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 76, 78-82, 85-86, 90-95 are pending. Claims 80, 82, and 94-95 are withdrawn from consideration as being directed to nonelected inventions/species.
Status of the Application
Applicant’s response and amendment filed 03 October 2025 are acknowledged and entered.
Applicant has amended Claims 76, 78, and 81. Applicant has cancelled claims 77, 83-84, and 87-89.
Response to Amendment
Applicant has not addressed the question about the priority date (see below).
Applicant has amended Claims 76, 78, and 81 to overcome the 112(a) rejection; the 112(a) rejection is partially maintained and partially withdrawn.
Applicant has amended Claims 76, 78, and 81 to overcome the 112(b) and Markush rejections; the 112(b) and Markush rejections are withdrawn.
Applicant has amended Claims 76, 78, and 81 to overcome the 103 rejections; the 103 rejections are partially maintained and partially withdrawn.
The NSDP rejection is maintained.
Claims 76, 78-79, 81, 85-86, and 90-93 are examined.
Arguments applicable to newly applied rejections to amended or newly presented claims are addressed below. Arguments that are no longer relevant are not addressed.
Rejections not reiterated here are withdrawn.
Priority
The filing receipt claims benefit of PRO 62849812, filed 17 May 2019 (“PRO812”). The PRO812 application discloses (Claims 4-5) what the claimed invention calls SEQ ID NOs 11-12. However, a search of PRO812 did not reveal disclosure of any other amino acid sequences. If other sequences are disclosed in PRO812, Applicant’s response should point out where.
All other sequences were disclosed in the second priority document, PCTUS2033476, filed 18 May 2020.
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 76, 78, 81, 85-86, 90-93 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. This rejection is maintained and updated in response to the claim amendments.
Claim 76 recites a compound comprising a modified oligonucleotide and a conjugate group comprising a conjugate moiety that comprises (ii) an AGTR1 binding cell-targeting moiety that is a peptide cell-targeting moiety and (i) a peptide extender that comprises SEQ ID NO 31 wherein X is lysine/D-lysine/L-lysine/N6-(2-azidoacetyl)-lysine. Claim 78 recites potential variants for one sequence structure/motif of the peptide cell-targeting moiety.
Therefore, the claims encompass the following broad genera and subgenera that can be used to bind AGTR1:
any AGTR1 binding cell targeting moiety that is a peptide, or
Claim 78: any AGTR1 binding cell targeting moiety comprising any sequences encompassed by the motif variants.
Any kind of peptide cell-targeting moiety that binds AGTR1, and any peptide sequence that encompassed by all the permutations recited in Claim78 would be encompassed by the claims as instantly presented.
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. teaches (p. 1 L20-30) the compounds are for modulating expression of target nucleic acid in cells expressing AGTR1.
The Spec. teaches about (starts at p. 36 L8) AGTR1-binding conjugate moieties. That § does not describe any structure requisite for binding AGTR1 or a peptide that binds AGTR1. Most of the discussion about AGTR1-binding moieties (starts at L35) focuses on peptides and some examples of peptide sequences that bind AGTR1 are provided: SEQ ID NO 11 (which encompasses a huge number of potential sequences) and SEQ ID NOs 12-14 and 16. Teachings on p. 43 indicate that SEQ ID NOs 15 and 17 are also AGTR1-binding moieties. Note that the AGTR1-binding moiety SEQ ID NO 15 can be considered to comprise the peptide extender of SEQ ID NO 31 because it comprises the 10-mer [K]PPPAGSSPG.
The Spec. teaches about (starts at p. 38 L25) peptide extenders. That § teaches they provide a distance or barrier between the oligont and the AGTR2 binding cell-targeting moiety such that the oligont does not inhibit activity of the AGTR1-binding moiety and the AGTR1-binding moiety doesn’t inhibit the oligont’s activity, or at least inhibits the activity less than would occur without the peptide extender.
The Examples (start on p. 69) disclose experiments using oligonts targeting a single target gene, mouse MALAT. They teach AGTR1-targeting moieties comprising SEQ ID NOs 14 and 15. They teach linkers comprising (p)-6-aminohexanol-1-carboxymethyl [triazolo BCN1] carbamate. Since SEQ ID NO 15 comprises SEQ ID NO 31, the Examples teach the sole peptide extender SEQ ID NO 31. Results show that at high doses the MALAT-targeting oligont–AGTR1-binding conjugates reduced MALAT expression.
The Examples did not show using any AGTR1-binding cell targeting moiety besides SEQ ID NO 14 (and SEQ ID NO 15 which incorporates SEQ ID NO 14).
The Spec. does not show exemplary members of the broad genus of AGTR1-binding cell targeting moieties that are peptides. Applicant has identified any AGTR1-binding moieties that are peptides, but tested only the AGTR1-binding cell targeting moieties SEQ ID NOs 14-15. Applicant has not demonstrated that any of the peptides encompassed by the claims or even by SEQ ID NO 11 (aside from SEQ ID NOs 14-15) possess the claimed function of binding AGTR1, nor have they demonstrated that the other SEQ ID NOs disclosed as AGTR1-binding moieties have that effect.
