DETAILED ACTION
Receipt of Arguments/Remarks filed on March 10 2026 is acknowledged. Claims 2-34, 36-66, 68-86, 88-108, 110-119, 121-124, 126-179, 181-183, 185-187, 189 and 192-194 were/stand cancelled. Claims 1, 87, 109, 120, 125 and 191 were amended. Claims 1, 35, 67, 87, 109, 120, 125, 180, 184, 188 and 190-191 are pending.
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 .
Withdrawn Rejections
The amendments filed March 10 2026 are sufficient to overcome the rejection of claims 1, 35, 47, 67, 87, 109, 120, 125, 173, 177, 179, 180, 184 and 188-194 under 35 USC 112(b). In claim 1, k has been amended to recite 1. Claim 47 was cancelled. Claim 177 and 179 were cancelled.
The cancellation of claim 173 has rendered the rejection under 112(d) moot.
The amendments filed March 10 2026 are sufficient to overcome the rejection of claims 1, 173, 177, 179, 184 and 191 under 35 U.S.C. 102(a)(1) as being anticipated by Barnes et al. As amended, instantly claimed L1 is distinguished from Barnes. L10 is only unsubstituted or hydroxymethyl substituted. So if L1B is C(O)NH-L10 (C10 alkylene), then L1C is a bond as the only other choice is R1C substituted C1-C10 alkylene which is not present in Barnes, L1D would have been a bond and L1E could be a C(O)NH but this would not result in the NH being bonded to the siRNA as recited in the instant claims. Therefore, the amendments which limit the substitutions allowed in the scope distinguish the instant claims from the examples in Barnes.
The cancellation of claims 173, 177 and 179 has rendered the rejection under 103 over Barnes et al. in view of Manoharan et al. moot. While claims 1, 184 and 191 were included in the rejection, these claims were also rejected under Kugimiya et al. Therefore, the rejection is moot in light of the claim amendments.
Modified Rejection Based on Amendments in the reply filed on March 10 2026
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1, 35, 67, 87, 109, 120, 125, 180, 184, 188 and 190-191 are rejected under 35 U.S.C. 103 as being unpatentable over Barnes et al. (USPGPUB No. 20160030585, cited in the Office Action mailed November 13 2025) in view of Kugimiya et al. (WO2018181428, cited on PTO Form 1449).
Applicant Claims
The instant application claims a compound of formula I
PNG
media_image1.png
69
326
media_image1.png
Greyscale
.
The instant application claims the compound has a formula II:
PNG
media_image2.png
88
482
media_image2.png
Greyscale
.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Barnes et al. is directed to a novel fatty acid and their use in conjugation to biomolecules. Taught are conjugates which have improved half-life and duration of action. Specifically, the fatty acids extend the half-life of biomolecules via conjugation (paragraph 0001). Taught are pharmaceutical compositions comprising a conjugate of the invention and one or more pharmaceutically acceptable carriers (paragraph 0012). Taught is administering to a subject a therapeutically effective amount of a conjugate (paragraph 0016). Fig. 1 shows that example 24 decreased plasma APOC3 levels. Conjugate of example 24 is a compound of the APOC3 siRNA conjugate. APOC3 transgenic mice spontaneously develop hypertriglyceridemia with markedly increased plasma TG content. This siRNA conjugate was injected subcutaneously to the transgenic mice (paragraph 0584). Claimed is a conjugate which comprises a biomolecule, such as an siRNA, linked to a fatty acid via a linker. The structures of the fatty acids are shown in claim 1. Linkers are recited in claims 4 and 5 (see below).
PNG
media_image3.png
720
518
media_image3.png
Greyscale
PNG
media_image4.png
432
612
media_image4.png
Greyscale
PNG
media_image5.png
664
646
media_image5.png
Greyscale
.
siRNA refer to any nucleic acid molecule capable of inhibiting or down regulating gene expression or viral replication by mediating RNA interference (RNAi) or gene silencing in a sequence-specific manner. These RNAi agents can be modified at the 2’ position such as O-methyl, fluoro, etc. (paragraph 0041). siRNA agent can be chemically synthesized using naturally-occurring nucleotides or variously modified nucleotides designed to decrease off-target effects, and/or increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives (paragraph 0931). A linkage between a sugar and a sugar in an oligonucleotide (internucleoside linkage) may be a linkage having a natural nucleic acid, phosphodiester (D-oligo), an artificially modified linkage or a linkage without phosphorus atom. Any linkage which is well-known in this field can be used. Examples of an artificially modified linkage are phosphorothioate (S-oligo) (paragraph 0007; 0040; 0467).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Barnes et al. exemplify an siRNA conjugate and a linker which comprises:
PNG
media_image6.png
124
242
media_image6.png
Greyscale
Barnes et al. does not expressly teach the type of connection between the siRNA and the linker. However, this deficiency is cured by Kugimiya et al.
