotide or chemical motifs for dsRNA agents which are advantageous for inhibition of target gene expression (paragraph 0010). Maier et al. taught dsRNA agents comprising a sense strand and antisense strand with various motifs, the sense strand having a length of 21 nucleotides, 2’-OMe modifications at positions 1-6,8,10,12-21, 2’F modifications at position 7 and 9, and phosphorothioate internucleotide linkages between nt positions 1 and 2 and 2 and 3, and taught the antisense strand having a length of 23 nucleotides, 2’-OMe modifications at positions 1,3,7,9,11,13,15,17,19-23 and 2’-F modifications at positions 2,4-6,8,10,12,14,16 and 18; phosphorothioate internucleotide linkages between positions 1 and 2 and 2 and 3, and between positions 21 and 22 and 22 and 23 counting from the 5’ end (paragraphs 0150-0158). Maier et al. also taught dsRNA agents comprising a sense strand comprising 2’-F modifications at positions 10 and 11 (paragraph 0171) and a sense strand comprising 2’-F modifications at positions 9-11 and 2’-OMe modifications at positions 1-6,8 and 12-21 (paragraph 0198) and phosphorothioate internucleotide linkages between nt positions 1 and 2 and 2 and 3, and an antisense strand comprising 2’-F modifications at positions 2,6,9,14 and 16, and 2’-OMe modifications at positions 1,3-5,7,8,10-13,15 and 17-23 (paragraph 0202) and phosphorothioate internucleotide linkages between positions 1 and 2 and 2 and 3, and between positions 21 and 22 and 22 and 23 counting from the 5’ end (paragraph 0203).
In addition, regarding claim 20, Maier et al. taught dsRNA agents capable of inhibiting expression of a target gene, wherein each strand of the dsRNA agent can range from 12-40 nucleotides in length. For example, each strand can be between 14-40 nucleotides in length, 17-37 nucleotides in length, 25-37 nucleotides in length, 27-30 nucleotides in length, 17-23 nucleotides in length, 17-21 nucleotides in length, 17-19 nucleotides in length, 19-25 nucleotides in length, 19-23 nucleotides in length, 19-21 nucleotides in length, 21-25 nucleotides in length, or 21-23 nucleotides in length (paragraph 0263), and the duplex region of a dsRNA agent may be 12-40 nucleotide pairs in length. For example, the duplex region can be between 14-40 nucleotide pairs in length, 17-30 nucleotide pairs in length, 25-35 nucleotides in length, 27-35 nucleotide pairs in length, 17-23 nucleotide pairs in length, 17-21 nucleotide pairs in length, 17-19 nucleotide pairs in length, 19-25 nucleotide pairs in length, 19-23 nucleotide pairs in length, 19-21 nucleotide pairs in length, 21-25 nucleotide pairs in length, or 21-23 nucleotide pairs in length (paragraph 0265).
Regarding claim 75, Haack et al teach a cell containing a dsRNA agent (If the sequence of the gene to be targeted in a mammal is known, 21-23 nt RNAs, for example, can be produced and tested for their ability to mediate RNAi in a mammalian cell) (paragraph 0179).
Regarding claim 76, Haack et al teach a pharmaceutical composition comprising the dsRNA agent (siRNA interference in a mammal using prepared dsRNA molecules may then be effected by administering a pharmaceutical preparation comprising the dsRNA to the mammal) (paragraph 0184); (Such dsRNA may then be used to inhibit ALK expression and activity in a cancer, by preparing a pharmaceutical preparation comprising a therapeutically-effective amount of such dsRNA, as described above, and administering the preparation to a human subject having a cancer) (paragraph 0185).
Regarding claim 78, Haack et al teach for oral administration, a ALK-inhibiting therapeutic will generally be provided in the form of tablets or capsules, as a powder or granules, or as an aqueous solution (paragraph 0188); For intramuscular, intraperitoneal, subcutaneous and intravenous use, the pharmaceutical compositions of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. The carrier may consist exclusively of an aqueous buffer (paragraph 0189).
Regarding claim 115, Haack et al. and Zhang et al. do not teach a vial, syringe or intrathecal pump comprising the dsRNA agent.