What Applicant has shown does not demonstrate possession of what is claimed: a compound comprising: any AGTR1-binding cell targeting moiety (aside from SEQ ID NOs 14-15), including any AGTR1-targeting peptide.
Altogether, the examples does not demonstrate possession of a compound comprising any AGTR1-binding cell-targeting moiety despite that they have claimed the broad genus. The Spec. does not provide support for the entire genus of AGTR1-binding cell-targeting moieties because the examples show only individual species.
The Specification does not provide sufficient evidence that the broad genus of AGTR1-binding cell targeting moieties claimed actually function as claimed and bind AGTR1. Although the claims either explicitly recite a functional characteristic (i.e., an AGTR1-binding cell targeting moiety), the functional characteristic is not coupled with a known structure.
Although the Specification teaches the examples discussed above, it does not identify a core structure necessary for binding AGTR1. No core structure, partial structure, physical or chemical property, or functional characteristic coupled with a known or disclosed structure/function relationship responsible for the binding AGTR1 is disclosed in such a way to demonstrate possession of the full invention as claimed at time of filing.
Regarding the AGTR1-binding moieties, the moieties encompassed by SEQ ID NO 11 have different structures, and peptides encompassed by the claims share no structure and can have different modes of action. Since the peptides encompassed by SEQ ID NO 11 can comprise different sequences, they cannot be deemed to share a core structure aside from the fact that each peptide is 8-mer. Applicant has not described a core structure responsible for binding AGTR1.
Altogether, sufficient data are not shown to substantiate claiming the broad genus of AGTR1-binding cell targeting moieties. The specification teaches only a couple members from the genus. For example, the AGTR1-binding cell targeting moiety SEQ ID NOs 14-15. However the number of species disclosed by complete structure is not sufficient to provide the written description support for the huge genus ofAGTR1-binding moieties.
While none of these elements is specifically required to demonstrate possession, in combination their lack 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 claimed invention. Claims 76 and 78 are rejected for failing to demonstrate possession of the claimed invention. Claims 78-79, 81, 86-86, and 90-93 are rejected because they depend from Claims76 and/or 78 and do not remedy the issues.
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.
Claim(s) 76, 78-79, 81, 85-86, and 90-93 are rejected under 35 U.S.C. 103 as being unpatentable over International Patent Application Publication Number WO 2015/179693 (published 26 November 2015, “WO693”, of record) in view of Rhodes (et al. 2009. AGTR1 overexpression defines a subset of breast cancer and confers sensitivity to losartan, an AGTR1 antagonist. PNAS 106[35]:10284–10289, “Rhodes”, of record), Balakumar (and Jagadeesh. 2014. Structural determinants for binding, activation, and functional selectivity of the angiotensin AT1 receptor. J. Molec. Endocrinol. 53:R71-R92, “Balakumar”, of record), International Patent Application Publication Number WO 2012/122042 (published on 13 September 2012, “WO042”, of record) and International Patent Application Publication Number WO 2013/074910 (published on 23 May 2013, “WO910”, of record). This rejection is maintained/updated in view of the claim amendments.
NOTE: references to p. # refer to the PDF p. #.
WO693 teaches (§Abstract) oligomeric compounds comprising conjugate groups. WO693 teaches (§i. Certain sequences and targets, pp. 70-71) the invention encompasses antisense oligont that are complementary to a target nucleic acid and result in antisense activity. WO693 teaches (same §, p. 71 L10-20) the compounds can comprise a cleavable moiety, one or more cleavable bonds, a linker, a protein binding moiety, and/or a cell-targeting moiety that can comprise one or more tethers.
Regarding the tether, WO693 teaches (p. 72 L5-18) conjugate groups comprise one or more tethers covalently attached to the linking group and the tether can comprise one or more cleavable bonds. WO693 teaches (p. 45 L19-27) a cleavable bond can be a peptide bond. WO693 teaches (pp. 72-74 L27-22) the tether can be various lengths and comprise various structures. Altogether, the cell-targeting moiety comprising a tether that comprises a cleavable bond reads on the instant conjugate moiety [that] comprises [a moiety] and a peptide extender. WO693 further teaches (p. 72 L5-20) the tether can be a disulfide group. A disulfide group is simply another term for a disulfide bridge. WO693 teaches (p. 197 L5-10) including a cleavable disulfide bond between a specific cell-targeting moiety (i.e., GalNAc) and the ASO because it can be cleaved by enzymes inside the cell. An artisan would realize including a disulfide bond between the oligo and the cell-targeting moiety or peptide extender reads on the limitation of instant Claim 81 wherein the modified oligonucleotide is attached to the cell-targeting moiety or the peptide extender via a disulfide bridge.
Regarding a linker, WO693 teaches (§ii. Certain Linking Groups, starts p.75) various structures and sizes for the linking group. WO693 teaches (p. 76 L 8-15) the linking group can comprise many compositions and can include a protein binding moiety and can be a peptide or PEG or a phosphodiester group, a vitamin, a carbon chain, or other structures. A conjugate group that comprises a peptide linker reads on the instant claims’ conjugate moiety [that] comprises [a moiety] and a peptide extender. WO693 further teaches (p. 75 L15-20) the linking group can be a disulfide group. A disulfide group is simply another term for a disulfide bridge.