Kugimiya et al. (wherein USPGPUB No. 20200384010 is serving as the English language equivalent) is directed to a complex of nucleic acid medicine and multibranched lipid. It is taught that nucleic acid medicines, such as siRNA, are easily degraded by nucleases in vivo and the efficiency of incorporation into target cells is low. To overcome two major problems, the nucleic acid itself can be modified or a drug delivery system that delivers the nucleic acid into the target cells have been used/studied (paragraph 0006). The complexes of the instant invention can enhance suppressing activity of the target gene expression (paragraph 0024). Taught is a complex in which a multibranched lipid binds through a linker to an oligonucleotide comprising a nucleic acid medicine (paragraph 0026). The linker is of the formula:
PNG
media_image7.png
162
524
media_image7.png
Greyscale
wherein L0 binds to the oligonucleotide and L6 binds to the lipid (paragraph 0028). A specific linker taught is:
PNG
media_image8.png
240
678
media_image8.png
Greyscale
wherein OL is the oligonucleotide, the 3’ means it binds the 3’end of the oligonucleotide, L0-1 is a bond, a nucleotide linker or a non-nucleotide linker, L5-1 is a bond, NH or O and LI is the lipid (paragraph 0028-0029). Other linkers falling within the instantly claimed scope is also shown (paragraph 0156). Administration of the siRNA in saline were administered to mice. After administration tissues and blood cells were collected and the RNA obtained (paragraph 0469). It is taught that the lipid can bind at the 3’ end and/or 5’ end of the oligonucleotide (paragraph 0032; claim 19).
siRNA are low molecular weight double-stranded RNA complementary to the target gene which consists of about 19 to 25 base pairs (paragraph 0004). Modifications of the sugar part include the 2’ position of the sugar. Examples are 2’-F, 2’-OCH3 and 2’-OCH2CH2OCH3 (paragraph 0046).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Barnes et al. and Kugimiya et al. and utilize the linker taught in Kugimiya et al. to link the fatty acid (lipid) of Barnes to the oligonucleotide. Since both Barnes et al. and Kugimiya et al. are concerned with improving the properties, specifically half-life, of the siRNA via conjugation to a lipid, one skilled in the art would have a reasonable expectation of success in replacing the linker of Barnes et al. with Kugimiya et al.as both are taught for the same purpose. This results in simple substitution of one known linker for another to obtain the predictable results of connecting the fatty acid/lipid to the siRNA (oligonucleotide). Note: MPEP 2143.
Regarding the claimed siRNA, both Barnes et al. and Kugimiya et al. suggest siRNA. Kugimiya et al. teaches the length of the of the siRNA falls within the scope claimed. Both Barnes et al. and Kugimiya et al. suggest the nucleotides can be sugar modified to increase stability and also teach that phosphorothioates can be utilized to increase stability. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Barnes et al. and Kugimiya et al. and utilize 2’-sugar modifications such as fluoro or methyl as well as phosphorothioate linkages in order to increase stability of the siRNA.
Regarding claim 35, a specific L1A-L1B claimed is
PNG
media_image9.png
148
386
media_image9.png
Greyscale
as shown above Kugimiya et al. teaches a linker of
PNG
media_image8.png
240
678
media_image8.png
Greyscale
which contains the same L1A-L1B. It is noted that claim 1 indicates that all of L1 can be a bond. Therefore, C-2 reads on instant claim 35.
