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 .
Claims 120-121, 141, 200-202, 208-209, 220, 237, 310-314 are pending.
Election/Restrictions
Applicant’s elections without traverse of the invention of Group II, drawn to dsRNA for inhibiting GRB14, and the species SEQ ID NOs 905 and 770 (dsRNA duplex AD-1399804, modified SEQ ID NOs 1175 and 1040) in the reply filed on 09 January 2026 is acknowledged.
Claims directed to nonelected invention Groups I and III were canceled in the claims submitted 09 January 2026. Claims 208-209, and 220 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09 January 2026.
Claims 120-121, 141, 200-202, 237, 310-314 are examined.
Information Disclosure Statement
The IDS has been considered.
The Spec. cites references.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see at least p. 36 L10-20; p .37 L25-35). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the following term(s):
Lipofectamine™ (at least p. 139 L27, p. 220 L9, p. 221 L2),
Dynabeads™ (at least p. 221 L21-22),
TaqMan™ (at least p. 221 L36),
Zetasizer™ (at least p. 163 L26), and
Triton™ (at least p. 163 L30)
which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
Claim 120 recites a dsRNA agent that comprises a sense strand and an antisense strand forming a double stranded region. That is interpreted as meaning that double stranded region is formed by base pairing between the sense and antisense (AS) strands.
Claims 120 and 202 recite for inhibiting expression of GRB14. Inhibiting expression of GRB14 is interpreted as an intended use. The limitation for inhibiting expression of GRB14 does not alter the structure of the compound and therefore adds no patentable weight.
Claim 310 recites: …substantially all of the nt … or all of the nt… comprise a modification. In the interest of compact prosecution, that is understood to mean that each nt included in “substantially all” or “all” comprises a modification, not that all the nt together comprise a single modification.
Claim 313 recites: The dsRNA agent of claim 237, wherein the lipophilic moiety is conjugated to one or more internal positions in the double stranded region of the dsRNA agent. In the interest of compact prosecution, internal positions is interpreted to mean “any nt of the dsRNA that is not at a 5’- or 3’-terminal end.”
Claim 314 depends from Claim 313 and recites:
The dsRNA agent of claim 237, wherein the lipophilic moiety is conjugated to one or more internal positions in the double stranded region of the dsRNA agent [Claim 313], wherein …
(c) the internal positions exclude a cleavage site region of the sense strand;
(d) the internal positions include all positions except positions 9-12, counting from the 5'-end of the sense strand;
(e) the internal positions include all positions except positions 11-13, counting from the 3'-end of the sense strand;
(f) the internal positions exclude a cleavage site region of the antisense strand;
(g) the internal positions include all positions except positions 12-14, counting from the 5'-end of the antisense strand;
(h) the internal positions include all positions except 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;
(i) the one or more lipophilic moieties are conjugated to one or more of the internal positions selected from the group consisting of positions 4-8 and 13-18 on the sense strand, and positions 6-10 and 15-18 on the antisense strand, counting from the 5'end of each strand;
(j) the one or more lipophilic moieties are conjugated to one or more of the internal positions selected from the group consisting of positions 5, 6, 7, 15, and 17 on the sense strand, and positions 15 and 17 on the antisense strand, counting from the 5'-end of each strand…
Since Claim 314 depends from Claim 313 which recites that the lipophilic moiety is conjugated to one or more internal positions, in the interest of compact prosecution, the internal positions recited in Claim 314 are interpreted as internal positions to which the lipophilic moiety is conjugated.
Claim Objections
Claims 202, 310-312, and 314 are objected to because of the following informalities:
Claim 202 should use the abbreviation for GRB14 recited in Claim 120 and should include a comma after gene. The claim should read: …expression of the GRB14 gene, comprising…
Claims 310-312 and 314 should add a colon after wherein: …wherein : …
Claim 311 (e) recites …each of the sense strand an antisense strand… but should recite …each of the sense strand and antisense strand….
Claim 312 should remove the and before wherein X is O or S in the last line of the claim. Right now it looks like wherein X is O or S follows (a)-(c) but that phrase should follow only (d).
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 120-121, 141, 200-202, 237, 310-314 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. This is a written description rejection.
