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 1-6, 10-11, and 17-26 are pending.
Election/Restrictions
Applicant has canceled Claims 8-9 and 15-16. Applicant has added Claims 23-26.
Applicant’s election without traverse of Invention Group I (drawn to a composition) and the species SEQ ID NOs 1840/13973 (sense strand) and 3694/13981 (AS strand) in the reply filed on 24 July 2026 is acknowledged.
Claims 20-22 and 24-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 24 July 2026.
Claims 1-6, 10-11, 17-19, and 23 are examined.
Information Disclosure Statement
The IDS(es) has been considered.
Claim Interpretation
Claims 1-6, 10-11, and 17-26 recite an oligont that targets ANGPTL4 is interpreted as requiring at least some amount of inhibitory activity. That interpretation is based on the fact that the claims recite a small interfering RNA (siRNA) which is known to inhibit gene expression and because the Spec. (¶4, ¶13) teaches the invention includes reducing ANGPTL4 protein or mRNA.
The claims are composition claims, so all claim text that recites outcomes (e.g., when administered to a subject in an effective amount decreases circulating triglycerides, decreases circulating glucose, decreases a liver steatosis measurement, increases circulating high-density lipoproteins [HDL], or increases insulin sensitivity [Claims 1-2 and 23]; wherein the increase or decrease is by about 10% or more, as compared to prior to administration [Claim 3]; when administered to a subject in an effective amount decreases a liver steatosis measurement in the subject [Claim 4]; and wherein the decrease is by about 10% or more, as compared to prior to administration [Claim 5]) are interpreted as intended uses that don’t change the structure of the composition and, therefore, do not carry any patentable weight.
Claim 11 recites an optional limitation. Any optional limitation is interpreted as purely optional and not required.
Some claims recite “about 10% or more”. The Spec. defines “about” at ¶282: the term "about" a number refers to that number plus or minus 10% of that number. The term "about" a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.
Claim Objections
Claims 1 and 6 are objected to because of the following informalities:
Claim 1 will be better if “…wherein the oligont comprises a small interfering RNA…” is moved onto the next line so the formatting reflects “…wherein the sense strand comprises modification pattern…”.
Claim 6 will be better if “…the antisense strand comprises modification pattern…” is indented so the formatting reflects “…the sense strand comprises modification pattern…”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6, 10-11, and 17-19 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 (WD) rejection.
Claims 1-2 and 4 recite a composition comprising an oligonucleotide (oligont) that targets ANGPTL4. As explained above in §Claim interpretation, the recitation an oligont that targets ANGPTL4 is interpreted as requiring at least some amount of inhibitory activity. That interpretation is based on the fact that the claims recite a small interfering RNA (siRNA) which is known to inhibit gene expression and because the Spec. (¶4, ¶13) teaches the invention includes reducing ANGPTL4 protein or mRNA.
The broad claims encompass the large genus of oligont that target ANGPTL4 that result in the outcome of inhibiting ANGPTL4 expression. Any kind of oligont that targets ANGPTL4 would be encompassed by the claims as instantly presented.
There is a WD problem because the claims encompass the broad genus of oligont molecules defined solely by their function of targeting (i.e., inhibiting) ANGPTL4 expression but the Spec. doesn’t disclose the oligont structure that is responsible for the inhibiting function. The Spec. doesn’t demonstrate that Applicant was in possession of any oligont that targets and inhibits ANGPTL4. Furthermore, results in the Spec. demonstrate that some of the oligont encompassed by the claims cannot meet the required function of targeting (i.e., inhibiting) ANGPTL4 and that highlights the failure to disclose the oligont structure that is responsible for the inhibiting function.
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. describes that (¶13) the claimed compositions target ANGPLT4 and describes (¶23-97) features of the oligont. The Spec. discloses (§ starting at ¶285 and continuing through p. 221) a huge number of dsRNAs. However, the Spec. also discloses (Table 5 starts after ¶320) that some of the dsRNAs do not possess the function of inhibiting ANGPTL4. For example, ETD00650 doubles the amount of ANGPTL4 mRNA and ETD00659 leaves the level of ANGPTL4 RNA essentially unchanged. That is shown in this modified excerpt of the table:
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327
838
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Greyscale
That indicates that any oligont designed to bind to ANGPTL4 does not necessarily inhibit ANGPTL4 expression.
Regarding what structure is encompassed by the oligont that targets (i.e., inhibits) ANGPTL4, the Spec. does not provide information describing its features. The Spec. does not disclose what physical structure responsible for the claimed function.
Applicant’s examples show a great number of oligont sequences designed to bind ANGPTL4. Those examples show that some of the oligont sequences target (i.e., inhibit) ANGPTL4. However, those examples are not sufficient to provide written description support for any oligont that targets (i.e., inhibits) ANGPTL4. Although the claims claim the functional characteristics (i.e., an oligont that targets ANGPTL4), the functional characteristic is not coupled with any known structure.
Although the Specification teaches the examples discussed above, it does not identify a core structure necessary for performing the claimed function(s) of targeting (i.e., inhibiting) ANGPTL4. The Spec. does not disclose any core structure, partial structure, physical or chemical property, or functional characteristic coupled with a known or disclosed structure/function relationship responsible for targeting (i.e., inhibiting) ANGPTL4 in such a way to demonstrate possession of the full invention as claimed at time of filing. The oligont shown in Table 1.2 do not share a core structure because each oligont has a different sequence.
The specification teaches only some species within the claimed genus/genera (i.e., some oligont shown in Table 5) but those are only a paltry number compared with the breadth of what is claimed and furthermore, the Spec. doesn’t disclose what nt structure is responsible for the inhibition. Altogether, the number of species disclosed by complete structure is not sufficient to provide the written description support for the huge genera and subgenera that are encompassed by the claims. In addition, the siRNAs shown in Table 5 are not clearly tied to any SEQ ID NO so an artisan wouldn’t know which EDT # corresponds to which SEQ ID NO(s).
While none of these elements is specifically required to demonstrate possession, in combination their absence means that one skilled in the art at the time of filing would conclude that the inventors lacked possession of the full breadth of the invention claimed. Claims 1-2 and 4 are rejected for failing to demonstrate possession of the claimed invention. Claims 3-6, 10-11, and 17-19 are rejected because they depend from Claim(s) 1-2 and/or 4 and do not remedy the issues.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4-6, 10-11, and 17-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1, 6, and 17-19 are indefinite for being “incomplete in itself”. It is noted that the terms 1S-16S and 1AS-15AS are abbreviations that merely represent modification patterns, and there is no reason, other than inconvenience, that the corresponding modification patterns themselves cannot be recited in the claims. See MPEP 2173.05(s):
Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant' s convenience.”
Claims 1, 6, and 17-19 are rejected for those reasons. Claims 4-6, 10-11, and 17-19 are rejected because they depend from Claim 1 and don’t remedy the issues. In the interest of compact prosecution, the terms are interpreted as they are defined in Spec. ¶167-168.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 3-6 and 18-19 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 3-5 fail to further limit the scope of the claim(s) from which they depend (Claims 2, 1, and 4) because Claims 3-5 limit the intended use which, as explained above in §Claim interpretation, do not change the structure of the composition and do not add any patentable weight.