Maier et al. taught dsRNA agents and their synthesis (Example 2), and that ligand conjugated oligonucleotides were purified reverse phase preparative HPLC (paragraph 0629) and that fractions containing full-length oligonucleotides were pooled, desalted, and lyophilized. Approximately 0.15 OD of desalted oligonucleotides were diluted in water to 150 μl and then pipetted in special vials for CGE and LC/MS analysis. Compounds were finally analyzed by LC-ESMS and CG (paragraph 0629)..
Regarding claim 123, Haack et al. and Zhang et al. do not teach a dsRNA comprising a phosphate or phosphate mimic at the 5’ end of the antisense strand.
Maier et al. taught dsRNA agents with a 5’-VP on the antisense strand (paragraphs 0052,0056), and the presence of a 5’-VP generally improves the in vivo activity (Paragraph 0247, Fig. 17).
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to provide a dsRNA agent that inhibits ALK expression as taught by Haack et al. to treat kidney cancer, and use the teachings of Haack et al. regarding if the sequence of the gene to be targeted in a mammal is known that 21-23 nt RNAs can be produced and tested for their ability to mediate RNAi and that sequences of effective dsRNA can be rationally designed/predicated screening the target mRNA of interest for target sites using a computer folding algorithm, in view of the sense sequence 86 of the ALK siRNA of Zhang et al. and the teachings of Maier et al. regarding chemical modifications, and arrive at the instant claims with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to design and provide a dsRNA agent that targets ALK based on the teachings of Haack et al., which taught the association of ALK as driving proliferation and survival of the subset of kidney cancer in which it is expressed (paragraph 0043), and that a patient whose kidney cancer expresses a polypeptide with ALK activity may respond favorably to administration of an ALK inhibitor (paragraph 0044), and that siRNA compositions which inhibit the activity of ALK through the process of RNA interference may be employed in the methods of the invention, and the teachings of Zhang et al. regarding ALK siRNAs including the sense sequence of sequence 86 and the effective nucleotide or chemical motifs for dsRNA agents which are advantageous for inhibition of target gene expression of Maier et al. One of ordinary skill in the art would be able to use the sense strand sequence of SEQ ID NO: 86 of Zhang et al. to arrive at the corresponding antisense sequence and introduce at least one modified nucleotide and at least one phosphorothioate internucleotide linkage based on the teachings of Maier et al.
Accordingly, the limitations of claims 3,14,20,75,76,78,114,115 and 123 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 4 is rejected under 35 U.S.C. 103 as being unpatentable over Haack et al. in view of Zhang et al. and Maier et al. as applied to claim 3 above, and further in view of NCBI Reference Sequence Accession number NM_004304 (publicly available 07 May 1999).
The teachings of Haack et al., Zhang et al. and Maier et al. as applicable to claim 3 have been described above.
Additionally, Haack et al. taught that dsRNA preferably 19-25 nucleotides in length comprising at least one sequence that is substantially identical to part of a target mRNA sequence and which dsRNA optimally has at least one overhang of 1-4 nucleotides at an end are most effective in mediating RNAi in mammals (paragraph 0178).
Haack et al., Zhang et al. and Maier et al. do not teach that the sense strand comprises the entire nucleotide sequence of SEQ ID NO: 165, and the antisense strand comprises the entire nucleotide sequence of SEQ ID NO: 465.
However, a blast search of the sense sequence of instant SEQ ID NO: 165 shows that nucleotides 1-20 of SEQ ID NO: 165 aligns with nucleotides 3322-3341 of Homo sapiens ALK receptor tyrosine kinase (ALK) transcript variant 1, mRNA of NM_004304.5.
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Likewise, a blast search of the antisense sequence of instant SEQ ID NO: 465 shows nucleotides 2-23 of SEQ ID NO: 465 aligns with nucleotides 3341-3320 of Homo sapiens ALK receptor tyrosine kinase (ALK) transcript variant 1, mRNA of NM_004304.5.
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The mRNA sequence of Homo sapiens ALK transcript variant 1 of NCBI Reference sequence NM_004304 was publicly available before the effective filing date (07 May 1999) and the mRNA sequence is shown below.