The teachings of WO693 indicate that its cell-targeting moiety comprising a tether and a linker read on the claimed conjugate group comprising a conjugate moiety and a conjugate linker, wherein the conjugate moiety comprises a… cell-targeting moiety and a peptide extender.
WO693 teaches (pp. 44-45 L25-6) the conjugate is a group of atoms bound to an oligont that can modify its pharmacodynamic, pharmacokinetic, binding, cellular distribution, or cellular uptake properties, among others. WO693 teaches (same §) a linker is a portion of the conjugate group that covalently links the oligo to any portion of the conjugate group. Regarding Claims 85-86, WO639 teaches (same §) the conjugate group can be attached to the oligont at either the 3’- or 5’-end.
Regarding Claim 90, WO693 teaches (pp. 68-69 L20-20) the modified oligont can be 8-30 or 12-30 nt long. Regarding Claim 91, WO693 teaches (pp. 2-3 L25-10) chemical modifications increase oligont potency, reduce toxicity, decrease potential for side effects, and increase resistance to degradation. WO693 teaches (pp. 23-24 L. 15-94) the oligont comprises at least one modified nt comprising a modified base, which can be a sugar surrogate. Regarding Claims 92-93, WO693 teaches (p. 26 L20-25) the oligont can be single stranded or double stranded and (p. 46 L10-15) double stranded means a pair of oligomeric compounds that are hybridized to one another or a single self-complementary oligomeric compound that forms a hairpin structure… in certain embodiments, a double-stranded oligomeric compound comprises a first and second oligomeric compound. That indicates that the teachings of WO693 read on instant Claim 93 wherein the two strands are complementary to one another.
Altogether, WO693 teaches limitations of the claimed invention: the compound comprising (a) a modified oligont and (b) a conjugate group comprising (i) a conjugate moiety that comprises (i.1.) a cell-targeting moiety that can be a peptide and can include (i.2) a tether that comprises a cleavable bond and (ii) a linker. Note that, as described above, either the tether or the linker can be considered a peptide extender.
WO693 teaches (p. 122) Table 1 that discloses numerous target nucleic acids that can be attached to the conjugate moiety: AR, ApoA, ApoB, ApoCIII, GCCR, GCGR, and STAT3, among others. WO693 teaches (§ starts p. 125) ApoA is involved in prothrombotic and antifibrinolytic properties and can enhance atherosclerotic progression. WO693 teaches (same §; §3. Apolipoprotein B; §4. Apolipoprotein C-III; and §D. Target Nucleic Acids. Regions and Segments, entire §) oligont targeting ApoA can treat cardiovascular and metabolic diseases. WO693 teaches (same §D and §13. STAT3) using oligont that target STAT3 to treat various cancer, including breast and prostate cancers.
WO693 does not teach a peptide cell-targeting moiety to use with the Apo- or STAT3-targeting oligont. WO693 does not teach a peptide cell-targeting moiety that targets AGTR1 specifically.
However, Rhodes, drawn to AGTR1 overexpression conferring sensitivity to the AGTR1 antagonist losartan, teaches (§Abstract) AGTR1 is markedly overexpressed in 10-20% of all breast cancer cases across multiple cohorts. Rhodes teaches (same §) ectopic overexpression of AGTR1 in primary mammary epithelial cells, combined with angiotensin II [AT] stimulation, led to a highly invasive phenotype that was attenuated by the AGTR1 antagonist losartan and losartan reduced tumor growth by 30% in AGTR1-positive breast cancer xenografts.
Rhodes teaches (§Results, p. 10286, first full ¶ through §Results p. 10287; Figs. 4,5) stimulating the AGTR1-overexpressing cells with AT significantly promote[d] cell invasion and the breast cancer had to be stimulated with AT in order for the losartan to have any effect on treating the breast cancer: Importantly, AGTR1 and AT-mediated invasion was attenuated in a dose-dependent manner with inclusion of the AGTR1 blocker, losartan. Losartan had no effect on the LacZ-transfected cells or the AGTR1-transfected cells not stimulated with AT (Fig. 4B). Rhodes also teaches (same §) they tested the effect of AT and losartan on AGTR1-overexpressing breast cancer lines and an invasive line of prostate cancer (the cell line DU145) that has low expression of AGTR1. Rhodes describes that AT induced an increase in invasion that was reversible with addition of losartan in each of the 4 AGTR1-overexpressing cell lines but that none of the 3 breast cancer cell lines with low AGTR1 expression, nor DU145, showed an increase in invasion upon 1 µM AT stimulation (Fig. 4C).
Balakumar, drawn to a review about the AGTR1 receptor, teaches (§Abstract) the renin-angiotensin system plays an important role in the pathophysiology of cardiovascular disorders. Balakumar teaches (Fig. 1) the peptide sequence of AGTR1 (bottom) and a peptide moiety (angiotensin II a.k.a. “Ang II” or “AT”) that binds it (top), shown here:
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Balakumar teaches (§Molecular determinants of Ang II for AT1 receptor binding, activation, inhibition, and signaling) Ang II binds the AGTR1 receptor: Ang II binds the receptor at several sites in the extracellular loops (ECL) and transmembrane helices. Balakumar teaches (§Molecular specifics of Ang II binding and activation of the AT1 receptor ¶1) the major contacts in Ang II that activate the receptor are aromatic AAs, Phe8 and Tyr4… the phenylalanine at position 8 of Ang II is critical for agonist activity. Therefore Balakumar teaches AAs critical for agonizing AGTR1.