Claims 6 and 18-19 do not include all the limitations of the claim from which they depend (Claim 1) because Claim 1 recites that the AS modification pattern must be one of 10AS-15AS and the sense strand modification pattern must be one of 7S-16S, but Claim 6 recites that the AS modification pattern can be 1AS-15AS and the sense strand mod pattern can be 1S-14S. Therefore Claim 6 is broader than Claim 1. Similarly, Claims 18 and 19 allow the AS mod pattern 6AS and are broader than Claim 1 for those reasons.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Note about Citations to Page and Paragraph Number
The following style is used for citations to page and paragraph number (including for documents that don’t have ¶ or line #s): p. # refers to PDF p. #. ¶1 refers to the first complete ¶ on a page. ¶0 refers to a partial ¶ that is the first ¶ on a page.
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.
Claim(s) 1-6, 10, and 17-19 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by International Publication Number WO 2021/178725 (published 10 September 2021 but effectively filed on at least 04 March 2021, “WO725”).
Although WO725 was published 10 September 2021, the content relied upon for this rejection was effectively filed in 04 March 2021, which is at least 3 months before the earliest provisional document of the instant application.
The WO725 content discussed in this rejection are entitled to the priority date of at least 04 March 2021 and are considered prior art under 35 U.S.C. 102(a)(2).
If the issue date of the U.S. patent or publication date of the U.S. patent application publication or WIPO published application is not before the effective filing date of the claimed invention, it may be applicable as prior art under AIA 35 U.S.C. 102(a)(2) if it was "effectively filed" before the effective filing date of the claimed invention in question with respect to the subject matter relied upon to reject the claim. MPEP § 2152.01 discusses the "effective filing date" of a claimed invention. AIA 35 U.S.C. 102(d) sets forth the criteria to determine when subject matter described in a U.S. patent document was "effectively filed" for purposes of AIA 35 U.S.C. 102(a)(2).
2154.01(a) WIPO Published Applications [R-11.2013]
[Editor Note: This MPEP section is only applicable to applications subject to examination under the first inventor to file (FITF) provisions of the AIA as set forth in 35 U.S.C. 100 (note). See MPEP § 2159 et seq. to determine whether an application is subject to examination under the FITF provisions, and MPEP § 2131-MPEP § 2138 for examination of applications subject to pre-AIA 35 U.S.C. 102.]
The WIPO publication of a PCT international application that designates the United States is an application for patent deemed published under 35 U.S.C. 122(b) for purposes of AIA 35 U.S.C. 102(a)(2) under 35 U.S.C. 374. Thus, under the AIA , WIPO publications of PCT applications that designate the United States are treated as U.S. patent application publications for prior art purposes, regardless of the international filing date, whether they are published in English, or whether the PCT international application enters the national stage in the United States. Accordingly, a U.S. patent, a U.S. patent application publication, or a WIPO published application that names another inventor and was effectively filed before the effective filing date of the claimed invention, is prior art under AIA 35 U.S.C. 102(a)(2). This differs from the treatment of a WIPO published application under pre-AIA 35 U.S.C. 102(e), where a WIPO published application is treated as a U.S. patent application publication only if the PCT application was filed on or after November 29, 2000, designated the United States, and is published under PCT Article 21(2) in the English language. See MPEP § 2136.03, subsection II.
§MPEP 2154.01
See also §MPEP 2152.01.
Regarding Claims 1-6 and 17-19: WO275 teaches (§Abstract) therapeutic agents, including (¶7, ¶305) dsRNAs, for modifying expression of a target gene, including (¶16) ANGPTL4. WO275 teaches (¶9, ¶170-171) the nucleic acids of their invention can comprise chemical modifications 2’-fluoro (2’-F) and 2’-O-methyl (2’-OMe) and phosphorothioate (PS) linkages. Further regarding modification patterns, WO275 teaches (¶174, ¶200) any part of their nonlimiting, exemplary modification patterns can be applied to any RNA sequence and (¶52) any nucleic acids, including siRNA, can comprise any known nucleotide analog or modified backbone residues or linkages.
WO275 teaches (¶14, ¶21) the compositions can be used to reduce target gene expression by at least 99.99%, treat familial hypercholesterolemia and cardiovascular disease, and reduce blood triglycerides.
Therefore, WO275 teachings encompass any nt sequence that targets ANGPTL4 which comprise(s) any combination of chemical modifications and linkages. That encompasses any of the claimed modification patterns. Therefore WO275 anticipates Claims 1-6 and 17-19.
Regarding Claim 10: WO275 teaches (¶189) the nucleic acids can comprise a GalNAc attached at the 3’end. Therefore, WO275 anticipates Claim 10.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-6, 10, and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2020/099478 (published 22 May 2020, “WO478”, of record), Sledz (and Williams. 2005. RNA interference in biology and disease. Blood 106[3]:787, “Sledz”, of record), and Foster (et al. 2018. Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates. Molec. Ther. 23[6]:708, “Foster”, of record).
WO478 teaches (§Abstract) single-stranded antisense oligont that target ANGPTL4 and (p. 6 L5-15) can be used to treat hypertriglyceridemia. WO478 teaches (p. 14 L1-5) their ASO can comprise 12-22 or 19, 20, or 21 nt. WO478 teaches (p. 5 L19-30) the ASO can comprise modified nucleotides (nt) including 2’-OMe and 2’-F. WO478 teaches (p. 14 L10-20) the oligont can comprise a modified phosphate backbone, including PS linkages. WO478 teaches (p. 4 L9-27) inhibition of ANGPTL4 (by knockout in mice) reduces triglyceride levels and inhibiting expression of ANGPTL4 reduces plasma lipid levels and can be used to treat familial cholesterolemia.
WO478 shows (Figs. 1-4, 7-8, 12-15, 17-18) their ASOs inhibit ANGPTL4 expression.
Sledz teaches (§Introduction ¶1) double-stranded interfering RNA (dsRNA) are more potent than single-stranded interfering RNA. Sledz teaches (§Stable RNA interference ¶1-2, Figs. 1-2) dsRNA comprise complementary strands that (§Introduction ¶1-2, §Mechanisms of RNA interference, §Stable RNA interference) can be 19-23 nt or around 22 nt long.
Foster teaches (§Abstract, §Introduction ¶1-5, §Results ¶1-3, §Discussion ¶1) altering the proportion of 2'-F and 2'-OMe within a dsRNA was known in the art for the benefit of optimizing stability and silencing activity.
Foster, drawn to siRNA designs to further improve in vivo performance of siRNA, teaches (§Abstract) refining the proportion of 2’-F and 2'-OMe ribosugar modifications across both strands of the dsRNA can enhance stability without compromising activity. Foster teaches advanced siRNA designs for further improving performance of GalNAc-siRNA conjugates. Foster teaches (§Abstract) further improving siRNA efficacy by optimizing positioning of 2’-F and 2'-OMe ribosugar modifications in a dsRNA. Foster used iterative modification changes to improve potency and duration of siRNA. Foster teaches (§Introduction ¶2) their GalNAc-siRNA conjugates comprise 2’-F and 2'-OMe sugar modifications throughout both strands and terminal PS linkages that provide protection against nucleases. Foster teaches (§Introduction ¶3) dsRNA modifications must balance bulk (caused by bulky 2'-OMes) with activity; 2' Fs are less bulky so they are used to optimize the balance. Foster used (§Introduction, final ¶, §Results ¶1-2) in silico modeling to identify an initial group of 2'-F/2'-OMe modified dsRNAs and followed that with in vitro tests and further tweaks.