Claim 120 recites (see §Claim interpretation and §112[b]) a dsRNA agent that comprises a sense strand and an antisense strand forming a double stranded region, wherein the AS strand (a) comprises a region of complementarity to an mRNA encoding GRB14, and (b) comprises at least 15 contiguous nt that differ by no more than 3 nt from SEQ ID NO 905. That broad claim encompasses the large genus of dsRNAs that (a) comprise complementarity to a GRB14-encoding mRNA and (b) comprise at least 15 nt and differ by no more than 3 nt from SEQ ID NO 905. That means the claimed dsRNA must comprise only 80% identity to only a 15-mer segment of SEQ ID NO 905. SEQ ID NO 905 is a 23-mer. That means the dsRNA can comprise a total of only 52.2% identity with SEQ ID NO 905 as long as a 15-mer segment comprises at least 80% identity with a 15-mer segment of SEQ ID NO 905. There is no upper limit to strand length so a strand could comprise far less than 52.2% identity with SEQ ID NO 905. Therefore the claim encompasses a huge number of dsRNAs and any dsRNA comprising those amounts of identity with SEQ ID NO 905 (i.e., only 52.2% identity with SEQ ID NO 905 as long as a 15-mer segment comprises at least 80% identity with SEQ ID NO 905) would be encompassed by the claims as instantly presented. The claims also recite an intended use. However, the Spec. does not disclose any specific sequence required for dsRNA function.
Claim 141 recites the dsRNA agent comprises a ligand and Claim 237 recites the ligand is a lipophilic moiety. Those broad claims encompass the large genus of ligands and the subgenus of ligands that are lipophilic. A person of ordinary skill would recognize those terms encompass huge groups of diverse compounds defined solely by their functions of binding any molecule (i.e., a ligand) and being lipophilic (i.e., a ligand that is a lipophilic moiety). Any ligand and any lipophilic moiety are encompassed by the claims. However Applicant has not demonstrated possession of dsRNAs comprising a representative number of ligands or lipophilic moieties.
An original claim may lack written description support when a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See MPEP 2163.
The Spec. discloses dsRNAs comprising at a region of at least 15 consecutive nt having at least 80% identity to SEQ ID NO 905 in Table 7. Those sequences are solely SEQ ID NO 905 itself. The two closest SEQ ID NOs to SEQ ID NO 905, namely SEQ ID NOs 904 and 906, comprise less than 80% identity over 15 consecutive nt to SEQ ID NO 905. SEQ ID NOs 904 and 906 comprise 100% identity to SEQ ID NO 905 over only 11 consecutive nt but less than 80% identity over 15 consecutive nt to SEQ ID NO 905. Therefore an artisan would determine that Applicant has demonstrated possession of only SEQ ID NO 905 itself.
Regarding what structure is encompassed by the limitation a dsRNA agent that comprises a sense strand and an antisense strand forming a double stranded region, wherein the AS strand (a) comprises a region of complementarity to an mRNA encoding GRB14, and (b) comprises at least 15 contiguous nt that differ by no more than 3 nt from SEQ ID NO 905, the Spec. does not provide information describing its features. The Spec. does not disclose any physical structure responsible for the intended function of inhibiting expression of a GRB14 gene.
Regarding dsRNAs that compris[e] a sense strand and an antisense strand forming a double stranded region, wherein the AS strand (a) comprises a region of complementarity to an mRNA encoding GRB14, and (b) comprises at least 15 contiguous nt that differ by no more than 3 nt from SEQ ID NO 905, Applicant’s examples discuss (start on p. 171; p. 223) the sole dsRNA species AD-1399804. However, those examples are not sufficient to provide written description support for any dsRNAs that compris[e] a sense strand and an antisense strand forming a double stranded region, wherein the AS strand (a) comprises a region of complementarity to an mRNA encoding GRB14, and (b) comprises at least 15 contiguous nt that differ by no more than 3 nt from SEQ ID NO 905. Although the claims encompass many dsRNAs, it is not clear that all of the encompassed dsRNAs would comprise complementarity to an mRNA encoding GRB14. The claims recite the intended functional characteristic of inhibiting expression of a GRB14 gene, but the functional characteristic is not coupled with any known structure.