Regarding the sequences recited in Claims 78-79, namely A1-8 wherein A1 is Asp, A2 is Arg, A3 is Val, A4 is Tyr, A5 is Ile, A6 is His, A7 is Pro, and A8 is Phe, Balakumar teaches that (Fig. 1, Table 1) amino acid sequence is the 8-mer DRVYIHPF. Balakumar teaches (§Abstract) AT (which it abbreviates Ang II) interacts with the AGTR1 receptor (which it calls AT1, but that is merely a different way to abbreviate AGTR1).
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 STAT3-targeting oligont conjugated to a cell-targeting moiety of WO693 with the teachings about breast cancer cells overexpressing AGTR1 and applying losartan to treat breast cancer of Rhodes and the AT/Ang II peptide sequence of Balakumar for the benefit of specifically targeting the STAT3-targeting oligos to breast cancer cells that have overexpressed AGTR1. One would have been motivated to do so with a reasonable expectation of success because Rhodes teaches AGTR1 is upregulated in 10-20% of breast cancer cases and WO693 teaches STAT3-targeting oligos conjugated to a cell targeting moiety for treating a subject with breast cancer and an artisan would have realized it is advantageous to use Balakumar’s AGTR1-targeting ligand to target WO693’s STAT3-targeting oligont to breast cancer cells wherein AGTR1 is upregulated. One would have been motivated to do so with a reasonable expectation of success because WO693 teaches using a cell targeting moiety and Balakumar teaches the peptide sequence of AT. It would have been a simple matter for an artisan to use the AT peptide as the cell targeting moiety to target the STAT3-targeting oligont to AGTR1 overexpressing breast cancer cells. Although Rhodes teaches AT can stimulate AGTR1, they teach that losartan reverses that effect. Therefore an artisan would have administered the STAT3-targeting oligont conjugated to AT to specifically deliver the oligont to breast cancer cells and then administered losartan, as done by Rhodes. Therefore, modifying the STAT3-targeting oligont conjugated to a cell-targeting moiety of WO693 with the teachings of Rhodes and the AT peptide sequence of Balakumar would have produced some limitations of Claims 76, 78-79, 81, 85-86, and 90-93.
WO693, Rhodes, and Balakumar do not teach the peptide extender sequence that is SEQ ID NO 31 (Claim 76).
However, WO042, drawn to peptide linkers, teaches (pp. 4-5 L25-12) compositions for delivering functional therapeutic agents to cells and discusses that their linker sequences operably join two polypeptides of interest to facilitate targeted delivery to particular cells. An artisan would realize the peptide linkers could be used to join any therapeutic compound to a targeting peptide and WO042 teaches (p 14 L1-22) the therapeutic compositions can be polynucleotides.
WO042 teaches (pp. 16-17 L15-11) the peptide linker is used a separation device that is used to join a therapeutic agent and a targeting agent. WO042 teaches (same §) the linker is also referred to as a spacer and it can be used to provide desirable flexibility to permit desired expression, activity and/or conformational positioning of the chimeric polypeptide.
WO042 teaches (p. 17 L 12-26) the linker peptide sequence can be various lengths, including no more than 45 and at least 10 amino acids long. That reads on the limitations of Claim 76 wherein the recited peptide extender consists of 10 amino acids.
Regarding SEQ ID NO 31 which is recited in Claim 76: WO042 teaches (pp. 19-20 L19-16) placing a proline residue within the first (e.g., 5' end) and/or last (e.g., 3' end) five amino acids of the linker provides for additional benefit within the linker. WO042 teaches proline’s cyclic side chain results in inflexibility which can keep the things connected via the linker appropriately separated. WO042 teaches (same §) the linker can have a proline in any or all of positions 1-5 from either end.
Altogether, an artisan would have recognized that the peptide linkers of WO042 are the same as the claimed peptide extenders—they serve the same purpose of separating the oligont and the cell targeting AGTR1 peptide moiety. The teachings of WO042 indicate that the exact length and composition of the peptide linker are design choices and can be optimized depending on particular needs. An artisan would have recognized that the teachings of WO042 encompass a peptide linker (i.e., “extender”) that is 10-40 amino acids long and which comprises three contiguous proline residues.
Furthermore, WO910, drawn to peptides that target a glucocorticoid receptor, teaches (¶11) a peptide conjugate comprising the formula Q-L-Y wherein Q is a peptide, Y is a receptor ligand, and L is a linking group. WO910 teaches (¶245) a heterologous moiety that is a “conjugate moiety” and can be a targeting agent or other therapeutic agent. WO910 teaches (¶269) compounds comprising two or more peptides bound via a linker wherein the peptides can be attached in a tail-to-tail orientation in which the C-terminal amino acids of each monomer are attached together. That indicates the orientation of the components can vary.