Foster teaches (§Introduction ¶4) 2’-F and 2'-OMe modifications should be balanced within a dsRNA to produce the compound(s) with best performance:
It is well known in the field that modifying the position of RNA can significantly enhance the nuclease stability of oligonucleotides and that sterically more demanding modifications, such as 2'-OMe, can have a greater stabilizing effect compared to less bulky modifications, such as 2-F. If not applied judiciously, however, the steric bulk introduced by such modifications can substantially reduce RNAi activity.
Foster teaches (§Introduction ¶4-5) dsRNA comprising 2'-F are well-tolerated while 2'-OMe has better stabilizing effects but is bulkier and can reduce RNAi activity. Foster suggests (same §) refining, analyzing, and further refining dsRNA to improve dsRNA potency and duration. Foster teaches (§Results ¶3) placing 2'-F at positions 2, 6, and 14 of the AS strand. Foster further teaches (§Discussion ¶1) their studies show that relatively small changes in design can have a large impact on metabolic stability, thereby affecting the in vivo performance of the siRNA conjugates, (¶2) the modification patterns on the strands have to be considered in context of each other, and (¶4) in vivo performance can be enhanced without sacrificing activity by optimizing the 2'-F/2'-OMe modification pattern, specifically by including a greater than 50% reduction in 2'-F content (vs. a parent strand; see Fig. 1) and concomitant increase in 2'-OMe content.
The sum teachings of Foster indicate that it is routine and conventional in the art of dsRNA design to change the proportion of 2’-F and 2'-OMe modifications in the strands of a dsRNA to find the proportion that works best for a chosen purpose.
KSR' s “obvious to try” rationale for supporting conclusion of obviousness requires the following three findings: (1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem; (2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem; (3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
Foster teaches that altering the proportion of 2’-F and 2'-OMe within a dsRNA was known in the art for the benefit of optimizing stability and silencing activity.
Regarding Claim 10: Foster teaches (§Introduction ¶1) GalNAc ligand binds with high affinity to hepatocytes and represents a promising approach for safe and effective targeted delivery of RNAi therapeutics to hepatocytes in vivo. Foster teaches (§Materials and Methods-siRNA Synthesis) the GalNAc ligand was introduced at the 3’end of the sense strand.
It would have been obvious to an artisan before the effective filing date of the claimed invention to modify the ANGPTL4-targeting ASO (and which comprise PS linkages in their backbone) of WO478 with the teachings that double stranded RNA are more potent than single-stranded ASO of Sledz and teachings about optimizing proportions of 2’-OMe and 2’-F modifications within an dsRNA to optimize in vivo performance of Foster for the benefit of producing an ANGPTL4-targeting dsRNA with improved nuclease stability. One would have been motivated to do so with a reasonable expectation of success because WO478 teaches modifying a backbone with PS linkages and Foster teaches (§Introduction ¶4) 2'-F and 2'-OMe modifications should be balanced within a dsRNA to produce the compound(s) with best performance. An artisan would have known from teachings in the cited art that (Sledz) dsRNA comprise complementary strands that (WO478) can be various lengths including 19-, 20-, or 21-mer.
Therefore, the limitations of Claims 1-6, 10, and 17-19 would have been obvious in view of WO478, Sledz, and Foster.
Claim(s) 1-6, 10, and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over WO478, Sledz, and Foster, as applied to Claims 1-6, 10, and 17-19 in the 103 rejection above, and further in view of International Publication Number WO 2020/160163 (published 06 August 2020, “WO163”).
The teachings of WO478, Sledz, and Foster as applicable to Claim(s) 1-6, 10, and 17-19 have been described above.
WO478, Sledz, and Foster teach ANGPTL4-targeting dsRNA that reduce triglyceride levels and can be used to treat familial cholesterolemia. WO478, Sledz, and Foster teach the dsRNA can comprise a GalNAc. WO478, Sledz, and Foster make obvious any of the claimed modification patterns, including a backbone comprising PS linkages.
As discussed above, WO478 teaches (p. 14 L1-5) their ASO can comprise 12-22 or 19, 20, or 21 nt. A person of ordinary skill in the art would have readily recognized that a dsRNA comprising strands on the longer side of that, e.g., 21-mer, would be more target-specific compared to dsRNA comprising strands with shorter lengths. Furthermore, Sledz teaches (§Mechanisms of RNA interference ¶2) dsRNA comprising 21 nt.
WO478, Sledz, and Foster make obvious but do not explicitly teach the exact pattern of PS and phosphodiester (PO) linkages in the claimed sense strand and AS strand modification patterns.
However, WO163 explicitly teaches the claimed PS/PO mod pattern. WO163 is drawn to oligont compounds for targeting another gene that is not ANGPTL4. However, the teachings of WO163 are relevant to and could have been applied to any oligont. WO163 teaches (p. 73 L20-25) RNAi compounds that can be double-stranded RNA (dsRNA).
WO163 teaches (p. 14 L30-34) embodiments wherein any inter-nt linkage is selected from PO and PS. WO163 teaches (p. 40 L16-32) benefits of PS linkages: they increase resistance to nucleases. WO163 teaches (p. 43 L5-p. 47 L14) oligont can comprise various modification motifs and inter-nt linkage motifs. WO163 teaches (p. 81 L22-25) the specific linkage motif (from 5’ to 3’) of: ssooooooooooooooooss; wherein ‘o’ represents a phosphodiester internucleoside linkage and ‘s’ represents a phosphorothioate internucleoside linkage. That is the exact PS/PO linkage motif referenced in the instant claims (it is the same linkage motif as at least 8S and 6AS).
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 dsRNAs for targeting ANGPTL4 of WO478, Sledz, and Foster with the PS/PO linkage motifs of WO163 for the benefit of increasing nuclease resistance using a known PS/PO linkage motif. One would have been motivated to do so with a reasonable expectation of success because WO478 teaches dsRNA that can comprise PS linkages and because WO163 teaches PS linkages improve nuclease resistance. WO163 also teaches specific linkage motifs for 21-mer nt. An artisan would have applied those linkage motifs to both the sense and AS strands that would have been obvious in view of WO478, Sledz, and Foster. Furthermore, it should be noted that WO163 teaches (p. 14 L30-34) embodiments wherein any inter-nt linkage is selected from PO and PS. That indicates it was routine and conventional to apply any PS/PO linkage motif comprising any combination of PS and PO linkages to the strands of a dsRNA. Therefore, it would have been obvious to try applying any combination of PS/PO linkages to any ANGPTL4-targeting dsRNA. Therefore, the limitations of Claims 1-6, 10, and 17-19 would have been obvious in view of WO478, Sledz, Foster, and WO163.
Claim(s) 1-6, 10-11, and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over WO478, Sledz, Foster, and WO163 as applied to Claims 1-6, 10, and 17-19 in the 103 rejection above, and further in view of International Publication Number WO 2018/183395 (published 04 October 2018, “WO395”).
The teachings of WO478, Sledz, Foster, and WO163 as applicable to Claim(s) 1-6, 10, and 17-19 have been described above.
WO478, Sledz, Foster, and WO163 make obvious ANGPTL4-targeting dsRNA comprising modification patterns that combine 2’-OMe, 2’-F, and PS linkages (as well as natural PO linkages which are not a modification) and wherein a GalNAc moiety is attached at the 3’end of the sense strand.