The Spec. does not identify a core structure necessary for comprising complementarity to an mRNA encoding GRB14 or performing the intended function(s) of inhibiting expression of a GRB14 gene. The Spec. does not disclose any core structure, partial structure, physical or chemical property, or functional characteristic coupled with a known or disclosed structure/function relationship responsible for comprising complementarity to an mRNA encoding GRB14 or performing the intended function(s) of inhibiting expression of a GRB14 gene in such a way to demonstrate possession of the full invention as claimed at time of filing.
The specification teaches only one species within the claimed genus/genera, namely SEQ ID NO 905, but that is only a paltry number compared with the breadth of what is claimed. .Altogether, the number of species disclosed by complete structure is not sufficient to provide the written description support for the huge genus encompassed by the claims.
Regarding ligands and lipophilic moieties, the Spec. discloses some ligands starting on p. 105 (L14) and exemplary lipophilic molecules (e.g., starting at p. 106 L20 and p. 108 L1). In those § the Spec. discloses characteristics of ligands and lipophilic moieties but does not disclose any physical structure(s) responsible for the function of being a ligand or a lipophilic moiety. A person or ordinary skill would recognize that ligands and lipophilic moieties are so structurally diverse that different species of the genus/subgenus may not share any physical structure.
Applicant’s examples discuss (p. 176 L16-23) dsRNAs conjugated to the specific GalNAc ligand L96 and to a C16 ligand. However, those examples are not sufficient to provide written description support for any ligand or any lipophilic moiety. Although the claims claim the functional characteristics (i.e., being a ligand which requires binding to a biomolecule and being a lipophilic ligand which requires being lipophilic and binding to a biomolecule), the functional characteristic is not coupled with any known structure.
Although the Specification teaches the examples discussed above, it does not identify a core structure necessary for performing the claimed function(s) of being a ligand or a lipophilic ligand. The Spec. does not disclose any core structure, partial structure, physical or chemical property, or functional characteristic coupled with a known or disclosed structure/function relationship responsible for being a ligand or a lipophilic ligand in such a way to demonstrate possession of the full invention as claimed at time of filing. The species encompassed by the vast claimed genus and subgenus do not share a core structure.
The specification teaches only these species within the claimed genus/genera namely GalNAc ligand L96 and a C16 ligand, but those are only a paltry number compared with the breadth of what is claimed. .Altogether, the number of species disclosed by complete structure is not sufficient to provide the written description support for the huge genera and subgenera that are encompassed by the claims.
While none of these elements is specifically required to demonstrate possession, in combination their absence means that one skilled in the art at the time of filing would conclude that the inventors lacked possession of the full breadth of the invention claimed. Claims 120, 141, 237, and 313-314 are rejected for failing to demonstrate possession of the claimed invention. Claims 121, 141, 200-202, 237, and 310-314 are rejected because they depend from Claim(s) 120, 141, 237, and/or 313 and do not remedy the issues.
To remediate these issues with Claim 120, Applicant can amend the claim to recite SEQ ID NO 905 itself or to recite a maximum length and specific segment of SEQ ID NO 905 that is required.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 120-121, 141, 200-202, 237, and 310-314 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A claim may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173. In the present instance, Claim 120 recites …wherein said antisense strand comprises a region of complementarity to an mRNA encoding GRB14 which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the antisense strand sequence set forth as SEQ ID NO: 905. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. It is not clear what which refers to—the antisense (AS) strand, the region of complementarity, or the mRNA. It is not clear what comprises at least 15 contiguous nucleotides (nt)—the AS strand, region of complementarity, or mRNA encoding GRB14. It is not clear what differs by no more than 3 nt from the AS strand sequence set forth as SEQ ID NO 905. The various combinations of the above mean the metes and bounds of the claim cannot be determined.
For example, it is not clear whether the antisense (AS) strand comprises a region of complementarity to an mRNA encoding GRB14 and the mRNA encoding GRB14 comprises at least 15 contiguous nt differing by no more than 3 nt from the AS strand sequence set forth as SEQ ID NO 905. It is not clear whether the AS strand comprises complementarity to an mRNA encoding GRB14 and the AS strand comprises at least 15 contiguous nt differing by no more than 3 nt from the AS strand sequence set forth as SEQ ID NO 905. It is further unclear what differs by no more than 3 nt from the AS strand sequence set forth as SEQ ID NO 905—the mRNA? the region of complementarity? The AS strand? Because of those issues—there are too many terms within the sentence that have an unclear reference—it is not possible to decipher the claim.