Regarding the specific sequences claimed, WO910 teaches (¶246) a peptide extension sequence attached to the C-terminus of Q that comprises an amino acid sequence of SEQ ID NO 1610. That sequence is GPSSGAPPPS, which, aside from the terminal “S”, is the exact same amino acids in the exact opposite order of claimed SEQ ID NO 31. WO910 also teaches (¶408) the extension sequences SEQ ID NO 1095 (which is identical to SEQ ID NO 1610), SEQ ID NO 1170, and SEQ ID NO: 1171. SEQ ID NO 1170 is GPSSGAPPPK which is the exact same amino acids in the exact opposite order of claimed SEQ ID NO 31 wherein X is K. SEQ ID NO 1171 is XGPSSGAPPPK. Those sequences both comprise terminal lysine. WO910 shows (¶779-780) compounds comprising the peptide and another therapeutic agent. That figure, shown here with a sequence similar to the claimed SEQ ID NO highlighted, shows peptides comprising claimed SEQ ID NO 31 wherein X is S:
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That figure shows the amino acids in the same order as the instant claims. Altogether, teachings in the art indicate it would have been obvious to modify the compounds of WO693, Rhodes, and Balakumar with the teachings of WO042 and any peptide extension sequences, including those of WO910. As discussed, the teachings of WO910 indicate it is acceptable to join an extension sequence to a peptide targeting moiety in variable orientations, including C-terminus to C-terminus.
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 compounds of WO693, Rhodes, and Balakumar with the teachings about peptide linkers of WO042 and the sequences of WO910 for the benefit of optimizing the length and sequence of the peptide extender. One would have been motivated to do so with a reasonable expectation of success because the teachings of WO693 and WO042 indicate that the exact length and composition of a peptide extender is merely a design choice and any peptide sequence can be used as a basis for modification. One would have been motivated to do so because WO910 teaches (see figure excerpt above) the peptide extension sequence followed by the GLP-1–targeting sequence and an artisan would have realized they could use the peptide extension sequence with any targeting sequence, including the AGTR1-targeting sequence of Balakumar. An artisan would have had a reasonable expectation of success using any of the peptide extension sequences of WO910 since any peptide extends and the sequences of WO910 were known peptide extenders. However, one would have been motivated to select the specific WO910 sequences SEQ ID NOs 1170 and 1610 because WO042 teaches using peptide linkers comprising proline residues and because the peptide extension sequence shown in the figure above is the same peptide extension sequence used in WO910’s figures and examples (see, e.g., ¶967, 969, 973, 976, 978). The fact that WO910 used the same sequence in their examples indicates that it was a preferred peptide extension sequence.
The instant claims do not specify whether the peptide extender is attached to the N- or C-terminus of the AGTR1 moiety. Attaching WO910’s SEQ ID NO 1170 to Balakumar’s AGTR1-binding moiety via the C-terminus of each (which WO910 teaches at (¶269) would have produced a moiety wherein claimed SEQ ID NO 12 is attached to claimed SEQ ID NO 31 as follows: DRVYIHPF-KPPPAGSSPG. Therefore modifying the compounds of WO693, Rhodes, and Balakumar with the teachings about peptide linkers of WO042 and the sequences of WO910 would have produced all the limitations of Claims76, 78-79, 81, 85-86, and 90-93.
The Spec. discloses (p. 37 L20-25) the AGTR1 peptide conjugate can comprise a K residue at either the amino or carboxy terminus and that the K can be directly or indirectly liked to the modified oligont or the linker. The Spec. discloses (p. 41 L5-10) the peptide extender’s terminal K residue can be at its amino or carboxy terminus and that the K can be directly or indirectly liked to the modified oligont or the linker. Those disclosures indicate that the presence of the two peptides (AGTR1-binding sequence and peptide extender) is important but their order is not.
Claim(s) 76, 78-79, 81, 85-86, and 90-93 are rejected under 35 U.S.C. 103 as being unpatentable over WO693, Rhodes, Balakumar, WO042, and WO910 as applied to Claims 76, 78-79, 81, 85-86, and 90-93, and further in view of Biomers.net (page archived on 26 June 2018. “Peptide oligonucleotide conjugates”. Retrieved via Wayback Machine on 29 May 2025. “Biomers”).
The teachings of WO693, Rhodes, Balakumar, WO042, and WO910 as applied to Claims 76, 78-79, 81, 85-86, and 90-93 have been described in the 103 rejection above. WO693, Rhodes, Balakumar, WO042, and WO910 teach a compound comprising (a) a modified oligont and b) a conjugate group comprising a conjugate moiety (which comprises the AGTR1 binding cell-targeting peptide moiety DRVYIHPF and a peptide extender) and a conjugate linker, wherein the conjugate linker links the conjugate moiety to the oligonucleotide via the peptide extender (which WO693 calls a tether), and wherein the peptide extender comprises SEQ ID NO 31.
WO693, Rhodes, Balakumar, WO042, and WO910 do not teach the modified oligont is attached to the cell-targeting moiety or the peptide extender via click chemistry or via a maleimide linker.
However, Biomers, drawn to peptide oligont conjugates, teaches (§Peptide oligonucleotide conjugates [POC] ¶2) it is not always possible to directly synthesize peptide–oligont conjugates so oligonucleotide and peptide are first synthesized separately and then linked via reactive linkers, e.g. azide-alkyne (Click Chemistry) or thiol-maleimide.
