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 .
Election/Restrictions
Claims 1, 2, and 108-129 are pending. New claims 108-129 have been added. Claims 3-107 are canceled. Applicant’s election without traverse of group I (claims 1, 2, 6, 9, 23, 24, 34, 36, 37, 40, 42, 56) in the election on 5/30/25 remains acknowledged.
Applicant elected the species without traverse:
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During the prior art document search, Examiner uncovered references that disclose double stranded RNA targeting the striatum which reduced expression of HTT as well as references disclosing detection of the dsRNA over multiple days. Therefore, the burden of search no longer exists for HTT and Examiner withdrew the election requirement between APP and HTT within the species of target genes. Examiner also included a duration of time of ten to twenty days within the election requirement of duration of time over which the target gene is reduced. New claims 122-124 and 126-129 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Examiner notes the elected target species is limited to APP and HTT genes.
Examination on the merits commences on claims 1, 2, 108-121, and 125.
35 USC § 112a and NSDP rejections of record for the claims are maintained.
Applicants are informed that the rejections and/or objections of the previous Office action not stated below have been withdrawn from consideration in view of the Applicant' s arguments and/or amendments. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement - MAINTAINED
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 1, 2, 108-121, and 125 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 reducing the expression of a APP, HTT, and SOD1 in a striatum tissue or cell by contacting the tissue or cell with a double-stranded iRNA which is conjugated to a terminal C16 hydrocarbon, does not reasonably enable the method for the genus of any dsRNA sequence with any lipophilic conjugate to target APP, HTT, and SOD1 or any other genes, using internally conjugated C16 hydrocarbons for reducing gene expression in the striatum by CSF delivery method, without specifying the dsRNA sequence with specific position and specific type of C16 hydrocarbon. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention and Breadth of claims
The claims are drawn to a method of reducing the expression of a target gene in a striatum tissue or cell, comprising: contacting the tissue or cell with an internally modified double-stranded dsRNA, wherein the agent includes an antisense strand complementary to the target gene; a sense strand complementary to the antisense strand; and one or more lipophilic moieties conjugated to one or more internal positions on at least one strand.
Guidance from the Specification
Guidance from the specification teaches use of conjugated RNAi knockdown of APP and SOD1 (Figs 13-19 and Figs 6-9 and Example 12 and 16 [00936]). However, this knockdown occurs from direct injection such as intrathecal injection. Although the Specification teaches numerous lipophilic moieties such as the lipophilic moiety is an aliphatic, cyclic such as alicyclic, or polycyclic such as polyalicyclic compound, such as a steroid (e.g., sterol) or a linear or branched aliphatic hydrocarbon [00226] or the lipophilic moiety is conjugated to the double-stranded iRNA agent via a linker a linker containing an ether, thioether, urea, carbonate, amine, amide, maleimide-thioether, disulfide, phosphodiester, sulfonamide linkage, a product of a click reaction (e.g., a triazole from the azide-alkyne cycloaddition), or carbamate [00229], the specification is brief in working examples demonstrating effectiveness of specific moieties which could be used effectively to target specific genes by crossing the blood brain barrier instead of by direct intrathecal or striatal injection. Figure 12 and Example 13 [0091] does teach the relative hydrophobicity for each position of the siRNA duplex modified by a lipophilic C16 moiety [00188].
State of the Art
A thorough search of the related art demonstrates effective use of targeting moieties as RNAi conjugates to reach target specific tissues but the art also demonstrates the unpredictability of delivering just any RNAi payload with any lipophilic conjugates to specific targets within the CNS without direct injection.
Regarding transport into the CNS, Pulgar of record (Pulgar, Victor M. "Transcytosis to cross the blood brain barrier, new advancements and challenges." Frontiers in neuroscience 12 (2019): 1019.) teaches the blood brain barrier (BBB) presents a formidable challenge to the delivery of drugs into the brain where strategies aim to overcome this obstacle and promote efficient and specific crossing through BBB of therapeutically relevant agents (abstract). Pulgar teaches one of those strategies uses the physiological process of receptor-mediated transcytosis (RMT) to transport cargo through the brain endothelial cells toward brain parenchyma (abstract).