Claim 120 is rejected for those reasons. Claims 121, 141, 200-202, 237, 310-314 are rejected because they depend from Claim 120 and don’t remedy the issues. In the interest of compact prosecution the claim is interpreted as: the antisense strand:
comprises a region of complementarity to an mRNA encoding GRB14, and
comprises at least 15 contiguous nt that differ by no more than 3 nt from SEQ ID NO 905.
That means as many as 3 nt within a region of 15 nt can differ from SEQ ID NO 905. That means the claimed sequence has a few as 12 nt in common with SEQ ID NO 905, as long as those 12 occur within a single 15-mer span.
Claim202 recites the limitation “… for inhibiting expression of the growth factor receptor bound protein 14 (GRB14) gene…” in L2. There is insufficient antecedent basis for this limitation—a GRB14 gene—in the claim because Claim 202 depends from Claim 120 which recites GRB14 but does not recite any GRB14 gene. In the interest of compact prosecution Claim 120 is interpreted as reciting a GRB14 gene.
Claim 310 recites substantially all of the [nt] …. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. The term "substantially" is not defined by the claim, the specification does not provide a clear definition for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Without a definition one of ordinary skill in the art would not know where the metes and the bounds of the claims are. One in the art would not know, whether 50% qualifies as, “substantially”. One in the art could assert that 80% is substantial and one could argue that 30% is substantial. Without a clear definition, one in the art would be required to make assumptions of the metes and bounds of the claim based on their opinion of what “substantially” would mean in the context of the instant claims. The Spec. discusses “substantially all of the nt are modified” on p. 58 (L1-2) but that does not provide any clearer definition of the metes and bounds because it says: "substantially all of the nucleotides are modified" are largely but not wholly modified and can include not more than 5, 4, 3, 2, or 1 unmodified nucleotides. What constitutes a number that is largely but not wholly is not definite. It is not clear whether the teaching can include not more than 5, 4, 3, 2, or 1 unmodified nucleotides is exemplary or limiting.
Claim 310 is rejected for those reasons. In the interest of compact prosecution the claim is interpreted as requiring that all or all but one nt comprise a modification or the recited kind of modification.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claim 314 recites:
The dsRNA agent of claim 313 [the dsRNA agent of claim 237, wherein the lipophilic moiety is conjugated to one or more internal positions in the double stranded region of the dsRNA agent], wherein …
(a) the internal positions include all positions except the terminal two positions from each end of the at least one strand;
(b) the internal positions include all positions except the terminal three positions from each end of the at least one strand;
(c) the internal positions exclude a cleavage site region of the sense strand;
(d) the internal positions include all positions except positions 9-12, counting from the 5'-end of the sense strand;
(e) the internal positions include all positions except positions 11-13, counting from the 3'-end of the sense strand;
(f) the internal positions exclude a cleavage site region of the antisense strand;
(g) the internal positions include all positions except positions 12-14, counting from the 5'-end of the antisense strand;
(h) the internal positions include all positions except 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...
Claim 314 therefore recites the broad recitation the dsRNA agent of claim 313 [the dsRNA agent of claim 237, wherein the lipophilic moiety is conjugated to one or more internal positions in the double stranded region of the dsRNA agent], and the claim also recites: the internal positions include all positions except… the internal positions exclude… which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The confusion arises because Claim 313 recites the lipophilic moiety is conjugated to one or more internal positions, indicating that the lipophilic moiety is conjugated to one or more internal positions, and then Claim 314 recites internal positions include or exclude specific internal positions. It is not clear whether Claim 314 requires the lipophilic moiety to be conjugated to each of the internal positions recited in (a) through (h) (i.e., required features of the claim) or if the internal positions are merely examples of potential internal positions to which the lipophilic moiety may be conjugated (i.e., merely exemplary).
