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 .
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Application Status
This action is written in response to applicant’s correspondence received on 07/28/2026. Claims 1, 15-16, 21, 26, 31, 33-40, 50-51, 57, 64, 66, 76, and 80-83 are currently pending. Claims 57, 64, 66 are withdrawn from prosecution as being drawn to nonelected subject matter. Accordingly, claims 1, 15-16, 21, 26, 31, 33-40, 50-51, 76, and 80-83 are examined herein.
Election/Restrictions
The restriction requirement mailed on 05/28/2026 is still deemed proper. Applicant's elected Group I and the species, a dsRNA wherein the antisense strand comprises at least 17 contiguous nucleotides from the nucleotide sequence 5'-AUGGCATCAAUGAAGGGUACGUU-3' of SEQ ID NO:357, and the sense strand comprises at least 17 contiguous nucleotides from the nucleotide sequence 5'- CGUACCCUUCAUUGAUGCCAU-3' of SEQ ID NO:75, without traverse in the reply filed on 07/28/2026.
Information Disclosure Statement
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.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a CON of PCT/US2022/031755 filed on 06/01/2022, claims priority to PRO 63/232,797 filed on 08/13/2021, and PRO 63/195,769 filed on 06/02/2021.
Specification
The use of the terms, Mermade, BioAutomation, AM Chemicals, Thermo-Fisher, Hongene, Chemgenes, GE Healthcare, Agilent, Gibco, ATCC, Opti-MEM, Invitrogen, Biotek, Applied Biosystems, TaqMan, Roche, Lightcycler, which are trade names or marks 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 Rejections - 35 USC § 101
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 50 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).
Claim 50 recites “a cell containing the dsRNA agent… of claim 1” with no limitation restricting the cell to an isolated, ex vivo, or cultured state. The specification’s own definition confirms that the “cell” of the invention includes a cell within a subject (Page 19, line 32; Page 21, lines 5-39; Page 23, line 9; Page 182, Example 4), such as a human subject, and the specification’s disclosed therapeutic embodiments confirm that the dsRNA agent is designed and intended to be delivered into hepatocytes in vivo, within the liver of a living human patient, as the primary mechanism of therapeutic action.
Because claim 50 contains no language excluding the claimed cell from an in vivo state, e.g., “isolated”, “ex vivo”, “cultured”, or “non-human”, under broadest reasonable interpretation (BRI), “a cell containing the dsRNA agent” reads on a hepatocyte inseparable from the body of a living human patient who has been administered the therapeutic agent as described in the specification, i.e. claim 50 encompasses a human organism. Thus, and is unpatentable under 35 U.S.C. § 101 in view of AIA § 33(a).
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)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 15-16, 21, 26, 31, 33-36, 40, 51, 76, and 80 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Saxena (US12084662B2, issued on 09/10/2024, priority to Pro 63/174,932, filed on 04/14/2021, supports all relevant teachings). All evidence cited below from Saxena (04/14/2021) has been verified as properly supported by disclosure in Pro 63/174,932.
Regarding claim 1, Saxena teaches oligonucleotides and composition for inhibiting or reducing Patatin-Like Phaspholipase Domain Containing 3 (PNPLA3) gene expression (Front page, Abstract). PNPLA3 gene expression happens inherently in a cell. Specifications discloses a double stranded ribonucleic acid (dsRNA) agent DsiRNA 33, comprising two asymmetric complementary strands with sequences set forth in SEQ ID NO: 73 and SEQ ID NO: 74 (Columns 47 & 48, Table 1). See alignment:
Saxena SEQ ID NO: 74 (27nt) 5'- UGGCAUCAAUGAAGGGUACGUUGUCAC-3"
:||||||||||||||||||||||
Instant SEQ ID NO:357 (23nt) 5'-AUGGCATCAAUGAAGGGUACGUU-3'
Saxena SEQ ID NO: 73 (25nt) 3'- ACCGUAGUUACUUCCCAUGCAAUAG-5'
:||||||||||||||||||||
Instant SEQ ID NO: 75 (21nt) 3'-UACCGUAGUUACUUCCCAUGC-5'
The antisense strand of Saxena comprises 22 contiguous nts of the claimed SEQ ID NO: 357
The sense strand of Saxena comprises 20 contiguous nts of the claimed SEQ ID NO: 75
Since 22>20>17, both strands of DsiRNA 33 meet the “at least 17 contiguous” limitation.