WO478, Sledz, Foster, and WO163 make obvious but do not explicitly teach dsRNA wherein all purines comprise either 2’-F mods or 2’-OMe mods while all pyrimidines comprise either 2’-OMe mods or 2’-F mods, and wherein the purines and the pyrimidines comprise different mods. WO478, Sledz, Foster, and WO163 do not explicitly teach dsRNA wherein all purines comprise either 2’-F mods or 2’-OMe mods while all pyrimidines comprise a mixture of 2’-OMe mods and 2’-F mods, or dsRNA wherein all pyrimidines comprise either 2’-F mods or 2’-OMe mods while all purines comprise a mixture of 2’-OMe mods and 2’-F mods (i.e., Claim 2).
However, WO395, drawn to (§Abstract) oligont probes that (¶57) can be used for therapeutic purposes, including (Table on p. 100, towards bottom left of page) to target ANGPTL4, teaches it was routine and conventional to apply such modification patterns to RNA compounds.
WO395 teaches (¶341) their oligonucleotide can be modified to incorporate a wide variety of modified nucleotides, and that:
The modifications can be the same or different. Some or all nucleotides may be modified, and those that are modified may contain the same modification. For example… All purine nucleotides may have one type of modification (or are unmodified), while all pyrimidine nucleotides have another, different type of modification (or are unmodified). Thus, the construct may comprise any combination of desired modifications, including for example, ribonucleotides (2’-OH)… 2’-fluoro nucleotides (2’-F) and 2’-O-methyl (2’-OMe) nucleotides.
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 ANGPTL4-targeting dsRNA of WO478, Sledz, Foster, and WO163 with WO395’s teachings about placing 2’-F or 2’-OMe mods on solely purines and pyrimidines (and other combinations) for the benefit of optimizing modification patterns. One would have been motivated to do so with a reasonable expectation of success because both Foster and WO395 indicate doing so was routine and conventional. Therefore, the limitations of Claim 2 (and Claims 1-6, 10, and 17-19) would have been obvious in view of WO478, Sledz, Foster, WO163, and WO395.
Claim(s) 1-6, 10-11, and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over WO478, Sledz, Foster, and WO163 as applied to Claims 1-6, 10, and 17-19 in the 103 rejection above, and further in view of International Publication Number WO 2018/044350 (published 08 March 2018, “WO350”), US Patent Application Publication No. 2013/0052130 (published 28 February 2013, “App130”) and Gaziova (et al. 2014. Chemically defined polyethylene glycol siRNA conjugates with enhanced gene silencing effect. Bioorg. Med. Chem. 22:2320–2326, “Gaziova”) as evidenced by US Patent Application Publication No. US 2016/0123988 (published 05 May 2016, “App988”).
The teachings of WO478, Sledz, Foster, and WO163 as applicable to Claim(s) 1-6, 10, and 17-19 have been described above.
WO478, Sledz, Foster, and WO163 make obvious ANGPTL4-targeting dsRNA comprising modification patterns that combine 2’-OMe, 2’-F, and PS linkages (as well as natural PO linkages which are not a modification) and wherein a GalNAc moiety is attached at the 3’end of the sense strand.
WO478, Sledz, Foster, and WO163 do not teach the specific GalNAc moiety shown in Claim 11.
However, that GalNAc moiety would have been obvious in view of the prior art.
WO350, drawn to (§Abstract) targeting ligands for RNAi agents, teaches (p. 3 L14-20) their targeting ligands enhance delivery of therapeutic compounds. WO350 teaches (p. 38 L1-5, p. 53 L1-10) PEG used in their invention can comprise 1-10 ethylene glycol units. WO350 discloses the following targeting moiety which, aside from the absence of a PEG linker, is identical to the claimed GalNAc:
PNG
media_image2.png
1
1
media_image2.png
Greyscale
PNG
media_image3.png
542
841
media_image3.png
Greyscale
App130, drawn to (§Abstract) PEG chains useful in attaching to a variety of biologically active groups, teaches (¶77) their invention can be used with nucleic acids. App130 teaches (p. 184) the following structure that comprises a PEG linker (which happens to be part of the GalNAc shown in Claim 11):
PNG
media_image4.png
287
663
media_image4.png
Greyscale
Although App130’s linker comprises 12 PEG units, an artisan would have understood that the PEG chain could be shortened.
Evidence from App988 demonstrates (p. 25, top right) such shorter PEG chain was known in the art:
PNG
media_image5.png
65
234
media_image5.png
Greyscale
Gaziova teaches it is routine and conventional in the art of dsRNA delivery to use PEG-siRNA conjugates and that (§3. Discussion ¶5) shorter PEG is better tolerated than longer, heavier PEG.
Altogether, those teachings indicate that there were many species of GalNAc and PEG linker and that it was routine and conventional to combine and modify those different elements to optimize delivery and efficacy of a biomolecule.
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 ANGPTL4-targeting dsRNA of WO478, Sledz, Foster, and WO163 with the GalNAc of WO350, the PEG linker of App130, and teachings of Gaziova for the benefit of optimizing the GalNAc attached to the dsRNA. One would have been motivated to do so with a reasonable expectation of success because using any one particular GalNAc species and any one particular PEG linker to use in a dsRNA is merely a design choice. Furthermore, WO350, App130, and Gaziova indicate that there were many options available and it was routine and conventional in the art of oligont delivery to modify known elements to optimize efficacy. Additionally, Gaziova teaches (§3. Discussion ¶5) shorter PEG is better tolerated than longer, heavier PEG, which would have motivated the artisan to shorten the linker length of App130’s PEG linker. Evidence from App988 demonstrates the shorter structure was known in the art. Therefore, the GalNAc of Claim 11 would have been obvious in view of WO478, Sledz, Foster, WO163, WO350, App130, and Gaziova.
Claim(s) 1-6, 10, 17-19, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over WO478, Sledz, and Foster, as applied to Claims 1-6, 10, and 17-19 in the 103 rejection above, and further in view of International Publication Number WO 2018/002719 (published 04 January 2018, “WO719”, of record on IDS).
The teachings of WO478, Sledz, and Foster as applicable to Claim(s) 1-6, 10, and 17-19 have been described above.
WO478, Sledz, and Foster teach ANGPTL4-targeting dsRNA that reduce triglyceride levels and can be used to treat familial cholesterolemia. WO478, Sledz, and Foster teach the dsRNA can comprise a GalNAc. WO478, Sledz, and Foster make obvious any of the claimed modification patterns.
WO478, Sledz, and Foster make obvious a dsRNA comprising strands that have lengths of 19-, 20-, or 21-mer.
WO478, Sledz, and Foster do not explicitly teach a dsRNA wherein the sense strand comprises a nt sequence comprising claimed SEQ ID NO 13973 and the antisense (AS) strand comprises a nt sequence comprising claimed SEQ ID NO 13981 (i.e., Claim 23).
However, WO719, drawn to compositions and methods for gene editing, teaches (¶43-44) a guideRNA comprising SEQ ID NO 18330, which comprises a sequence having 100% identity to claimed SEQ ID NO 13973, as shown by the following alignment:
BET25048
ID BET25048 standard; DNA; 20 BP.
XX
AC BET25048;
XX
DT 22-FEB-2018 (first entry)
XX
DE ANGPTL4 gene editing gRNA spacer, SEQ ID:18330.
XX
KW CRISPR-Cas9 system; adenocarcinoma; antiarteriosclerotic; antiarthritic;
KW antiinflammatory; arteriosclerosis; cardiovascular disease;
KW cardiovascular-gen.; cytostatic; gRNA; genetic-disease-gen.;
KW genome editing; growth-disorder-gen.; guide RNA; immunosuppressive;
KW ischemia; motor neurone disease; neuroleptic; neuroprotective;
KW ophthalmological; retinitis pigmentosa; rheumatoid arthritis;
KW schizophrenia; spacer; ss; therapeutic; vasotropic.