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It would have been obvious to one of ordinary skill in the art before the effective filing date, to have modified the ALK siRNA of Haack et al. in view of Zhang et al. and Maier et al., based on the publicly available mRNA sequence of ALK (NCBI Reference Sequence Accession number NM_004304) to arrive at the instant claimed sequences of claim 4 with a reasonable expectation of success. There would be a reasonable expectation of success because nucleotides 1-20 of SEQ ID NO: 165 aligns with nucleotides 3322-3341 of Homo sapiens ALK receptor tyrosine kinase (ALK) transcript variant 1, mRNA of NM_004304.5, and instant nucleotides 2-23 of SEQ ID NO: 465 aligns with nucleotides 3341-3320 of Homo sapiens ALK receptor tyrosine kinase (ALK) transcript variant 1, mRNA of NM_004304.5. One of ordinary skill in the art would have been motivated to target the ALK gene and to design siRNA that targets ALK based on the teachings of Haack et al. and Zhang et al. Haack et al. teaches that if the sequence of the gene to be targeted in a mammal is known, 21-23 nt RNAs can be produced. Therefore, an ordinary artisan would know that there is design choice in the length of the sense and antisense strands of siRNA, and there are design choices in blunt ends or overhangs based on the teachings of Haack et al., as well as including mismatches or not. Therefore, absent a demonstration of criticality, any of these options would be obvious to arrive at the claimed sequences. One of ordinary skill in the art would have been motivated to arrive at the instant sequences because Zhang et al. taught ALK siRNA sequences designed for the ALK gene locus including the sense strand sequence of ALK siRNA, including Sequence number 86 (alignment is shown again below of nucleotides 1-18 of instant SEQ ID NO: 165 with nucleotides 2-19 of sequence 86 of Zhang et al.), and an ordinary artisan could have used the teachings of Haack et al. regarding the design, construction, and use of dsRNA for RNAi are available, See e.g., Dharmacon’s “RNAi Technical Reference and Application Guide”; Promega’s “RNAi: A Guide to Gene Silencing”, that small dsRNA less than 49 nt in length, preferably 19-25 nucleotides comprising at least one sequence that is substantially identical to part of a target mRNA sequence are most effective in mediating RNAi in mammals (paragraph 0178), and that if the sequence of the gene to be targeted in a mammal is known, 21-23 nt RNAs can be produced and tested for their ability to mediate RNAi in a mammalian cell such as a human or other primate cell or the sequences of effective dsRNA can be rationally designed/predicated screening the target mRNA of interest for target sites using a computer folding algorithm, and various parameters may be used to determine which sites are the most suitable target sites within the target RNA sequence (paragraphs 0180,0181) and the publicly available mRNA sequence of ALK (NCBI Reference Sequence Accession number NM_004304) to arrive at the instant sense strand sequence comprising SEQ ID NO: 165 and the antisense strand sequence comprising SEQ ID NO: 465 with a reasonable expectation of success.
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Accordingly, the limitations of claim 4 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 7,58,59,64, and 119-122 are rejected under 35 U.S.C. 103 as being unpatentable over Haack et al. in view of Zhang et al. and Maier et al. as applied to claim 3, above, and further in view of Bettencourt et al. (US 20160115476, Published 28 April 2016).
The teachings of Haack et al. in view of Zhang et al. and Maier et al. as applicable to claim 3 are described above.
Haack et al. in view of Zhang et al. and Maier et al. do not teach wherein the sense strand, the antisense strand or both the sense and the antisense strand is conjugated to one or more lipophilic moieties, or a targeting ligand which is a GalNAc conjugate.