In addition Claim 314 recites:
(i) the one or more lipophilic moieties are conjugated to one or more of the internal positions selected from the group consisting of positions 4-8 and 13-18 on the sense strand, and positions 6-10 and 15-18 on the antisense strand, counting from the 5'end of each strand;
(j) the one or more lipophilic moieties are conjugated to one or more of the internal positions selected from the group consisting of positions 5, 6, 7, 15, and 17 on the sense strand, and positions 15 and 17 on the antisense strand, counting from the 5'-end of each strand…
There is insufficient antecedent basis for this limitation (the one or more lipophilic moieties) in the claim because Claim 314 depends from Claim 313 which recites only one lipophilic moiety. Furthermore the chain of dependent claims (Claims 237, 141, and 120) recite only a single ligand. Nothing in any of those claims recites more than one single lipophilic moiety.
The metes and bounds of the claims are further indefinite because it is unclear how many lipophilic moieties are allowed by the claims and where they are conjugated.
Claim 314 rejected for those reasons. In the interest of compact prosecution the claim is interpreted as requiring that the lipophilic moiety be conjugated to any of the recited internal positions. The claim is not interpreted as requiring the sole lipophilic moiety is conjugated to all of the recited internal positions. Claim 314 is interpreted as if Claim 313 allows for at least one lipophilic moiety.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 200 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
The claim can be interpreted to read on a human organism because the claim recites a cell containing the dsRNA agent of Claim 120 and that cell could be within a human organism. The specification notes that the iRNA compositions affect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a GRB10 or GRB14 gene, which GRB10 or GRB14 genes may be within a cell, e.g., a cell within a subject, such as a human (page 33, lines 15-17).
Amending the claim to recite an isolated cell containing the dsRNA agent of claim 120, as appropriate, would be remedial.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 120-121, 141, 200-202, 237, and 310-313 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by United States Patent Application Publication No. US 2006/0148743 (published on 06 July 2006, “App743”).
It is noted that the claims are directed to compounds that have an intended use that does not affect the physical structure of the claimed compounds. Therefore any compound that is encompassed by the claims anticipates them.
App743 discloses (Title, §Abstract) double stranded RNAs for inhibiting expression of an HDAC gene.
Regarding Claims 120 and 311: App743 discloses SEQ ID NO 1771, a 19-mer that comprises only 2 mismatches to claimed SEQ ID NO 905, as shown by the following alignment:
RESULT 27
US-11-217-936-1771
(NOTE: this sequence has 1 duplicate in the database searched.
See complete list at the end of this report)
Sequence 1771, US/11217936
Publication No. US20060148743A1
GENERAL INFORMATION
APPLICANT: Jadhab, Vasant
APPLICANT: Carroll, Joseph
APPLICANT: Sirna Therapeutics, Inc.
TITLE OF INVENTION: RNA Interference Mediated Inhibition Of Histone Deacetylase
TITLE OF INVENTION: (HDAC) Gene Expression Using Short Interfering Nucleic Acid
TITLE OF INVENTION: (siNA)
FILE REFERENCE: 05-727 (400/271)
CURRENT APPLICATION NUMBER: US/11/217,936
CURRENT FILING DATE: 2005-09-01
NUMBER OF SEQ ID NOS: 5036
SEQ ID NO 1771
LENGTH: 19
TYPE: DNA
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Synthetic
Query Match 68.7%; Score 15.8; Length 19;
Score over Length 83.2%;
Best Local Similarity 89.5%;
Matches 17; Conservative 0; Mismatches 2; Indels 0; Gaps 0;
Qy 5 UAAGAAACCAUGAAUUUCA 23 Claimed SEQ ID NO 905
| ||||| |||||||||||
Db 1 UGAGAAAACAUGAAUUUCA 19 App743 SEQ ID NO 1771
App743 teaches Table 2 (starts at ¶540) which discloses (p. 130 L4 in Table 2) SEQ ID NO 1771 is the “lower sequence” of the dsRNA and the reference teaches (¶497) the lower sequence is the antisense strand. Since SEQ ID NO 905 comprises complementarity to GRB14 mRNA and App743 SEQ ID NO 1771 comprises complementarity to SEQ ID NO 905, App743 SEQ ID NO 1771 also inherently possesses physical structure that comprises complementarity to GRB14 mRNA. Therefore App743 anticipates Claim 120. Since both the sense and AS strands are 19-mer, that reads on Claim 311 limitations (e) and (f) that each strand is no more than 23- or 30-mer. Therefore App743 anticipates Claim 311(e)(f).