XX
OS Synthetic.
XX
CC PN WO2018002719-A1.
XX
CC PD 04-JAN-2018.
XX
CC PF 29-JUN-2017; 2017WO-IB000953.
XX
PR 29-JUN-2016; 2016US-0355907P.
PR 22-FEB-2017; 2017US-0461831P.
XX
CC PA (CRIS-) CRISPR THERAPEUTICS AG.
XX
CC PI Lundberg AS, Kulkarni S, Klein L, Padmanabhan HK;
XX
DR WPI; 2018-01203W/08.
XX
CC PT Editing an Angiopoietin-like 4 (ANGPTL4) gene comprises introducing, into
CC PT the cell, the DNA endonucleases to effect single-strand breaks or double-
CC PT strand breaks within or near the ANGPTL4 gene or ANGPTL4 regulatory
CC PT elements.
XX
CC PS Claim 32; SEQ ID NO 18330; 133pp; English.
XX
CC The present invention relates to a method of editing an Angiopoietin-like
CC 4 (ANGPTL4) gene in a cell using genome editing, such as a CRISPR/Cas
CC system. The method comprises introducing into the cell one or more DNA
CC endonucleases to effect single-strand breaks or double-strand breaks
CC within or near the ANGPTL4 gene or ANGPTL4 regulatory elements resulting
CC in permanent insertions, deletions or mutations of a nucleotide within or
CC near the ANGPTL4 gene, and so reducing or eliminating the expression or
CC function of ANGPTL4 gene products. Also described: (1) an ex vivo or in
CC vivo method for treating a patient having an ANGPTL4 related condition or
CC disorder; (2) altering the contiguous genomic sequence of an ANGPTL4 gene
CC in a cell by contacting the cell with a DNA endonuclease; (3) a single-
CC molecule guide RNA (sgRNA) comprising a spacer sequence that is an RNA
CC sequence corresponding to any of SEQ ID NO:5305-19006 (BET12023-BET25724)
CC ; (4) a DNA encoding the sgRNA of (3); and (5) a vector comprising the
CC DNA of (4). The methods are used for editing an ANGPTL4 gene in a cell;
CC treating a patient having an ANGPTL4 related condition or disorder; and
CC altering the contiguous genomic sequence of an ANGPTL4 gene in a cell.
CC The ANGPTL4 related condition or disorder includes adenocarcinoma,
CC amyotrophic lateral sclerosis, arteriosclerosis, rheumatoid arthritis,
CC cardiovascular diseases, ischemia, schizophrenia, renal glomerular
CC disease and retinitis pigmentosa.
XX
SQ Sequence 20 BP; 9 A; 2 C; 4 G; 5 T; 0 U; 0 Other;
Query Match 100.0%; Score 19; Length 20;
Best Local Similarity 73.7%;
Matches 14; Conservative 5; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CAGAGUUCUUGGAAUAAAA 19 SEQ ID NO 13973
|||||::|::||||:||||
Db 2 CAGAGTTCTTGGAATAAAA 20 WO719 SEQ ID NO 18330
WO719 further teaches a guideRNA comprising SEQ ID NO 9113 (and also SEQ ID NO 15444), which comprises a sequence having 100% identity to claimed SEQ ID NO 13981, as shown by the following alignment:
BET15831
(NOTE: this sequence has 2 duplicates in the database searched)
ID BET15831 standard; DNA; 20 BP.
XX
AC BET15831;
XX
DT 22-FEB-2018 (first entry)
XX
DE ANGPTL4 gene editing gRNA spacer, SEQ ID:9113.
XX
KW CRISPR-Cas9 system; adenocarcinoma; antiarteriosclerotic; antiarthritic;
KW antiinflammatory; arteriosclerosis; cardiovascular disease;
KW cardiovascular-gen.; cytostatic; gRNA; genetic-disease-gen.;
KW genome editing; growth-disorder-gen.; guide RNA; immunosuppressive;
KW ischemia; motor neurone disease; neuroleptic; neuroprotective;
KW ophthalmological; retinitis pigmentosa; rheumatoid arthritis;
KW schizophrenia; spacer; ss; therapeutic; vasotropic.
XX
OS Synthetic.
XX
CC PN WO2018002719-A1.
XX
CC PD 04-JAN-2018.
XX
CC PF 29-JUN-2017; 2017WO-IB000953.
XX
PR 29-JUN-2016; 2016US-0355907P.
PR 22-FEB-2017; 2017US-0461831P.
XX
CC PA (CRIS-) CRISPR THERAPEUTICS AG.
XX
CC PI Lundberg AS, Kulkarni S, Klein L, Padmanabhan HK;
XX
DR WPI; 2018-01203W/08.
XX
CC PT Editing an Angiopoietin-like 4 (ANGPTL4) gene comprises introducing, into
CC PT the cell, the DNA endonucleases to effect single-strand breaks or double-
CC PT strand breaks within or near the ANGPTL4 gene or ANGPTL4 regulatory
CC PT elements.
XX
CC PS Claim 32; SEQ ID NO 9113; 133pp; English.
XX
CC The present invention relates to a method of editing an Angiopoietin-like
CC 4 (ANGPTL4) gene in a cell using genome editing, such as a CRISPR/Cas
CC system. The method comprises introducing into the cell one or more DNA
CC endonucleases to effect single-strand breaks or double-strand breaks
CC within or near the ANGPTL4 gene or ANGPTL4 regulatory elements resulting
CC in permanent insertions, deletions or mutations of a nucleotide within or
CC near the ANGPTL4 gene, and so reducing or eliminating the expression or
CC function of ANGPTL4 gene products. Also described: (1) an ex vivo or in
CC vivo method for treating a patient having an ANGPTL4 related condition or
CC disorder; (2) altering the contiguous genomic sequence of an ANGPTL4 gene
CC in a cell by contacting the cell with a DNA endonuclease; (3) a single-
CC molecule guide RNA (sgRNA) comprising a spacer sequence that is an RNA
CC sequence corresponding to any of SEQ ID NO:5305-19006 (BET12023-BET25724)
CC ; (4) a DNA encoding the sgRNA of (3); and (5) a vector comprising the
CC DNA of (4). The methods are used for editing an ANGPTL4 gene in a cell;
CC treating a patient having an ANGPTL4 related condition or disorder; and
CC altering the contiguous genomic sequence of an ANGPTL4 gene in a cell.
CC The ANGPTL4 related condition or disorder includes adenocarcinoma,
CC amyotrophic lateral sclerosis, arteriosclerosis, rheumatoid arthritis,
CC cardiovascular diseases, ischemia, schizophrenia, renal glomerular
CC disease and retinitis pigmentosa.
XX
SQ Sequence 20 BP; 5 A; 4 C; 2 G; 9 T; 0 U; 0 Other;
Query Match 100.0%; Score 19; Length 20;
Best Local Similarity 57.9%;
Matches 11; Conservative 8; Mismatches 0; Indels 0; Gaps 0;
Qy 1 UUUUAUUCCAAGAACUCUG 19 SEQ ID NO 13981
::::|::||||||||:|:|
Db 1 TTTTATTCCAAGAACTCTG 19 WO719 SEQ ID NO 9113
Although WO719 is (¶3) directed to gene editing, it acknowledges that (¶6) gene editing is permanent. WO719 also discusses (¶167-169, ¶203) compositions comprising dsRNA and that modifications (2’-F and 2’-OMe nt and PS linkages) applied to dsRNA can improve their nuclease resistance and can offset the immune-stimulatory effects that occur with unmodified dsRNA. WO719 acknowledges (¶203) dsRNA can induce potent gene silencing.