Before the effective filing date, Bettencourt et al. taught iRNA agents and that they can be in the form of conjugates and may be attached at any suitable location in the iRNA molecule, e.g. at the 3’ end or the 5’ end of the sense or antisense strand (paragraph 0348). Bettencourt et al. taught that the iRNA agent is chemically linked to one or more conjugates, which may confer functionality by enhancing the activity, cellular distribution or cellular uptake of the iRNA, and that such moieties include lipid moieties such as a cholesterol moiety, cholic acid, a thiocholesterol, a phospholipid (paragraph 0349). Bettencourt et al. taught lipid conjugates can increase resistance to degradation of the conjugate, increase targeting or transport into the target cell or cell membrane and/or be used to adjust binding to a serum protein (paragraph 0364) or can be used to modulate the binding of the conjugate to a target tissue (paragraph 0365). Bettencourt et al. taught that 3’ ligand conjugated strands can be synthesized using a solid support containing the corresponding ligand, and for example the introduction of cholesterol unit in the sequence is performed from a hydroxyprolinol-cholesterol phosphoramidite (paragraph 0688). Bettencourt et al. taught conjugation of ligands to the 5’ end and/or internal positions is achieved by using appropriately protected ligand-phosphoramidite building block (paragraph 0688). Therefore, Bettencourt et al. taught the limitations of claims 7,58,59,119-122 in that a lipophilic moiety which is a polyalicyclic compound (cholesterol) is conjugated via a carrier which is hydroxyprolinol (a pyrrolidinyl), and can be conjugated to the internal positions.
Regarding claim 64, Bettencourt et al. taught iRNA agents in the form of conjugates, e.g. a carbohydrate conjugate which may serve as a targeting moiety and/or ligand, attached to the 3’ end of the sense strand of the dsRNA, and the conjugate make be attached by a linker (paragraph 0027). Bettencourt et al. taught the conjugate comprises one or more acetylgalactosamine (GalNAc) derivatives, which targets the RNAi agents to a particular cell (paragraph 0028).
It would have been obvious to one of ordinary skill in the art before the effective filing date, to have modified the sense strand, antisense strand or both strands of the ALK siRNA of Haack et al. in view of Zhang et al. and Maier et al. to form a conjugate with one or more lipophilic moieties, or conjugation of the lipophilic moieties to internal positions of the siRNA using a carrier which is with a reasonable expectation of success. There would be a reasonable expectation of success because Haack et al., Zhang et al., Maier et al. and Bettencourt pertain to dsRNA for inhibiting gene expression of a target gene and therefore are in the same field of endeavor. One of ordinary skill in the art would have been motivated to modify the sense strand or antisense strand or both of the ALK siRNA Haack et al., Zhang et al., Maier et al. by conjugating to one or more lipophilic moieties, or for one or more lipophilic moieties to be conjugated to one or more internal positions on at least one strand in the ds region of the ds siNA, because Bettencourt et al. taught iRNA agents can be in the form of conjugates and may be attached at any suitable location in the iRNA molecule, (paragraph 0348) and that conjugation of ligands to the 5’ end and/or internal positions is achieved by using appropriately protected ligand-phosphoramidite building block (paragraph 0688), and for example the introduction of cholesterol unit in the sequence is performed from a hydroxyprolinol-cholesterol phosphoramidite (paragraph 0668), and teach the benefits of such a lipophilic conjugation which include enhancing the activity, cellular distribution or cellular uptake of the iRNA and that lipid conjugates can increase resistance to degradation of the conjugate, increase targeting or transport into the target cell or cell membrane and/or be used to adjust binding to a serum protein (paragraph 0364) or can be used to modulate the binding of the conjugate to a target tissue (paragraph 0365).
Accordingly, the limitations of claims 7,58,59 and 119-122 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to have modified the ALK siRNA of Haack et al. in view of Zhang et al. and Maier et al. to comprise a targeting ligand which is a GalNAc conjugate with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to provide the ALK siRNA of Haack et al. in view of Zhang et al. and Maier et al. with a targeting ligand which is a GalNAc conjugate because Bettencourt et al. taught iRNA agents in the form of conjugates, e.g. a carbohydrate conjugate which may serve as a targeting moiety and/or ligand, attached to the 3’ end of the sense strand of the dsRNA, and the conjugate make be attached by a linker (paragraph 0027) and taught the conjugate comprises one or more acetylgalactosamine (GalNAc) derivatives, which targets the RNAi agents to a particular cell (paragraph 0028).
Accordingly, the limitations of claim 64 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim 66 is rejected under 35 U.S.C. 103 as being unpatentable over Haack et al. in view of Zhang et al. and Maier et al. as applied to claim 3 above, and further in view of Jahns et al. (Nature Communications, 6:6317,Published 6 March 2015) and Hassler et al. (Nucleic Acids Research, 2018, Vol. 46, No. 5, pages 2185-2196).
The teachings of Haack et al. in view of Zhang et al. and Maier et al. as applicable to claim 3 are described above.