Regarding the claimed modifications of Claims 121 and 310(a)(b)(c)(d)(e)(f)(g)(h), App743 teaches (¶2, ¶12, ¶36, ¶53) a short interfering nucleic acid (siNA) of their invention can comprise at least one chemical modification or can be modified or unmodified to varying amounts (5-100% are disclosed amounts of modification), and can comprise various modifications including 2’-OMe nt, 2’-deoxy-2’-fluoro (which is called 2’-fluoro in the instant claims), phosphorothioate linkages, and many other kinds of modifications. Those varying amounts read on substantially all or all nt of either or both strands comprising a modification. Therefore App743 anticipates Claims 121 and 310, including all elements of 310(a)(b)(c)(d)(e)(f)(g) and most of the modification species of 310(h).
Regarding Claims 141 and 237, App743 discloses (Figs. 27-29, ¶77) dsRNAs comprising targeting ligands that include cholesterol—which is a lipophilic moiety—and GalNAc. Fig. 39 shows cholesterol conjugated to the sense strand. Therefore App743 anticipates Claims 141 and 237.
Regarding Claims 200-202: App743 discloses (¶74) the invention encompasses an expression vector comprising aa nucleic acid encoding the siNA molecules and a cell comprising the expression vector. App743 discloses (¶77) the invention encompasses an siNA that can mediate RNAi inside a cell. App743 discloses (¶71, ¶160) a composition comprising their siNA molecule and a pharmaceutically acceptable carrier and using their siNA in pharmaceutical compositions. Therefore App743 anticipates Claims 200-202.
Regarding Claim 311(a)(b), App743 discloses (¶84-86) their invention can comprise 1-8 or more PS linkages in each strand and one or more PS linkages at the 3’-end, 5’-end, or both ends. Therefore App743 anticipates Claim 311(a)(b).
Regarding Claim 311(c)(d), App743 SEQ ID NO 1771 has a region of complementarity with SEQ ID NO 29 of the instant application (taught on Spec. p. 36 L28-34) to comprise GRB14 mRNA that is 19-mer region of complementarity comprising just 2 mismatches. An alignment of that is shown here:
RESULT 1
NASEQ2_02052026_165347/c
Query Match 0.7%; Score 15.8; DB 1; Length 19;
Best Local Similarity 89.5%;
Matches 17; Conservative 0; Mismatches 2; Indels 0; Gaps 0;
Qy 878 TGAAATTCATGGTTTCTTA 896 Instant App. SEQ ID NO 29
||||||||||| ||||| |
Db 19 TGAAATTCATGTTTTCTCA 1 App743 SEQ ID NO 1771
Therefore App743 anticipates Claim 311(c)(d).
Regarding Claims 311(g)(h), App743 discloses (¶33) siNA molecules with 1- to 3-mer overhangs. Therefore App743 anticipates Claim 311(g)(h).
Regarding Claim 312(a)(b): App743 discloses (¶420) complexing their siNA with GalNAc derivative. App743 discloses (¶121) a conjugate may be attached to the 3’end of the sense strand. Therefore App743 anticipates Claims 312(a)(b).
Regarding Claim 313, App743 discloses (¶259) non-nt components can be added to the ends of the siNA or internally and shows (Fig. 28) ligands conjugated to internal positions. Since App743 also discloses (Figs. 27-29, ¶77) ligands such as the lipophilic moiety cholesterol, their teachings encompass conjugating cholesterol to one or more internal positions of the RNA. Therefore App743 anticipates Claim 313.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 120-121, 141, 200-202, 237, and 310-313 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application Publication No. US 2006/0148743 (published 06 July 2006, “App743”) as applied to Claim(s) 120-121, 141, 200-202, 237, 310-313 in the 102 rejection above, and further in view of International Publication Number WO 2018/098328 (published 21 May 2018, “WO328) and United States Patent Application Publication No. US 2016/0244763 (published 25 August 2016, “App763”, of record on IDS).
The teachings of App743 as applicable to Claim(s) 120-121, 141, 200-202, 237, 310-311, and 312 have been described above.
App743 teaches a dsRNA that comprises an AS strand comprising at least 15 contiguous nt differing by no more than 3 nt from SEQ ID NO 905. App743 discloses conjugating their siNA to GalNAc or to a lipophilic ligand.