Regarding lipophilic conjugates, Melquist of record (Melquist, S., US-20180195070-A1, published July 12 2018) teaches RNAi agents effectively conjugated to a targeting group which can include a cell receptor ligand, such as a galactose cluster, including a galactose cluster comprising an N-acetyl-galactosamine trimer (col 2 line 24). Melquist teaches the RNAi agent is conjugated to the targeting ligand such as a galactose cluster where the targeting group is linked by a linker (col 94 line 6) where the cluster can be a GalNAc N-acetyl-galactosamine trimer (col 2 line 24).
Regarding AAVs as targeting machinery to reach CNS tissues, Gao of record (Gao, G., US20140335054A1) teaches rAAVs carrying transgenes are spread throughout CNS tissue following direct administration into the cerebrospinal fluid (CSF) via intrathecal injection to subjects in an effective treatment of ALS [0006]. Gao teaches recombinant AAVs that achieve wide-spread distribution throughout CNS tissue of a subject. In some embodiments, the rAAVs spread throughout CNS tissue following direct administration into the cerebrospinal fluid (CSF), e.g., via intrathecal and/or intracerebral injection. In other embodiments, the rAAVs cross the blood-brain-barrier and achieve wide-spread distribution throughout CNS tissue of a subject following intravenous administration. In some aspects the invention relates to rAAVs having distinct central nervous system tissue targeting capabilities
Regarding lipids moieties as delivery conjugates, Shen of record (Shen, H., WO2018140826A1, published August 2 2018) teaches efficiently deliver nucleic acid molecules (including, for example, mRNAs encoding one or more cancer- or tumor-specific antigens) packaged within a "core" structure, and encapsulated with an outer hydrophilic lipid bilayer-containing "shell," to one or more selected mammalian cells (including, for example, one or more antigen-presenting cells, such as dendritic cells, macrophages, and B cells, without limitation. The presence of the lipophilic shell encapsulating the inner hydrophobic core protects the nucleic acids from degradation by tissue enzymes or interaction with other immune cells [0015]. Shen teaches mRNA condensed inside a positively-charged polymer, which together formed a tight polyplex "core" structure a few nanometers to a few hundred nanometers in diameter (Fig. 1A [0176]).
After a thorough search of the related art, in the administration method of delivering any dsRNA sequence with any C16 conjugate to target any gene for reducing that gene expression in the striatum by any administration, evidence in the art is lacking as to whether the method as claimed could be effective.
Taking this into consideration the lack of related examples in the specification, the lack of knowledge in art, the established difficulty of bridging the blood-brain-barrier, and the large genus of lipophilic and RNAi agents recited in the claims, it is the conclusion that undue experimentation would be required to use the described invention as claimed. Examiner suggests incorporating into the independent claims a specific gene target as targeted by a specifically modified dsRNA with a specific sequence and at a specific position with a specific C16 hydrocarbon, i.e., with the specific dsRNA structures of the working examples of the Specification.
Dependent claims
Although claims 2 and 125 describe the specific and elected target genes of APP and HTT, the lacking dsRNA sequence and specific position of the C16 hydrocarbon modification fails to resolve the issues described above and therefore the claims lack adequate enablement for the reasons applied above.
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 1, 2, 6, 23, 36, 37, 40, 42, are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over Claims 1, 2, 4, and 36 of co-pending Application No. 18263155 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims anticipate the instant claims.
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have combined the independent and dependent claims into a single claim given the reference teachings.
Regarding instant claims 1 and 2, co-pending claim 1 teaches a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of an amyloid precursor protein (APP) gene, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region.
Copending claim 2 teaches double stranded ribonucleic acid (RNAi) agent of claim 1, wherein (i) the dsRNA agent comprises at least one modified nucleotide,(ii) the double stranded region is 15-30 nucleotide pairs in length, and (iii) the sense strand or the antisense strand is conjugated to one or more lipophilic moieties.