Regarding claim 15, Saxena further teaches that “In certain instances, all nucleotides in an oligonucleotide include a 2'-modification…” (Column 5, lines 52-53). The recitation “an oligonucleotide” encompasses both the sense and antisense strands of a dsRNA oligonucleotide under BRI.
Regarding claim 16, Saxena further teaches “… 2'-fluoro, 2'-O-methyl…” (Column 5, line 50).
Regarding claim 21, Saxena further teaches the double stranded region of (dsRNA) agent DsiRNA 33 (sequences shown above in SEQ ID NOs: 73 & 74) is 25nt, see alignment below:
Saxena SEQ ID NO: 74 (27nt) 5'- UGGCAUCAAUGAAGGGUACGUUGUCAC-3"
Saxena SEQ ID NO: 73 (25nt) 3'- ACCGUAGUUACUUCCCAUGCAAUAG-5'
Regarding claim 26, Saxena further teaches DsiRNA 33 (sequences shown above in SEQ ID NOs: 73 & 74), wherein each strand is independently no more than 30 nucleotides in length.
Regarding claim 31, Saxena further teaches DsiRNA 33 (sequences shown above in SEQ ID NOs: 73 & 74), wherein the antisense strand comprises a 3’ overhang of 2 nucleotides, and 2>1.
Regarding claim 33, Saxena further teaches dsRNA agents, further comprising a “targeting ligand” (Column 6, lines 1-3).
Regarding claim 34, Saxena further teaches dsRNA agents, further comprising a “targeting ligand” (Column 6, lines 1-3), wherein the ligand is conjugated to the 3’ end of the sense strand of the dsRNA agent in some embodiments (Column 31, line 21).
Regarding claim 35, Saxena further teaches dsRNA agents, further comprising a “targeting ligand” and “In some embodiments, the targeting ligand is a N-acetylgalactosamine (GalNAc) moiety” (Column 6, lines 1-3).
Regarding claim 36, Saxena further teaches that “the GalNAc moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety…” and demonstrates several embodiments including one “monovalent GalNAc attached to an adenine nucleotide” and using a “GAAA acetal linker” (Column 33; Column 34, lines 63-65; the “L” symbol in structural examples).
Regarding claim 40, Saxena further teaches “examples of modified internucleotide linkages include, but are not limited, to, …, a phosphorothioate linkage, …” (Column 29, lines 1-3).
Regarding claim 51, Saxena further teaches at least some embodiments of “pharmaceutical composition” (column 8, line 14) comprising the disclosed dsRNA agent DsiRNA 33 (sequences shown above in SEQ ID NOs: 73 & 74) as discussed above.
Regarding claim 76, Saxena further teaches that “kits are described that include at least one oligonucleotide herein…”, at least some embodiments encompass the disclosed dsRNA agent DsiRNA 33 (sequences shown above in SEQ ID NOs: 73 & 74) as discussed above.
Regarding claim 80, Saxena further teaches DsiRNA 33 (sequences shown above in SEQ ID NOs: 73 & 74), wherein the antisense strand of Saxena SEQ ID NO: 74 comprises 22nt of the claimed SEQ ID NO: 357, and the sense strand of Saxena SEQ ID NO: 73 comprises 20nt of the claimed SEQ ID NO: 75. Since 20>19, both strands of DsiRNA 33 meet the “at least 19 contiguous” limitation.
Claim Rejections - 35 USC § 103
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 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.