App743 does not teach the specific species of GalNAc or conjugation shown in Claim 312(c)(d).
However, WO328, drawn to dsRNA for inhibiting expression of a target gene, teaches (§ starting at ¶332) a variety of ligands and reasons to couple them to a dsRNA. WO328 teaches (¶339) lipophilic molecules and (¶353) GalNAc, including the same structure shown in Claim 312(c), shown in this modified excerpt of WO328:
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.
WO328 teaches ligands provide benefits, including (¶333) altering the distribution, targeting or lifetime of the molecule into which it is incorporated and providing an enhanced affinity for a selected target and (¶334) providing endosomolytic properties that promote lysis of the endosome and/or transport of the composition of the invention, or its components, from the endosome to the cytoplasm of the cell.
WO328 teaches (¶359) the ligands can be couple to the dsRNA at various places, including internal positions.
App763 is also drawn to dsRNA compounds and teaches (¶23-24) GalNAc, including the same structure shown in Claim 312(d), as shown in this modified excerpt of US763:
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543
852
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Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the dsRNA of App743 with the GalNAc of WO328 and the conjugation scheme of App763 for the benefits of altering the distribution, targeting or lifetime of the dsRNA into which it is incorporated and providing enhanced affinity for a selected target. One would have been motivated to do so with a reasonable expectation of success because WO328 teaches (¶333-334) ligands including GalNAc impart benefits to a dsRNA. One would have had a reasonable expectation of success because App743 teaches applying GalNAc to their dsRNA, and using any GalNAc, including that of WO328 and App763 would have been merely a design choice well within the purview of a person of ordinary skill in the art. Choosing where to place any ligand would have also been a design choice and placing any ligand (including the lipophilic ligand cholesterol of App743) at an internal position would have been a design choice and obvious in view of the teachings of WO328. Therefore the limitations of Claim 312(c)(d)—in addition to Claims 120-121, 141, 200-202, 237, and 310-313—would have been obvious in view of App743, WO328, and App763.
Claim(s) 120-121, 141, 200-202, 237, and 310-314 are rejected under 35 U.S.C. 103 as being unpatentable over App743, WO328, and App763 as applied to Claim(s) 120-121, 141, 200-202, 237, 310-313 in the 103 rejection above, and further in view of Leuschner (et al. 2006. Cleavage of the siRNA passenger strand during RISC assembly in human cells. EMBO Rep. 7[3]:314-320, “Leuschner”).
The teachings of App743, WO328, and App763 as applicable to Claim(s) 120-121, 141, 200-202, 237, and 310-313 have been described above.
App743, WO328, and App763 teach a dsRNA that comprises an AS strand comprising at least 15 contiguous nt differing by no more than 3 nt from SEQ ID NO 905, wherein the dsRNA is conjugated to a lipophilic ligand at an internal position.
App743, WO328, and App763 do not teach the internal positions exclude a cleavage site region of the sense strand (Claim 314[c]).
However, Leuschner, drawn to cleavage of the siRNA passenger strand during RISC assembly, teaches that (§Introduction ¶1-2) the guide/AS strand is assembled into RISC which uses it as a guide to endonucleolytically cleave complementary RNAs. Leuschner teaches that (same §) for efficient removal of the passenger/sense strand from the guide strand, the passenger [sense strand] has to be cleavable at its “natural site”, that is, at 10 nt from the 5’-phosphate of the guide strand. If this cleavage step is blocked, the siRNA duplex still becomes loaded into RISC, but target RNA cleavage is severely impaired owing to the non-efficient removal of the passenger strand.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the dsRNA comprising a lipophilic moiety conjugated to an internal position of App743, WO328, and App763 with the teachings of Leuschner for the benefit of optimizing the efficiency of the system. One would have been motivated to conjugate the lipophilic moiety to an internal position that is not a cleavage site region of the sense strand because Leuschner teaches the passenger [sense strand] has to be cleavable at its “natural site”, that is, at 10 nt from the 5’-phosphate of the guide strand otherwise the passenger strand can’t be efficiently removed from the guide strand and that will have the detrimental effect of severely impairing target RNA cleavage. One would have been motivated to do so with a reasonable expectation of success because the teachings of App743, WO328, and App763 indicate it was routine and conventional in the art of dsRNA to conjugate a lipophilic moiety to a dsRNA at any internal position and the teachings of Leuschner would have motivated the artisan to avoid conjugating the lipophilic moiety to the cleavage site region. Therefore the limitations of Claim 314 (specifically 314[c]) would have been obvious in view of App743, WO328, App763, and Leuschner.