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 compound of WO693, Rhodes, Balakumar, WO042, and WO910 with the synthesis protocol of Biomers for the benefit of using a common method to conjugate the oligont to the peptide cell-targeting moiety or the peptide extender. One would have been motivated to do so with a reasonable expectation of success because Biomers teaches direct synthesis of peptide oligonucleotide conjugates is not possible because the conventional protecting group strategies of oligonucleotide and peptide synthesis are not or only hardly compatible and teaches synthesis of separate oligont and peptide molecules via click chemistry or a maleimide linker is standard in the art. Doing so would have produced the limitations of Claims 76, 78-79, 81, 85-86, and 90-93 and the alternative limitations of Claim 81.
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 76, 78-79, 81, 85-86, and 90-93 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,8, 10, 22-26, 28, 31, 106-107, 115-116, 118-119, 122, and 129 of copending Application No. 17/998141 (reference application, “App141”, of record) in view of International Patent Application Publication Number WO 2015/179693 (published 26 November 2025, “WO693”, of record), Rhodes (et al. 2009. AGTR1 overexpression defines a subset of breast cancer and confers sensitivity to losartan, an AGTR1 antagonist. PNAS 106[35]:10284–10289, “Rhodes”, of record), and Balakumar (and Jagadeesh. 2014. Structural determinants for binding, activation, and functional selectivity of the angiotensin AT1 receptor. J. Molec. Endocrinol. 53:R71-R92, “Balakumar”, of record). This rejection is maintained/updated in view of the claim amendments.
Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to overlapping subject matter. The instant claims are directed to a compound comprising a modified oligont (that can be single- or double-stranded) and a conjugate group comprising a conjugate moiety and a conjugate linker, wherein the conjugate moiety comprises an AGTR1 binding cell-targeting moiety and a peptide extender that comprises SEQ ID NO 31, and wherein the conjugate linker links the conjugate moiety to the oligonucleotide via the peptide extender; wherein the AGTR1 binding cell targeting moiety can be a peptide moiety comprising SEQ ID NO 12 and can be attached to the oligont via a maleimide linker or click chemistry; wherein the oligo is 12-30 nt and comprises certain kinds of modification.
The copending App141 claims are directed to an oligomeric compound comprising an oligonucleotide and a conjugate group comprising a conjugate moiety, and a conjugate linker that links the conjugate moiety to the oligonucleotide, wherein the conjugate moiety comprises a cell-targeting peptide of certain sequences; wherein the compound can comprise peptide extenders comprising SEQ ID NOs 48-68 or 82.
Both claim sets are directed to oligomeric compounds comprising an oligo and a conjugate and a peptide extender. The peptide extender sequences of App141 are identical to those of the instant claims, as shown by the following exemplary sequence alignment of App141 SEQ ID NO 49 to claimed SEQ ID NO 31:
US-17-998-141-49
Filing date in PALM: 2022-11-07
Sequence 49, US/17998141
GENERAL INFORMATION
APPLICANT: Ionis Pharmaceuticals, Inc.
TITLE OF INVENTION: CONJUGATED OLIGONUCLEOTIDES AND USES THEREOF
FILE REFERENCE: CORE0153USA
CURRENT APPLICATION NUMBER: US/17/998,141
CURRENT FILING DATE: 2022-11-07
PRIOR APPLICATION NUMBER: PCT/US2021/032906
PRIOR FILING DATE: 2021-05-18
PRIOR APPLICATION NUMBER: 63/026,648
PRIOR FILING DATE: 2020-05-18
NUMBER OF SEQ ID NOS: 83
SEQ ID NO 49
LENGTH: 10
TYPE: PRT
ORGANISM: Artificial sequence
FEATURE:
OTHER INFORMATION: Synthetic peptide
FEATURE:
NAME/KEY: misc_feature
LOCATION: (1)..(1)
OTHER INFORMATION: Xaa can be any naturally occurring amino acid
ALIGNMENT:
Query Match 100.0%; Score 53; Length 10;
Best Local Similarity 100.0%;
Matches 10; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 XPPPAGSSPG 10 SEQ ID NO 31
||||||||||
Db 1 XPPPAGSSPG 10 App141 SEQ ID NO 49
Note that App141 Claim 26 specifies that the peptide extender can comprise a sequence at least 70% identical to App141 SEQ ID NO 49 which is X1PPPAGSSPG, wherein X1 is selected from lysine, 2-azido-acetyl lysine, D-lysine, L-lysine, N6-(2-azido-acetyl)-D-lysine, and N6-(2-azido-acetyl)-L-lysine. Therefore the App141 claims recite the same sequence as what is recited in amended Claim 76 as SEQ ID NO 31 wherein X is lysine, D-Lysine, L-lysine, orN6-(2-azidoacetyl)-lysine.
An artisan might not know what the peptide sequences in App141 Claim 1 are, so they’d look in the Spec. and discover (pp. 1-2) the sequences target sortilin, a membrane bound receptor protein. An artisan would realize that the concept of the App141 could be used to target oligos to a specific receptor.
The App141 claims do not recite an AGTR1 binding cell targeting moiety or the AGTR1-binding peptide sequence comprising SEQ ID NO 12.