Claims 37-39 are rejected under 35 U.S.C. 103 as being unpatentable over Saxena (04/14/2021; Full citation see §102 above), as applied to claim 1 above, in further view of Fitzgerald (US20170340661A1, published on 11/30/2017).
The teachings of Saxena (04/14/2021) have been discussed above and as applied to claims 1, 15-16, 21, 26, 31, 33-36, 40, 51, 76, and 80.
Saxena does not teach specific embodiments of targeting ligands as claimed by claims 37-39.
However, Fitzgerald (2017) teaches the exact claimed structures, see comparison below:
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417
657
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459
702
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Instant claim 37. Fitzgerald (2017) Page 2, ¶[0016].
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432
700
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505
834
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Instant claim 38. Fitzgerald (2017) Page 3, ¶[0017].
It would have been obvious to persons having ordinary skills in the art (PHOSITAs) before the effective filing date of the claimed invention to have further modified the dsRNA agents taught by Saxena (04/14/2021) to comprise the specific GalNAC derivative ligand with specific conjugation scheme, taught by Fitzgerald (2017). It would have merely amounted to a simple combination or substitution of prior art elements according to known methods to yield predictable results. One would have been motivated to do so because Fitzgerald (2017) teaches that these specific ligand modifications improved efficacy, stability, potency, durability, and safety (Page 10, ¶[0074]). One would have reasonable expectation of success because the same design rationales, same structures, and congruent mechanisms and drug actions described by both Saxena and Fitzgerald, in addition to successful gene knockdown by these modified dsRNA agents in vivo (Saxena, Columns 77-78, 83-87, involving non-human primates; Fitzgerald, Page 107, Example 4, involving mice).
Regarding claim 37, Fitzgerald (2017) teaches an identical structure of ligand (FIGs above).
Regarding claim 38, Fitzgerald (2017) teaches an identical structure of ligand schematic to an RNAi agent (FIGs above).
Regarding claim 39, Fitzgerald (2017) further teaches that the X is O or S (Page 4, first line).
Allowable Subject Matter
Claims 81-83 are objected to as being dependent upon a rejected base claim 1, but would be allowable if the claims are rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
Claims 81-83 describe specific chemical modifications at clearly defined nucleotide positions and defined internucleotide linkages along a specified dsRNA molecule comprising a sense strand and an antisense strand with specific sequences set forth in SEQ ID NOs: 357 & 930.
The closest prior art is the DsiRNA 33 dsRNA agent disclosed by Saxena (2021), see alignment above in the §102 rejection. Sequence search reveals 95.2% sequence identity matches for both strands of the claimed dsRNA molecules, however, claims 81-83 require a specific pattern of modification for each nucleotide and specific internucleotide linkages that Saxena does not teach.
Although several distinct lines of research aiming at improving the performance of dsRNA compounds provide relevant elemental teachings regarding: Internucleotide linkage and full sequence nucleotide modifications or ligand conjugation by Foster (Mol Ther. 2018;26(3):708-717; Cited on IDS filed on 07/28/2026); Thermally Destabilization Modifications by Theile (WO2018098328A1, published 05/31/2018) and Schlegal (WO2018098117A1, published 05/31/2018); And additional optimization assays taught by Sano (Nucleic Acids Res. 2008 Oct;36(18):5812-21) and Kim (Nat Biotechnol. 2005 Feb;23(2):222-6; Page 222, Abstract; Page 223, Figure 1), none of Saxena, Foster, Theile, Schlegal, Sano, and Kim teaches the specific sequences of SEQ ID NOs: 357 & 75. There is insufficient teaching, strategy, or motivation and insufficient reasonable expectation of success to combine all variables and arrive at the fully modified sequences set forth in SEQ ID NO: 647 & 930.
Thus, claims 81-83 encompass subject matter that is free of prior art.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Delphinus D. Yu whose telephone number (571) 272-1576. The examiner can normally be reached Mon-Thr 7:30am to 4:30pm Fri 10am to 2pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil P Hammell can be reached on (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DELPHINUS DOU YI YU/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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