Claim(s) 120-121, 141, 200-202, 237, and 310-314 are rejected under 35 U.S.C. 103 as being unpatentable over App743, WO328, App763 and Leuschner as applied to Claim(s) 120-121, 141, 200-202, 237, 310-314 in the 103 rejection above, and further in view of Ding (et al. 2020. Inhibition of Grb14, a negative modulator of insulin signaling, improves glucose homeostasis without causing cardiac dysfunction. Sci. Rep. 10:3417, “Ding”, of record on IDS) and NCBI GRB14 (1998. Homo sapiens Grb14 mRNA, complete eds, GenBank: L76687.1, "NCBI GRB14", of record).
The teachings of App743, WO328, App763 and Leuschner as applicable to Claim(s) 120-121, 141, 200-202, 237, and 310-314 have been described above.
App743, WO328, App763, and Leuschner teach a dsRNA that comprises an AS strand comprising at least 15 contiguous nt differing by no more than 3 nt from SEQ ID NO 905, wherein the dsRNA is conjugated to a lipophilic ligand at an internal position.
App743, WO328, App763, and Leuschner do not teach using the dsRNA to inhibit expression of GRB14.
However, Ding teaches GRB14 was a target of interest in modulating insulin signaling. Ding teaches (§Abstract) Grb14 knockdown in liver, white adipose tissues, and heart using an AAV-shRNA (Grb14-shRNA) improves glucose homeostasis in diet-induced obese (DIO) mice without negatively affecting cardiac function. Ding teaches (§Materials and Methods-Generation of recombinant adenoviral associated viral vector [AAV] expressing shRNA against mouse Grb14) designing multiple shRNAs that target various regions of the mouse GRB14 mRNA and then further developing the most potent one. Therefore Ding demonstrates that GRB14 was a target of known interest.
NCBI GRB14 provides evidence that the mRNA of GRB14 was known.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to search the art for existing dsRNA sequences that could be used against a target of known interest, namely Ding’s GRB14. It would have been obvious to use the GRB14 mRNA sequence of NCBI GRB14 to find those pre-existing GRB14-targeting sequences.
Therefore, in that search, an artisan would have identified App743’s dsRNA comprising SEQ ID NO 1771 as being complementary to a GRB14 mRNA target and would have tried using it to inhibit expression of GRB14 for the benefit of inhibiting GRB14 to improve glucose homeostasis without causing cardiac dysfunction in human cells or human organoids. One would have been motivated to do so with a reasonable expectation of success because it would have been a simple matter to search for known dsRNA sequences complementary to a known target mRNA and to use those dsRNA to try to inhibit expression of any gene target whose mRNA is complementary. Therefore using the dsRNA of App743, WO328, App763, and Leuschner to inhibit expression of GRB14 would have been obvious in view of App743, WO328, App763, Leuschner, Ding, and NCBI GRB14.
Double Patenting
Noted in the interest of compact prosecution: a search was conducted to identify patents and applications directed to or encompassing the same or overlapping subject matter. None were identified at this time. However, Applicant has filed Provisional and PCT applications directed to overlapping subject matter. If, in the future, claims of a converted application are found to have overlapping subject matter and any rejections remain in this application, the instant claims will be subject to an NSDP rejection.
Sequence(s) Free of the Prior Art of Record
The following sequences were searched and found to be free of the prior art of record: SEQ ID NO 905.
Conclusion
Claims 120-121, 141, 200-202, 237, 310-314 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUTHIE S ARIETI whose telephone number is (571)272-1293. The examiner can normally be reached M-Th 8:30AM-4PM, alternate Fridays 8:30AM-4PM (ET).
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RUTHIE S ARIETI
Examiner (Ruth.Arieti@uspto.gov)
Art Unit 1635
/RUTH SOPHIA ARIETI/Examiner, Art Unit 1635
/NANCY J LEITH/Primary Examiner, Art Unit 1636