Haack et al. in view of Zhang et al. and Maier et al. do not teach specific terminal, chiral modifications occurring at the specified internucleotide linkages as in (a),(b),(c),(d), or (e) recited in instant claim 66.
Before the effective filing date, Jahns et al. taught that an established means of improving pharmacokinetic properties of oligoribonucleotides is to exchange their phosphodiester linkages for phosphorothioates, and that the phosphorothioate group is chiral at phosphorus (Rp/Sp centers) (Abstract). Jahns et al. teach a study of whether the control of stereochemistry of PS ORN strands in a siRNA can be exploited to improve their pharmacological properties, and that the choice of the activating agent during the synthesis of PS RNA shifts the Rp/Sp ratio in the PS linkages and when assembled into duplexes (Page 2, right column). Jahns et al. taught that distinct tetrazole activators produce a stereogenic bias during the solid-phase synthesis of PS ORNs, and this bias substantially influences the biophysical and biological properties of the duplex. Specifically, compared with tetrazole, ribonucleoside coupling catalysed by BTT yields a higher fraction of Rp PS linkages in an ORN, as evidenced by elevated Tms which surprisingly this produces a more potent PS siRNA (Discussion, page 7).
Hassler et al. taught a variety of chemical modification patterns have been explored to improve siRNA stability, and taught systematically comparing the distribution, tissue accumulation, and efficacy of partially and fully modified siRNAs (Intro, page 2185). Hassler et al. taught a fully-modified siRNA, with phosphorothioate internucleotide linkages at the first and second internucleotide linkage at the 5’ end of the antisense strand, and the 7 internucleotide linkages at the 3’ end of the antisense strand, as well as phosphorothioate internucleotide linkages at the first and second internucleotide linkages of the 5’ end of the sense strand (Figure 1 A), with the red showing the phosphorothioate internucleotide linkages below:
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Hassler et al. taught the single-strand region of the guide strand contains phosphorothioate linkages, providing additional stabilization and enhancing
cellular internalization (page 2189, left column), and that two phosphorothioate linkages were added to both 5’ and 3’ ends of the passenger and guide strands to provide additional resistance to exonucleases (page 2189, left column).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the dsRNA of Haack et al. in view of Zhang et al. and Maier et al. based on the teachings of Jahns et al. and Hassler et al. to comprise the terminal, chiral modifications at the recited internucleotide linkages at the recited ends of the antisense and sense strand and in the recited Rp or Sp configurations with a reasonable expectation of success. There would be a reasonable expectation of success, because Haack et al., Zhang et al., Maier et al. Jahns et al. and Hassler et al. all pertain to dsRNA agents that are for inhibiting target gene expression, and Maier et al. teaches phosphorothioate internucleotide linkages, and because this would amount to applying a known technique of chirally-modified phosphorothiaote internucleotide linkages to a known product (siRNA) ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Jahns et al. taught that the phosphorothioate group is chiral at phosphorus (Rp/Sp centers) and taught determining whether the control of stereochemistry of PS ORN strands in a siRNA can be exploited to improve their pharmacological properties as well as whether the choice of the activating agent during the synthesis of PS RNA shifts the Rp/Sp ratio in the PS linkages, and because Hassler et al. taught systematically comparing the distribution, tissue accumulation, and efficacy of partially and fully modified siRNAs with phosphorothiaote linkages at the first and second internucleotide linkage at the 5’ end of the antisense strand, and the 7 internucleotide linkages at the 3’ end of the antisense strand, as well as phosphorothioate internucleotide linkages at the first and second internucleotide linkages of the 5’ end of the sense strand (Figure 1 A). Therefore, the ordinary artisan would have been motivated by Jahns et al. and Hassler et al. to arrive at a dsRNA with the terminal, chiral modifications as recited in instant claim 66 based on the teachings Jahns et al. and Hassler et al. in order to test the dsRNAs for their pharmacological properties to arrive at a dsRNA with improved resistance to degradation or improved uptake.
Accordingly, the limitations of claim 66 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim 118 is rejected under 35 U.S.C. 103 as being unpatentable over Haack et al. in view of Zhang et al. and Maier et al. as applied to claim 3 above, and further in view of NCBI Reference Sequence Accession number NM_004304 (publicly available 07 May 1999) and Bettencourt et al. (US 20160115476, Published 28 April 2016).