Copending claim 4 teaches the double stranded ribonucleic acid (RNAi) agent of claim 1, wherein at least one of said sense strand and said antisense strand comprises one or more lipophilic moieties conjugated to one or more internal nucleotide positions.
Copending claim 12 teaches the double stranded RNAi agent of claim 4, wherein the internal positions include all positions except the terminal two positions from each end of the strand, or wherein the internal positions include all positions except terminal three positions from each end of the strand, or wherein the internal positions exclude the cleavage site region of the sense strand, or wherein the internal positions exclude positions 9-12, counting from the 5'-end of the sense strand, or wherein the internal positions exclude positions 11-13, counting from the 3'-end of the sense strand, or wherein the internal positions exclude the cleavage site region of the antisense strand, or wherein the internal positions exclude positions 12-14, counting from the 5'-end of the antisense strand, or wherein the internal positions-excluding positions 11-13 on the sense strand, counting from the 3'-end, and positions 12-14 on the antisense strand, counting from the 5'-end.
Copending claim 36 teaches wherein the administration of the double stranded RNAi to the subject causes a decrease in A3 accumulation, optionally the administration of the double stranded RNAi to the subject causes a decrease in A3(1-40) and/or A3(1-42) accumulation, or wherein the administration of the double-stranded RNAi to the subject causes a decrease in amyloid plaque formation and/or accumulation in the subject, or wherein the administration of the double-stranded RNAi to the subject reduces the expression of a target gene in a brain or spine tissue, optionally wherein the brain or spine tissue is selected from the group consisting of cortex, cerebellum, striatum, cervical spine, lumbar spine, and thoracic spine.
This is a provisional rejection because the copending claims have not yet been patented.Allowable Subject Mater
A thorough search of the prior art did not discover, before the time of filing, C16 hydrocarbons internally modifying dsRNA with enhanced targeting of genes of the striatum. The various C16 hydrocarbon modifying structures existing in the prior art such as palmitic acid and hexadecyl and alkyl glycerol/ether appear exclusively as terminal modifications for targeting gene reduction and where internal modifications are often disruptive of complementary base pair binding causing reduced C16-dsRNA efficacy.
Response to Arguments
Applicant’s arguments (following the 10/2/25 claim set) are directed to the withdrawn §102 and §112b. Therefore, the arguments are moot.
Applicants argue, regarding the §112a Scope of Enablement rejection, stating the surprising discovery that intrathecal injection of double-stranded iRNA agents having a saturated or unsaturated C16 hydrocarbon chain conjugated to position 6 on the sense strand, counting from the 5' end of the strand, into the cerebrospinal fluid (CSF) of a subject reduces the expression of a target gene in a striatum tissue or cell in the subject. Applicants argue the specification provides ample teachings, including working examples, regarding methods for producing double stranded RNAi agents, and therefore, the claims provide sufficient enablement.
Applicant’s arguments have been thoroughly reviewed and found unpersuasive. Applicants note that the enhanced efficacy of their internally positioned C16 hydrocarbon modification was a surprising and unexpected finding. As such, it would not be predictable, as described in the 112a rejection above, that any sequence with variously positioned internally conjugated C16 hydrocarbon modifications would have enhanced efficacy in reducing ANY target gene expression in the striatum of subject, and even targeting the elected species of APP and HTT without an exactly specified modified RNAi structure. As described above, a specific sequence with a specific position conjugated specific hydrocarbon would be necessary for sufficient predictability of a specified target gene reduction in the difficult to target internal striatal tissue of a subject. Furthermore, the disclosure lacks a comparison of terminally conjugated C16 dsRNA from internally conjugated C16 modified dsRNA which undermines any statement of unexpected results which depends on the variance between terminal and internal conjugation.
Conclusion
No claims are allowable.
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN CHARLES MCKILLOP whose telephone number is (703)756-1089. The examiner can normally be reached Mon-Fri 8:30-5:30.
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/JOHN CHARLES MCKILLOP/Examiner, Art Unit 1637
/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637
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