Regarding claim 67, a specific L1 claimed is:
PNG
media_image10.png
178
690
media_image10.png
Greyscale
Kugimiya et al. teaches a linker (paragraph 0156):
PNG
media_image11.png
184
454
media_image11.png
Greyscale
where OL is an oligonucleotide, Zd is a O, V3 and V4 are integers from 1 to 4. As claimed L5 can be C(O)NR9 or NR9C(O) (claim 13). Therefore, the difference between the linker in paragraph 0156 is the switching of the C(O) and NH as well as the missing CH2OH. However, as claimed the use of either C(O)NH or NHC(O) are both taught. Since linkers expressly taught include the CH2OH, one skilled in the art would have been motivated to form the linker as recited in instant claim 67. There are a finite number of choices recited in claim 14 for the choice for L5 such that one skilled in the art would recognize that either the nitrogen or the carbonyl can be first (i.e. easily reversible) and that the alkyl chain can contain the CH2OH as this is a substitution used in numerous structures taught in Kugimiya et al.
Regarding claims 180 and 189, both Barnes et al. and Kugimiya et al. teach administration to mice. Kugimiya et al. teaches that siRNA are incorporated into cells. Kugimiya et al. also expressly teaches isolation of tissues and cells which contain the RNA.
Regarding claim 184, Barnes et al. expressly teaches administering (subcutaneous injection) to a subject (a transgenic mouse) the compound. Barnes et al. expressly teaches these transgenic mice spontaneously develop hypertriglyceridemia. This equates to the subject having a disease of the heart.
Regarding claim 87, 109, 120, 125, 183 and 194, Kugimiya et al. teaches that the lipid can be bound at the 3’ and/or the 5’ end of the oligonucleotide. This suggests binding of more than one lipid molecule to the oligonucleotide. Since there are only three choices (at the 3’ end, the 5’ end or both) one skilled in the art would envision attaching the lipid at any of the three positions. The lipid of Kugimiya et al. has the following structure (claim 1):
PNG
media_image12.png
160
418
media_image12.png
Greyscale
Wherein A3-A5, A8-A10 can be a bond. A13-15 are alkyl groups. Y3 can be a bond. X3 can be NR1C(O) wherein R1 can be an H, X4 can be a bond, X5 can be NR3C(O) wherein R3 is H. This reads on the instantly claimed L5 and L6 being NHC(O) and R1-R3 is alkyl. Regarding the L3 and L4, this reads on the linker which is rendered obvious above (i.e. C2).
Response to Arguments
Applicants’ arguments filed March 10 2026 have been fully considered but they are not persuasive.
Applicants argue that the compounds of the present invention are structurally distinct from the compounds of Barnes and there is no suggest in Kugimiya et al. to make the compounds of the instant invention. The instantly claimed oligonucleotides are linked to a C2-C22 alkylene with a terminal COOH group. None of the compounds in Barnes et al. or Kugimiya et al. disclose this functionality nor is it suggested to incorporate the specific L2-COOH group into a siRNA conjugate.
Regarding applicants argument, the examiner cannot agree. As claimed in Barnes, the invention is a conjugate in which a linker connects a fatty acid to a biomolecule. Specific biomolecules taught include siRNA.
PNG
media_image3.png
720
518
media_image3.png
Greyscale
. For example, A3 include a COOH-alkyl wherein the alkyl is a branched C6-C30 alkylene which overlaps with the instantly claimed L2 as the instant specification (paragraph 0039) teaches alkyl includes both straight chain and branched. The other C(O)OH is then linked to the linker. Kugimiya et al. also teaches using a linker to connect a lipid with a siRNA. As set forth in the rejection obvious, it would have been obvious to utilize the linkers of Kugimiya et al. to link the fatty acids of Barnes et al. to an siRNA. Barnes et al. teaches coupling between an acid and an amine to connect two functional groups (see for example paragraph 0976). Therefore, coupling of the linkers of Kugimiya et al. to one of the acids in the fatty acids of Barnes et al. would result in the instant claims. While L1 as instantly claimed recites -L1A-L1B-L1C-L1D-L1E- this L1 can be attached at either end to the L2-COOH. Thus, the use of the linkers of Kugimiya et al. with the fatty acid of Barnes et al. which is then connected to an siRNA would result in the instantly claimed Formula I. Specifically, for example the use of linker C2 would result in the same compounds claimed.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ABIGAIL VANHORN whose telephone number is (571)270-3502. The examiner can normally be reached M-Th 6 am-4 pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ABIGAIL VANHORN/ Primary Examiner, Art Unit 1636
Prosecution Insights