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 ANGPTL4-targeting dsRNA (which comprise the various modification patterns that would have been obvious in view of Foster) of WO478, Sledz, and Foster with the specific strand sequences of WO719 for the benefit of producing a compound that inhibits ANGPTL4 but does not require permanently editing a genome. One would have been motivated to do so with a reasonable expectation of success because Sledz, Foster, and WO719 indicate that dsRNA technology is a technology with proven gene-knockdown capabilities and one would have wanted to use a reversible knockdown strategy rather than permanently editing a genome to avoid producing a genetically modified organism. Teachings in the cited art indicate that changing any known ANGPTL4-targeting sequence into a dsRNA was well within the purview of an artisan of ordinary skill. Furthermore, an artisan would have wanted to test whether permanently editing a specific genome site (i.e., the site targeted by a dsRNA comprising WO719 SEQ ID NOs 18330 and 9113) offers any real benefits compared with reversibly knocking down the gene using the dsRNA. Therefore all the limitations of Claim 23 (and Claims 1-6, 10, and 17-19) would have been obvious in view of WO478, Sledz, Foster, and WO719.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6, 10-11, 17-19, and 23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,377,658 (“US658”) in view of Foster (et al. 2018. Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates. Molec. Ther. 23[6]:708, “Foster”, of record), International Publication Number WO 2018/044350 (published 08 March 2018, “WO350”), US Patent Application Publication No. 2013/0052130 (published 28 February 2013, “App130”) and Gaziova (et al. 2014. Chemically defined polyethylene glycol siRNA conjugates with enhanced gene silencing effect. Bioorg. Med. Chem. 22:2320–2326, “Gaziova”) as evidenced by US Patent Application Publication No. US 2016/0123988 (published 05 May 2016, “App988”).
Although the claims at issue aren’t identical they are directed to overlapping subject matter because the instant claims are directed to dsRNA compounds for targeting ANGPTL4. The claimed dsRNAs comprise certain modification patterns, SEQ ID NOs, and GalNAc.
The patented US658 claims are directed to dsRNA compositions for targeting ANGPTL4. The US658 claimed compounds comprise certain modification patterns and can comprise GalNAc.
Both claim sets are directed to ANPTL4-targeting dsRNA that can comprise the following identical sequences:
US-17-476-317-13973
(NOTE: this sequence has 5 duplicates in the database searched.
See complete list at the end of this report)
Sequence 13973, US/17476317
Publication No. US20220002731A1
GENERAL INFORMATION
APPLICANT: EMPIRICO INC.
TITLE OF INVENTION: OLIGONUCLEOTIDES FOR TREATMENT OF ANGIOPOIETIN LIKE 4 (ANGPTL4)
TITLE OF INVENTION: RELATED DISEASES
FILE REFERENCE: 54462-712.301
CURRENT APPLICATION NUMBER: US/17/476,317
CURRENT FILING DATE: 2021-09-15
PRIOR APPLICATION NUMBER: PCT/US2020/063824
PRIOR FILING DATE: 2020-12-08
PRIOR APPLICATION NUMBER: 62/945,732
PRIOR FILING DATE: 2019-12-09
NUMBER OF SEQ ID NOS: 14292
SEQ ID NO 13973
LENGTH: 19
TYPE: DNA
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
oligonucleotide
Query Match 100.0%; Score 19; Length 19;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CAGAGUUCUUGGAAUAAAA 19 SEQ ID NO 13973
|||||||||||||||||||
Db 1 CAGAGUUCUUGGAAUAAAA 19 SEQ ID NO 13973
SEQ ID NO 13981
LENGTH: 19
TYPE: DNA
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
oligonucleotide
Query Match 100.0%; Score 19; Length 19;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 UUUUAUUCCAAGAACUCUG 19 SEQ ID NO 13981
|||||||||||||||||||
Db 1 UUUUAUUCCAAGAACUCUG 19 SEQ ID NO 13981
Both claim sets are directed to ANPTL4-targeting dsRNA that can comprise the exact same modification patterns.
The patented US658 claims don’t recite every mod pattern recited in the instant claims. The patented US658 claims don’t recite the exact GalNAc moiety shown in the instant claims.
However, those features would have been obvious in view of the prior art:
Foster teaches (§Abstract, §Introduction ¶1-5, §Results ¶1-3, §Discussion ¶1-4) altering the proportion of 2'-F and 2'-OMe within a dsRNA was known in the art for the benefit of optimizing stability and silencing activity. Foster indicates that it was routine and conventional in the art of dsRNA design to change the proportion of 2’-F and 2'-OMe modifications in the strands of a dsRNA to find the proportion that works best for a chosen purpose.
WO350 (§Abstract; p. 3 L14-20; p. 38 L1-5, p. 53 L1-10) teaches targeting ligands for enhancing delivery of therapeutic compounds and that the ligands can comprise a PEG linker. App130 teaches (§Abstract, ¶77, p. 184) PEG chains useful in attaching to a variety of biologically active groups including nucleic acids. Evidence from App988 demonstrates (p. 25, top right) such shorter PEG chain was known in the art. Gaziova teaches (§3. Discussion ¶5) it was routine and conventional in the art of dsRNA delivery to use PEG-siRNA conjugates and that shorter PEG is better tolerated than longer, heavier PEG.
It would have been obvious to an artisan before the effective filing date of the claimed invention to modify the ANGPTL4-targeting dsRNA of the patented claims with Foster’s teachings about optimizing proportions of 2’-OMe and 2’-F modifications within an dsRNA to optimize in vivo performance and WO350/App130/App988/Gaziova’s teachings about specific GalNAc moieties and PEG linkers for the benefits of optimizing the dsRNA by improving its nuclease stability and optimizing the GalNAc attached to the dsRNA. One would have been motivated to alter the 2’-F and 2’-OMe composition with a reasonable expectation of success because Foster teaches (§Introduction ¶4) 2'-F and 2'-OMe modifications should be balanced within a dsRNA to produce the compound(s) with best performance. In doing so, they would have arrived upon the claimed mod patterns.
One would have been motivated to optimize a GalNAc moiety by combining elements known in the art with a reasonable expectation of success because determining which GalNAc species and which PEG linker is merely a design choice. Furthermore, WO350, App130, and Gaziova indicate that there were many options available and it was routine and conventional in the art of oligont delivery to modify known elements to optimize efficacy.
Therefore the instant claims would have been obvious in view of the patented claims, Foster, WO350, App130, evidence from App988, and Gaziova.
Claims 1-6, 10-11, 17-19, and 23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 12,674,165 (“US165”) in view of Foster, WO350, App130, evidence from App988, and Gaziova.
Although the claims at issue aren’t identical they are directed to overlapping subject matter because the instant claims are directed to dsRNA compounds for targeting ANGPTL4. The claimed dsRNAs comprise certain modification patterns, SEQ ID NOs, and GalNAc.
The patented US165 claims are directed to methods of treating a subject having a cardiovascular disorder using dsRNA compositions for targeting ANGPTL4. The US165 claimed compounds comprise certain modification patterns and can comprise GalNAc.