However, Rhodes teaches (§Abstract) AGTR1 is overexpressed in 10-20% of breast cancer cases. WO693 teaches (P. 71 L10-15) oligos that comprise a cell targeting moiety and (p. 37 L1-6) oligos that target a nucleic acid encoding STAT3 and (p. 150 L1-6) using them to treat breast cancer. Balakumar teaches (Fig. 1) the peptide sequence of angiotensin II (AT) which binds AGTR1 and which comprises the sequence DRVYIHPF, as shown by this modified excerpt of Fig. 1:
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That indicates that the sequence of a peptide known to bind AGTR1 was known.
Therefore it would have been obvious to an artisan before the effective filing date of the claimed invention to modify the invention of the App141 claims with the teachings about AGTR1 being upregulated in breast cancer of Rhodes, the STAT3-targeting oligos for treating breast cancer of WO693, and the AGTR1-binding sequence, namely the AT peptide sequence, of Balakumar for the benefit of targeting the STAT3-targeting oligos for treating breast cancer to cells wherein the extracellular receptor, AGTR1, is upregulated vs noncancerous cells. One would have been motivated to do so with a reasonable expectation of success because Rhodes teaches AGTR1 is upregulated in many breast cancer cases and WO693 teaches oligos for targeting STAT3 to treat breast cancer and Balakumar teaches a peptide ligand that targets cells bearing AGTR1. It would have been a simple matter for an artisan to swap the AGTR1-targeting peptide ligand of Balakumar for the peptide conjugates comprising SEQ ID NO 3, 32, 72-75 of the App141 claims and one would have been motivated to do so because they would have wanted to deliver the oligont for treating breast cancer of WO693 to cancerous cells where AGTR1 is upregulated. Doing so would have produced the claimed invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 03 October 2025 have been fully considered but they are not persuasive. Arguments that are no longer relevant are not addressed.
112(a) Written description (WD)
Applicant’s arguments (pp. 5-10) in response to the WD rejection are not persuasive. Applicant argues that the WD does not apply because they have amended Claim 76 to recite just one species of peptide extender, namely SEQ ID NO 31. That amendment has obviated that aspect of the WD rejection. Similarly, Applicant’s arguments (pp. 6-7) that the AGTR1-binding moiety can be attached to any oligont are found persuasive and the WD over that aspect is withdrawn.
However, Applicant’s Spec. does not show possession of the full breadth of compounds encompassed by Claim 76 (i.e., any AGTR1-binding moiety that is a peptide) or that any of the compounds encompassed by Claim 78 are indeed capable of binding AGTR1. Nor have the Remarks provided any evidence to that effect. Nor has Applicant described any known AGTR1-binding motif that is shared by the compounds encompassed by Claims 76 and 78.
It is recommended that Applicant amend the claims to recite the specific AGTR1-binding moieties SEQ ID NOs 14 and 15 or provide evidence showing that (1) at time of filing, Applicant was in possession of the full breadth of AGTR1-binding compounds encompassed by Claim 76 and (2) any of the compounds encompassed by Claim 78 binds AGTR1.
103
Applicant’s arguments (pp. 12-21) are not found persuasive. Applicant argues that the 103 rejection is overcome because they have specified that the peptide extender comprises SEQ ID NO 31. They argue that WO693 doesn’t mention AGTR1 or teach SEQ ID NO 31. They argue that Rhodes does not teach SEQ ID NO 31. They argue that Balakumar doesn’t teach SEQ ID NO 31.
Those arguments are not persuasive because none of those references was used to show SQE ID NO 31 was known in the art. Those arguments are not persuasive because they do not take into account that it is routine and customary for a person of ordinary skill to synthesize teachings from multiple diverse references.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, WO693 teaches the concept of conjugating a modified oligonucleotide to a cell-targeting moiety via a peptide extender. WO693 also teaches oligonucleotides for inhibiting STAT3 to treat breast cancer. Together those teachings indicate that the general concept of the claimed invention was known and could be used to get a drug into cells to treat breast cancer. Then Rhodes teaches reasons why an artisan would have wanted to target cells expressing AGTR1 (it is commonly overexpressed in breast cancer cells) and Balakumar teaches a peptide moiety for targeting AGTR1. Together, those references would have indicated to an artisan that they could use the AGTR1-targeting moiety of Balakumar and Rhodes (namely AT/Ang II) to target WO693’s STAT3-targeting oligonucleotide to cells expressing AGTR1 to treat breast cancer.
Regarding Applicant’s arguments about SEQ ID NO 31, the 103 rejection explains that WO910 teaches a sequence comprising SEQ ID NO 31. Applicant argues that WO910 fails to remedy the deficiencies of the other references because WO910 merely discusses glucagon superfamily peptides conjugated with glucagon receptor ligands. Applicant argues that WO910 doesn’t mention oligonucleotides, that a person of ordinary skill would have had no reason to look at WO910, and that the sequence—WO910 SEQ ID NO 1170—is oriented in the opposite direction as SEQ ID NO 31.