The teachings of Haack et al. in view of Zhang et al. and Maier et al. as applicable to claim 3 are described above. As stated in the 103 rejection above, Maier et al. taught dsRNA agents comprising a sense strand and antisense strand with various motifs, the sense strand having a length of 21 nucleotides, 2’-OMe modifications at positions 1-6,8,10,12-21, 2’F modifications at position 7 and 9, and phosphorothioate internucleotide linkages between nt positions 1 and 2 and 2 and 3, and taught the antisense strand having a length of 23 nucleotides, 2’-OMe modifications at positions 1,3,7,9,11,13,15,17,19-23 and 2’-F modifications at positions 2,4-6,8,10,12,14,16 and 18; phosphorothioate internucleotide linkages between positions 1 and 2 and 2 and 3, and between positions 21 and 22 and 22 and 23 counting from the 5’ end (paragraphs 0150-0158). Maier et al. also taught dsRNA agents comprising a sense strand comprising 2’-F modifications at positions 10 and 11 (paragraph 0171) and a sense strand comprising 2’-F modifications at positions 9-11 and 2’-OMe modifications at positions 1-6,8 and 12-21 (paragraph 0198) and phosphorothioate internucleotide linkages between nt positions 1 and 2 and 2 and 3, and an antisense strand comprising 2’-F modifications at positions 2,6,9,14 and 16, and 2’-OMe modifications at positions 1,3-5,7,8,10-13,15 and 17-23 (paragraph 0202) and phosphorothioate internucleotide linkages between positions 1 and 2 and 2 and 3, and between positions 21 and 22 and 22 and 23 counting from the 5’ end (paragraph 0203).
Maier et al. taught dsRNA agents with a 5’-VP on the antisense strand (paragraphs 0052,0056), and the presence of a 5’-VP generally improves the in vivo activity (Paragraph 0247, Fig. 17).
Maier et al. taught the inventors found that having 2’-OMe modifications at nucleotide positions 2 and 14 from the 5’ end of the antisense strand dampened gene silencing activity (paragraph 0261).
Haack et al. in view of Zhang et al. and Maier et al. do not teach the sense strand comprises the sequence and all the modifications of SEQ ID NO: 765 and the antisense strand comprises the sequence and all the modifications of SEQ ID NO: 1065.
However, a blast search of the sense sequence of instant SEQ ID NO: 765 shows that nucleotides 1-20 of SEQ ID NO: 765 aligns with nucleotides 3322-3341 of Homo sapiens ALK receptor tyrosine kinase (ALK) transcript variant 1, mRNA of NM_004304.5.
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Likewise, a blast search of the antisense sequence of instant SEQ ID NO: 1065 shows nucleotides 2-23 of SEQ ID NO: 1065 aligns with nucleotides 3341-3320 of Homo sapiens ALK receptor tyrosine kinase (ALK) transcript variant 1, mRNA of NM_004304.5.
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The mRNA sequence of Homo sapiens ALK transcript variant 1 of NCBI Reference sequence NM_004304 was publicly available before the effective filing date (07 May 1999) (see in 103 rejection above).
Before the effective filing date, Bettencourt taught iRNA agents chemically linked to one or more ligands, moieties or conjugates which may confer functionality, by enhancing the activity, cellular distribution, or cellular uptake of the RNAi, and such moieties include a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-phosphonate (paragraph 0349) and taught that oligonucleotides can contain the nucleotide (Chd) or “2-O-hexadecyl-cytidine-3’-phosphate” (Table 1, page 67).
Therefore, it was known in the prior art to provide a dsRNA wherein the sense strand has heavy 2'-O-methyl modifications in the 5' and 3' regions and 2’-F in positions 7 and 9-11, and incorporate a 2'-O-hexadecyl nucleoside (e.g., guanosine). Similarly, it was known in the art to formulate the antisense strand having a 5' VP and a mixture of 2'-O-methyl and 2'-F with at least 7 consecutive 2'-O-methyl in the 3' region of the antisense, as well as the phosphorothioate internucleotide linkages at the recited positions in the sense and antisense sequences.