Both claim sets are directed to ANPTL4-targeting dsRNA that can comprise the following identical sequences:
US-17-736-928-13973
Filing date in PALM: 2022-05-04
Sequence 13973, US/17736928
Publication No. US20220340907A1
GENERAL INFORMATION
APPLICANT: EMPIRICO INC.
TITLE OF INVENTION: OLIGONUCLEOTIDES FOR TREATMENT OF ANGIOPOIETIN LIKE 4 (ANGPTL4)
TITLE OF INVENTION: RELATED DISEASES
FILE REFERENCE: 54462-712.302
CURRENT APPLICATION NUMBER: US/17/736,928
CURRENT FILING DATE: 2022-05-04
PRIOR APPLICATION NUMBER: 17/476,317
PRIOR FILING DATE: 2021-09-15
PRIOR APPLICATION NUMBER: PCT/US2020/063824
PRIOR FILING DATE: 2020-12-08
PRIOR APPLICATION NUMBER: 62/945,732
PRIOR FILING DATE: 2019-12-09
NUMBER OF SEQ ID NOS: 14292
SEQ ID NO 13973
LENGTH: 19
TYPE: DNA
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
oligonucleotide
Query Match 100.0%; Score 19; Length 19;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CAGAGUUCUUGGAAUAAAA 19 SEQ ID NO 13973
|||||||||||||||||||
Db 1 CAGAGUUCUUGGAAUAAAA 19 SEQ ID NO 13973
SEQ ID NO 13981
LENGTH: 19
TYPE: DNA
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
oligonucleotide
Query Match 100.0%; Score 19; Length 19;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 UUUUAUUCCAAGAACUCUG 19 SEQ ID NO 13981
|||||||||||||||||||
Db 1 UUUUAUUCCAAGAACUCUG 19 SEQ ID NO 13981
Both claim sets are directed to ANPTL4-targeting dsRNA that can comprise the exact same modification patterns.
The patented US165 claims don’t recite every mod pattern recited in the instant claims. The patented US165 claims don’t recite the exact GalNAc moiety shown in the instant claims.
However, those features would have been obvious in view of the prior art:
Foster teaches (§Abstract, §Introduction ¶1-5, §Results ¶1-3, §Discussion ¶1-4) altering the proportion of 2'-F and 2'-OMe within a dsRNA was known in the art for the benefit of optimizing stability and silencing activity. Foster indicates that it was routine and conventional in the art of dsRNA design to change the proportion of 2’-F and 2'-OMe modifications in the strands of a dsRNA to find the proportion that works best for a chosen purpose.
WO350 (§Abstract; p. 3 L14-20; p. 38 L1-5, p. 53 L1-10) teaches targeting ligands for enhancing delivery of therapeutic compounds and that the ligands can comprise a PEG linker. App130 teaches (§Abstract, ¶77, p. 184) PEG chains useful in attaching to a variety of biologically active groups including nucleic acids. Evidence from App988 demonstrates (p. 25, top right) such shorter PEG chain was known in the art. Gaziova teaches (§3. Discussion ¶5) it was routine and conventional in the art of dsRNA delivery to use PEG-siRNA conjugates and that shorter PEG is better tolerated than longer, heavier PEG.
It would have been obvious to an artisan before the effective filing date of the claimed invention to modify the ANGPTL4-targeting dsRNA of the patented claims with Foster’s teachings about optimizing proportions of 2’-OMe and 2’-F modifications within an dsRNA to optimize in vivo performance and WO350/App130/App988/Gaziova’s teachings about specific GalNAc moieties and PEG linkers for the benefits of optimizing the dsRNA by improving its nuclease stability and optimizing the GalNAc attached to the dsRNA. One would have been motivated to alter the 2’-F and 2’-OMe composition with a reasonable expectation of success because Foster teaches (§Introduction ¶4) 2'-F and 2'-OMe modifications should be balanced within a dsRNA to produce the compound(s) with best performance. In doing so, they would have arrived upon the claimed mod patterns.
One would have been motivated to optimize a GalNAc moiety by combining elements known in the art with a reasonable expectation of success because determining which GalNAc species and which PEG linker is merely a design choice. Furthermore, WO350, App130, and Gaziova indicate that there were many options available and it was routine and conventional in the art of oligont delivery to modify known elements to optimize efficacy.
Therefore the instant claims would have been obvious in view of the patented claims, Foster, WO350, App130, evidence from App988, and Gaziova.
Claims 1-6, 10-11, 17-19, and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 26-30, 33-34, 36-38, 44, 56-58, 62, 69-72 of copending Application No. 18037960 (“App960”) in view of International Publication Number WO 2020/099478 (published 22 May 2020, “WO478”, of record), Sledz (and Williams. 2005. RNA interference in biology and disease. Blood 106[3]:787, “Sledz”, of record), Foster (of record), International Publication Number WO 2020/160163 (published 06 August 2020, “WO163”), and International Publication Number WO 2018/002719 (published 04 January 2018, “WO719”).
Although the claims at issue aren’t identical they are directed to overlapping subject matter because the instant claims are directed to dsRNA compounds for targeting ANGPTL4. The claimed dsRNAs comprise certain modification patterns, SEQ ID NOs, and GalNAc.
The copending App960 claims are directed to GalNAc compositions that are attached to an oligont and improve siRNA bioavailability and which are intended for use in targeting the siRNA to a hepatocyte.
Both claim sets are directed to dsRNA that comprise GalNAc intended for use in targeting the liver.
The copending App960 claims don’t recite that the oligont targets ANGPTL4 or comprise specific mod patterns, specific SEQ ID NOs, or other elements, but all of those elements would have been obvious in view of the prior art:
WO478 teaches (§Abstract, p. 6 L5-15, p. 14 L1-5, p. 5 L19-30, p. 14 L10-20, p. 4 L9-27, Figs. 1-4, 7-8, 12-15, 17-18) single-stranded antisense oligont that target ANGPTL4 for reducing triglyceride levels.
Sledz teaches (§Introduction ¶1; §Stable RNA interference ¶1-2, Figs. 1-2, §Introduction ¶1-2, §Mechanisms of RNA interference, §Stable RNA interference) double-stranded interfering RNA (dsRNA) are more potent than single-stranded interfering RNA and dsRNA can be around 22 nt long.
Foster teaches (§Abstract, §Introduction ¶1-5, §Results ¶1-3, §Discussion ¶1-4) altering the proportion of 2'-F and 2'-OMe within a dsRNA was known in the art for the benefit of optimizing stability and silencing activity. Foster indicates that it was routine and conventional in the art of dsRNA design to change the proportion of 2’-F and 2'-OMe modifications in the strands of a dsRNA to find the proportion that works best for a chosen purpose. Foster teaches (§Introduction ¶1, §Materials and Methods-siRNA Synthesis) a GalNAc ligand that has high affinity to hepatocytes in vivo and which is placed at the 3’end of the sense strand.
WO163 explicitly teaches (p. 73 L20-25, p. 14 L30-34, p. 40 L16-32, p. 43 L5-p. 47 L14, p. 81 L22-25) the specific linkage motif (from 5’ to 3’) of: ssooooooooooooooooss; wherein ‘o’ represents a phosphodiester internucleoside linkage and ‘s’ represents a phosphorothioate internucleoside linkage. WO163 teaches PS linkages increase resistance to nucleases and oligont can comprise various modification motifs and inter-nt linkage motifs.