Those arguments are not found persuasive they amount to piecemeal analysis of the references. As discussed in the ¶ above, it is routine and customary for artisans to take pieces of knowledge from different sources and synthesize them when trying to optimize a technology. An artisan would have used any peptide extender sequence and they would have been motivated to select the specific sequences in WO910 (SEQ ID NOs 1170 and 1610) because WO042 teaches using peptide linkers comprising proline residues. That teaching would have motivated them to seek out sequences with those properties. They would have used WO910’s SEQ ID NOs 1170 and 1610 because WO910 uses those sequences in figures and examples, indicating they are preferred. Applicant’s arguments that WO910 doesn’t mention oligonucleotides are incorrect because WO910 discusses (¶244-245; p. 350 items 44-45) that Q can be conjugated to various heterologous moieties including therapeutic agents or a nucleic acid.
Regarding Applicant’s arguments that the WO910 sequence in the opposite direction as claimed SEQ ID NO 31, the rejection explains that WO910 shows (¶779-780) compounds comprising the peptide and another therapeutic agent; that figure (shown above) shows the AA comprising SEQ ID NO 31 (wherein X is S, WO910’s SEQ ID NO 1610) in the same order as instantly claimed and an artisan would have known they could use any extender sequence in that orientation. The rejection further explains that WO910 teaches (¶269) compounds comprising two or more peptides bound via a linker, wherein the peptides can be attached in a tail-to-tail orientation in which the C-terminal amino acids of each monomer are attached together, which indicates the orientation of the components can vary. Those teachings of WO910 indicate it is acceptable to join an extension sequence to a peptide targeting moiety in variable orientations, including C-terminus to C-terminus. The rejection explains that the instant claims do not specify whether the peptide extender is attached to the N- or C-terminus of the AGTR1 moiety. Attaching WO910’s SEQ ID NO 1170 to Balakumar’s AGTR1-binding moiety via the C-terminus of each (which WO910 teaches at (¶269) would have produced a moiety wherein claimed SEQ ID NO 12 is attached to claimed SEQ ID NO 31 as follows: DRVYIHPF-KPPPAGSSPG. The rejection discusses that WO042 teaches proline’s cyclic side chain results in inflexibility which can keep the things connected via the linker appropriately separated.
Applicant has not argued that the orientation of SEQ ID NO 31 has any bearing on its function and there is nothing in the art to indicate that the orientation of an extender peptide does affect its ability to separate two things. Teachings of WO910 indicate that its orientation doesn’t matter—that is why peptide sequences can be arranged C-terminus to C-terminus if desired. WO910 SEQ ID NO 1170 is the same peptide sequence as SEQ ID NO 31, merely in the opposite order. Since each sequence is merely an extender sequence, all it has to do is extend, and Applicant hasn’t discussed or shown any evidence that the orientation of SEQ ID NO 31 matters for that purpose. Since no evidence has been presented demonstrating otherwise, SEQ ID NO 31 is deemed an obvious variant of WO910 SEQ ID NO 1170 and considered to have the same extending/separating function. Altogether, while Applicant argues (p. 19) WO910 doesn’t teach SEQ ID NO 31, they have not discussed any reasons why that sequence performs an extender function any differently from WO910 SEQ ID NO 1170. Note, SEQ ID NO 31 and WO910 are not proteins comprising secondary or higher level structure. They are a short peptide—a 10-AA extender sequence whose only function is to separate a cell-targeting moiety from another agent.
Regarding Applicant’s arguments about Biomers, those arguments, which focus on the asserted novelty of SEQ ID NO 31, are not persuasive because the arguments about WO693, Rhodes, Balakumar, WO042, and WO901 are not persuasive. Regarding Applicant’s arguments about CN169, those are not persuasive because the reference is no longer relied upon.
Applicant is recommended to show why SEQ ID NO 31’s orientation matters.
NSDP
Applicant’s arguments (pp. 21-22) are not persuasive because App141’s Claim 26 recites SEQ ID No 49 which is identical to claimed SEQ ID NO 31. Applicant’s arguments that App141 is later filed is also not persuasive because (1) the claimed invention is not ready to allow and (2) the Non-final Office Action explained that (§Priority) SEQ ID NO 31 is not disclosed in the instant application’s priority documents (PRO dated 17 May 2019) and was found only in the PCT filed a year and a day later. That means that App141 and the claimed content have the same effective filing date: 18 May 2020. Applicant was asked to explain where in the PRO document peptide sequences other than SEQ ID NOs 11-12 are located, but that information was not provided.
Note that unless the content in question is shown to be in the PRO document, the content of both applications have the same effective filing date, a terminal disclaimer is the only way to overcome this rejection:
(ii) Application under examination has the same patent term filing date
If both the application under examination and the reference application have the same patent term filing date, the provisional nonstatutory double patenting rejection made in each application should be maintained until it is overcome. Provisional nonstatutory double patenting rejections are subject to the requirements of 37 CFR 1.111(b). Thus, applicant can overcome a provisional nonstatutory double patenting rejection by filing a reply that either shows that the claims subject to the rejection are patentably distinct from the claims of the reference application, or includes a compliant terminal disclaimer under 37 CFR 1.321 that obviates the rejection. If the reply is sufficient, the examiner will withdraw the nonstatutory double patenting rejection in the application in which it was submitted.
MPEP 804(I)(B)(1)(b)(i)
Therefore the NSDP rejection must be maintained.
Conclusion
No claim is allowed.
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 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