Although the cited art does not specifically teach the exact modification pattern, it would have been obvious for one ordinarily skilled in the art to perform routine optimization of the pattern to achieve improved results. As noted in In re Aller, 105 USPQ 233 at 235, more particularly, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05 provides In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."
In the instant case, the focus is in the change of form, or substitution of equivalents over the prior art. Substitution of equivalents in terms of identifying optimal locations, both in terms of potency and reduced toxic effects, for 2’F and 2’-OMe modifications in dsRNA, since varying 2’-F and 2’-OMe positions in a double stranded nucleic acid for optimal or better results in known in the prior art.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date to provide a dsRNA agent that inhibits ALK expression as taught by Haack et al. to treat kidney cancer and to use the teachings of Zhang et al. regarding the ALK siRNA sense sequence 86 and the teachings of Haack et al. regarding if the sequence of the gene to be targeted in a mammal is known that 21-23 nt RNAs can be produced and that dsRNA having at least one overhang of 1-4 nucleotides at an end are most effective in mediating RNAi in mammals, and that sequences of effective dsRNA can be rationally designed/predicated screening the target mRNA of interest for target sites using a computer folding algorithm, and NCBI Reference Sequence Accession number NM_004304 regarding the ALK mRNA sequence, and the teachings of Bettencourt et al. and Maier et al. regarding the chemical modifications, and arrive at the claimed invention with a reasonable expectation of success. Therefore, an ordinary artisan would know that there is design choice in the length of the sense and antisense strands of siRNA, and there are design choices in blunt ends or overhangs based on the teachings of Haack et al., as well as including mismatches or not. Therefore, absent a demonstration of criticality, any of these options would be obvious to arrive at the claimed sequences. One of ordinary skill in the art would have been motivated to design and provide a dsRNA agent that targets ALK based on the teachings of Haack et al. and teachings of Zhang et al. regarding ALK siRNAs including the sense sequence of sequence 86 and to use the known mRNA sequence of NCBI Reference Sequence Accession number NM_004304 to arrive at the instant sequences of SEQ ID NOs: 765 and 1065 or SEQ ID NOs: 1665 and 1065 based on the teachings of Haack et al., which taught the association of ALK as driving proliferation and survival of the subset of kidney cancer in which it is expressed (paragraph 0043), and that a patient whose kidney cancer expresses a polypeptide with ALK activity may respond favorably to administration of an ALK inhibitor (paragraph 0044), and that siRNA compositions which inhibit the activity of ALK through the process of RNA interference may be employed in the methods of the invention. In addition, because the mRNA sequence of ALK (NCBI Reference Sequence Accession number NM_004304) was publicly available, and nucleotides 1-20 of SEQ ID NO: 765 aligns with nucleotides 3322-3341 of Homo sapiens ALK receptor tyrosine kinase (ALK) transcript variant 1, mRNA of NM_004304.5, and instant nucleotides 2-23 of SEQ ID NO: 1065 aligns with nucleotides 3341-3320 of Homo sapiens ALK receptor tyrosine kinase (ALK) transcript variant 1, mRNA of NM_004304.5, an ordinary artisan could have used the teachings of Haack et al. and Zhang et al. to arrive at the instant sense and antisense sequences with a reasonable expectation of success, because Haack et al. taught that detailed technical manuals on the design, construction, and use of dsRNA for RNAi are available, See e.g., Dharmacon’s “RNAi Technical Reference and Application Guide”; Promega’s “RNAi: A Guide to Gene Silencing”, that that ALK-inhibiting siRNA products are also commercially available and may be employed in the methods of the invention (paragraph 0177), that that small dsRNA less than 49 nt in length, preferably 19-25 nucleotides comprising at least one sequence that is substantially identical to part of a target mRNA sequence are most effective in mediating RNAi in mammals (paragraph 0178), and that if the sequence of the gene to be targeted in a mammal is known, 21-23 nt RNAs can be produced and tested for their ability to mediate RNAi in a mammalian cell such as a human or other primate cell or the sequences of effective dsRNA can be rationally designed/predicated screening the target mRNA of interest for target sites using a computer folding algorithm, and various parameters may be used to determine which sites are the most suitable target sites within the target RNA sequence (paragraphs 0180,0181).