WO719 teaches (¶43-44) a guideRNA comprising SEQ ID NO 18330 (which comprises a sequence having 100% identity to claimed SEQ ID NO 13973) and a guideRNA comprising SEQ ID NO 9113 (and also SEQ ID NO 15444, both of which comprise a sequence having 100% identity to claimed SEQ ID NO 13981). Those sequences comprise a sequence having 100% identity to claimed SEQ ID NOs, as shown by the alignments in the 103 rejection above.
It would have been obvious to an artisan before the effective filing date of the claimed invention to use any of the GalNAcs encompassed by the App960 claims and attach it to a modified ANGPTL4-targeting dsRNA that would have been obvious in view of WO478, Sledz, Foster, WO163, and WO719.
It would have been obvious to modify the ANGPTL4-targeting ASO of WO478 with Sledz’s teachings that dsRNA are more potent than single-stranded ASO, Foster’s teachings about optimizing proportions of 2’-OMe and 2’-F modifications and GalNAc-conjugated dsRNA, the PS/PO linkage motif of WO163, and the specific ANGPTL4-targeting sequences of WO719 because WO478 explains why an artisan would want to target ANGPTL4, Sledz teaches dsRNA are more potent than ASOs, Foster teaches balancing 2’-F and 2’-OMe mods to improve performance and using a GalNAc to target hepatocytes, WO163 teaches linkage motifs that improve nuclease resistance, and WO719 teaches specific SEQ ID NOs that can be used to target ANGPTL4. (Although WO719 is [¶3] directed to gene editing, it acknowledges that [¶6] gene editing is permanent but [¶167-169, ¶203] dsRNA compositions induce potent silencing, have good nuclease resistance, and induce few immune-stimulatory effects.)
One would have been motivated to do so with a reasonable expectation of success because the App960 claims reciting attaching their GalNAc to any oligont and as discussed, there was a need in the art for ANGPTLA4-targeting dsRNAs. As explained such ANGPTL4-targeting dsRNAs comprising the mod patterns and sequences that happen to be the same as those claimed would have been obvious in view of the prior art.
Therefore the instant claims would have been obvious in view of the copending claims, WO478, Sledz, Foster, WO163, and WO719.
This is a provisional nonstatutory double patenting rejection.
Claims 1-6, 10-11, 17-19, and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 19706874 (“App874”) in view of Foster, WO350, App130, evidence from App988, and Gaziova.
Although the claims at issue aren’t identical they are directed to overlapping subject matter because the instant claims are directed to dsRNA compounds for targeting ANGPTL4. The claimed dsRNAs comprise certain modification patterns, SEQ ID NOs, and GalNAc.
The copending App874 claims are directed to methods of treating a subject having a cardiovascular disorder using dsRNA compositions for targeting ANGPTL4. The App874 claimed compounds comprise certain modification patterns and can comprise GalNAc.
Both claim sets are directed to ANPTL4-targeting dsRNA that can comprise the following identical sequences:
US-17-736-928-13973
Filing date in PALM: 2022-05-04
Sequence 13973, US/17736928
Publication No. US20220340907A1
GENERAL INFORMATION
APPLICANT: EMPIRICO INC.
TITLE OF INVENTION: OLIGONUCLEOTIDES FOR TREATMENT OF ANGIOPOIETIN LIKE 4 (ANGPTL4)
TITLE OF INVENTION: RELATED DISEASES
FILE REFERENCE: 54462-712.302
CURRENT APPLICATION NUMBER: US/17/736,928
CURRENT FILING DATE: 2022-05-04
PRIOR APPLICATION NUMBER: 17/476,317
PRIOR FILING DATE: 2021-09-15
PRIOR APPLICATION NUMBER: PCT/US2020/063824
PRIOR FILING DATE: 2020-12-08
PRIOR APPLICATION NUMBER: 62/945,732
PRIOR FILING DATE: 2019-12-09
NUMBER OF SEQ ID NOS: 14292
SEQ ID NO 13973
LENGTH: 19
TYPE: DNA
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
oligonucleotide
Query Match 100.0%; Score 19; Length 19;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CAGAGUUCUUGGAAUAAAA 19 SEQ ID NO 13973
|||||||||||||||||||
Db 1 CAGAGUUCUUGGAAUAAAA 19 SEQ ID NO 13973
SEQ ID NO 13981
LENGTH: 19
TYPE: DNA
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
oligonucleotide
Query Match 100.0%; Score 19; Length 19;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 UUUUAUUCCAAGAACUCUG 19 SEQ ID NO 13981
|||||||||||||||||||
Db 1 UUUUAUUCCAAGAACUCUG 19 SEQ ID NO 13981
Both claim sets are directed to ANPTL4-targeting dsRNA that can comprise the exact same modification patterns.
The copending App874 claims don’t recite every mod pattern recited in the instant claims. The copending App874 claims don’t recite the exact GalNAc moiety shown in the instant claims.
However, those features would have been obvious in view of the prior art:
Foster teaches (§Abstract, §Introduction ¶1-5, §Results ¶1-3, §Discussion ¶1-4) altering the proportion of 2'-F and 2'-OMe within a dsRNA was known in the art for the benefit of optimizing stability and silencing activity. Foster indicates that it was routine and conventional in the art of dsRNA design to change the proportion of 2’-F and 2'-OMe modifications in the strands of a dsRNA to find the proportion that works best for a chosen purpose.
WO350 (§Abstract; p. 3 L14-20; p. 38 L1-5, p. 53 L1-10) teaches targeting ligands for enhancing delivery of therapeutic compounds and that the ligands can comprise a PEG linker. App130 teaches (§Abstract, ¶77, p. 184) PEG chains useful in attaching to a variety of biologically active groups including nucleic acids. Evidence from App988 demonstrates (p. 25, top right) such shorter PEG chain was known in the art. Gaziova teaches (§3. Discussion ¶5) it was routine and conventional in the art of dsRNA delivery to use PEG-siRNA conjugates and that shorter PEG is better tolerated than longer, heavier PEG.
It would have been obvious to an artisan before the effective filing date of the claimed invention to modify the ANGPTL4-targeting dsRNA of the copending claims with Foster’s teachings about optimizing proportions of 2’-OMe and 2’-F modifications within an dsRNA to optimize in vivo performance and WO350/App130/App988/Gaziova’s teachings about specific GalNAc moieties and PEG linkers for the benefits of optimizing the dsRNA by improving its nuclease stability and optimizing the GalNAc attached to the dsRNA. One would have been motivated to alter the 2’-F and 2’-OMe composition with a reasonable expectation of success because Foster teaches (§Introduction ¶4) 2'-F and 2'-OMe modifications should be balanced within a dsRNA to produce the compound(s) with best performance. In doing so, they would have arrived upon the claimed mod patterns.
One would have been motivated to optimize a GalNAc moiety by combining elements known in the art with a reasonable expectation of success because determining which GalNAc species and which PEG linker is merely a design choice. Furthermore, WO350, App130, and Gaziova indicate that there were many options available and it was routine and conventional in the art of oligont delivery to modify known elements to optimize efficacy.
Therefore the instant claims would have been obvious in view of the copending claims, Foster, WO350, App130, evidence from App988, and Gaziova.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. International Publication No. WO 2018223081 (published 06 December 2018, “WO081”). WO081 discloses (¶48) sugar modifications that, used in combination, would result in the claimed modification patterns.
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RUTHIE S ARIETI
Examiner
Art Unit 1635
/RUTH SOPHIA ARIETI/Examiner, Art Unit 1635
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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