One of ordinary skill in the art would have been motivated to arrive at the specific modification pattern based on the combined teachings of Bettencourt et al. that iRNA agents chemically linked to one or more ligands, moieties or conjugates which may confer functionality by enhancing the activity, cellular distribution, or cellular uptake of the RNAi, and such moieties include a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-phosphonate (paragraph 0349) and taught that oligonucleotides can contain the nucleotide (Chd) or “2-O-hexadecyl-cytidine-3’-phosphate” (Table 1, page 67), and therefore would be motivated to provide a 2’-O-hexadecyl modification on other nucleotides including guanosine with a reasonable expectation of success, and Maier et al. teaching the phosphorothioate, 2’-O-Me, 2’-F at specific positions, and a 5’-VP on the antisense strand which improves the in vivo activity and that having 2’-OMe modifications at nucleotide positions 2 and 14 from the 5’ end of the antisense strand dampened gene silencing activity (paragraph 0261).
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Regarding Applicant’s arguments pertaining to the rejection of claims 3 and 118 under 35 U.S.C. 103 as unpatentable over Haack in view of NCBI Access. No. NM_004304, Bettencourt and Maier on page 24-25 of the response, as stated above the rejection was withdrawn due to the amendments to claim 3 requiring at least 18 contiguous nucleotides differing by no more than 2 nucleotides from the antisense sequence set forth in SEQ ID NO: 465 and a new ground of rejection was made in view of the claim amendments, and provides Zhang et al. (US 2018223277) which teaches ALK siRNA sequences including a sense strand sequence 86. Alignment between the instant sense strand sequence of SEQ ID NO: 165 (Qy) and the ALK sense strand sequence of SEQ ID NO: 86 of Zhang et al. (Db) shows alignment of 18 contiguous nucleotides at 100% identity to those 18 contiguous nucleotides:
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While Zhang et al. do not teach the antisense sequence of the siRNA having the sense strand sequence of SEQ ID NO: 86, one of ordinary skill in the art would be able to use the sense strand sequence of SEQ ID NO: 86 of Zhang et al. to arrive at the corresponding antisense sequence. An ordinary artisan would then be able to use the mRNA sequence of ALK NCBI Access. No. NM_004304 to arrive at the sequences of the instant claims. In addition, regarding Applicant’s argument about unexpected results on page 24, the surprising results claimed by Applicant are not persuasive. First, the results are not commensurate in scope with the claims. Claim 3 as well as most of the claims do not require the entire sequence of the antisense and sense strands that duplex AD-1335131 has or a specific chemical modification pattern and only requires the antisense strand to comprise a region of complementarity to an mRNA encoding ALK wherein the region of complementarity comprises at least 18 contiguous nucleotides different by no more than 2 nucleotides from the antisense sequence of SEQ ID NO: 465 and wherein the dsRNA comprises at least one modified nucleotide and at least one phosphorothioate internucleotide linkage. Therefore, claim 3 allows for 2 nucleotides different from the recited sequence, and it is not clear if substitution of any 2 nucleotides would result in such a high effect. In addition, it is not clear if Duplex AD-1335131 in Table 5 that Applicant states reduces ALK expression in Hepa 1-6 cells by about 90% pertains to the unmodified duplex or the chemically modified duplex. Claim 118 is the only claim that requires both the entire sense and antisense sequence as well as the specific chemical modification pattern. Secondly, the unexpected results do not appear to be unexpected, as AD-1335131 is not the only sequence that produces an effect of around 90% knockdown of ALK mRNA. AD-1335153 on page 181 resulted in 12.723 % ALK mRNA remaining, AD-1335132 on page 182 resulted in 13.408% ALK mRNA remaining. Therefore the surprising results claimed by Applicant are not commensurate in scope with the claims.
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.). Note: MPEP 716.02(d).
Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. An unexpected property or result must actually be unexpected and of statistical and practical significance. The burden is on the applicant to establish the results are in fact unexpected, unobvious and of statistical and practical significance. See MPEP 716.02.
Conclusion
Claims 3,4,7,14,20,58,59,64,66,75,76,78,114,115 and 118-123 are rejected.
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.
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/STEPHANIE L SULLIVAN/ Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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