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 124-159 are pending.
Election/Restrictions
Applicant’s election without traverse of Invention Group, directed to Claims 124-152, in the reply filed on 26 August 2026 is acknowledged.
Claims 153-159 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected invention groups, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 26 August 2026.
Claims 124-152 are examined.
Information Disclosure Statement
The Spec. cites references.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The IDS(es) has been considered.
Drawings
The drawings are objected to because of the following informalities:
Fig. 10: for examination purposes, please explain the diagonal lines. (Adding any new matter to the Spec. will result in an objection.)
The Spec. says Fig. 5C shows SEQ ID NO 19 but the SEQ Listing for SEQ ID NO 19 does not disclose that nt 13 is an LNA nt.
Figs. 12-13, 20, 22, 25A, 27, 29-30: the text is illegible or should be clearer.
Fig. 18B: identify the structure with a SEQ ID NO. Whether Fig. 18B is supposed to show SEQ ID NO 18 or 19, the structure shown does not match either of those sequences in the SEQ Listing. If Fig. 18B is supposed to show SEQ ID NO 18, nt 13 should be 5-methyl-C. If Fig. 18B is supposed to show SEQ ID NO 19, nt 13 should not be LNA.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
The sequence shown in Fig. 18B is not in the SEQ listing. Fig. 18B shows the nt at position 13 is an LNA C nt.
Whether Fig. 18B is supposed to show SEQ ID NO 18 or 19, the structure shown does not match either of those sequences in the SEQ Listing. If Fig. 18B is supposed to show SEQ ID NO 18, nt 13 should be 5-methyl-C. If Fig. 18B is supposed to show SEQ ID NO 19, nt 13 should not be LNA. There is no SEQ listed wherein nt 13-16 are LNA nts and only nts 14-15 are 5-methyl C. The nt in question (nt 13) is identified in the annotated Fig 18B below.
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Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. There are two instances in ¶117 and instances in ¶118 and ¶246. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is objected to because of the following informalities: at ¶181 the Spec. should say …or about 20 mg to about 50 mg.
Appropriate correction is required.
Claim Objections
Claims 124, 146, and 152 are objected to because of the following informalities:
The claims should define PCSK9 on first use so Claim 124 should spell out PCSK9: …encoding Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)…
Claim 146 should replace and with to so it recites …or about 20 mg to about 50 mg.
Claim 152 is missing a period at the end.
Appropriate correction is required.
Claim Interpretation
Claim 124 recites that the antisense oligomer is 16 contiguous nt in length. That is interpreted as requiring that the antisense oligomer is exactly 16 nt long.
The claims recite a gapmer. That is interpreted as a region of at least 6-7 DNA nt flanked on either end by a region of 1-6 RNA nt or nt analogs. That interpretation is based on ¶324 in the Spec. and the art of Qiagen (2017. Antisense LNA® GapmeRs Handbook. Available online at Qiagen.com. Accessed on 10 September 2026, “Qiagen”) which describes (§Introduction) the art-recognized structure of a gapmer.
Claim 124 also recites a composition for oral administration to a subject in need thereof… wherein the composition is formulated for release of the ASO in the subject’s small intestine following oral administration. The phrase for oral administration to a subject in need thereof… is interpreted as an intended use. The phrase wherein the composition is formulated for release of the ASO in the subject’s small intestine following oral administration is interpreted as a property inherent to formulation in an enteric coating (which is required by the claim), see next ¶.
The claims recite an enteric coating. That is interpreted as a coating that doesn’t dissolve in the gastric acids of the stomach but will dissolve in the more alkaline environment of the small intestine. That interpretation is based on the Spec. (¶189) and the plain meaning of “enteric coating” as described in its Wikipedia page (“Enteric coating”. Page saved 27 August 2020. Available online at Wikipedia.org. Accessed on 10 September 2026, “Wikipedia”, of record on IDS), see §Discussion. Therefore, any enteric coating inherently possesses the property of being formulated for release in a subject’s small intestine following oral administration.
Any optional limitation is interpreted as fully optional and not required. Since Claim 149 depends from an optional limitation of Claim 148, that claim is fully optional.
Claim 150 recites that the composition comprising ASO and 5-CNAC are in a “dry blend”. The Spec. defines that term at ¶198: the term "dry blending" means thoroughly mixing several components together (e.g., CIVI 800 and 5-CNAC) in the absence of a liquid medium. In some aspects, a component of the dry blend (e.g., CIVI 800, 5-CNAC, or both) can be in powder form. That indicates that a powder comprising recited ingredients is a dry blend.
Claim Rejections - 35 USC § 112
112(a)
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 142, 144, 148, and 150-152 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.
Claims 142 and 148 recite an inhibitor of bile acid transporters and a regulator of hepatic CYP7a. That broad claim encompasses the large genera of bile transporter inhibitors and hepatic CYP7a regulators. Any kinds of bile transporter inhibitors and any kinds of hepatic CYP7a regulators would be encompassed by the claims as instantly presented.
Those claims encompass inhibitors and regulators whose structures cannot be envisioned because the claims encompass generic inhibitors and regulators defined solely by their functions of inhibiting a bile transporter or regulating hepatic CYP7a. Each of those genera does not comprise a group of species with a known structure–function relationship.
Claim 144 recites an enzyme-inhibiting agent that prevents enzymatic degradation…. That broad claim encompasses the large genus of agents that inhibit any enzyme and prevent any enzymatic degradation in the stomach and/or small intestine. Any kind of agent that inhibits any enzyme would be encompassed by the claims as instantly presented. Any kind of agent that prevents any enzyme degradation in the stomach and/or small intestine would be encompassed by the claims as instantly presented.
That claim encompasses agents whose structures cannot be envisioned because the claims encompass generic agents defined solely by their functions of inhibiting any enzyme and preventing any enzymatic degradation in the stomach and/or small intestine. That genus does not comprise a group of species with a known structure–function relationship.
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 written description requirement mandates that the invention disclosure (i.e., Spec.) must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See MPEP §2163(II)(A)(3)(a)(ii).
In this case, the Spec. provides (¶427) only one example of a bile acid transporter inhibitor and (same ¶) no examples of a hepatic CYP7a regulator. Regarding the “enzyme-inhibiting agent”, that genus is so broad it encompasses countless species, and the Spec. discusses enzyme-inhibiting agents only in ¶189 and ¶451 and doesn’t provide any examples of agents that prevent enzymatic degradation in the stomach/small intestine or disclose any structure underlying the claimed function.
The art of Wikipedia (“Cholesterol 7 alpha-hydroxylase”. Available online at Wikipedia.org. Accessed on 10 September 2026, “Wikipedia”) teaches (§Function-Synthesis of bile acid) CYP7a is secreted by the liver and (§Function-Regulation of activity) there are several levels of its regulation, including synthesis, bile acids, steroid hormones, inflammatory cytokines, insulin, and growth factors which inhibit CYP7A1 transcription through the 5′-upstream region of the promote; phosphorylation-dephosphorylation, and other mechanisms. An artisan would readily understand that modulating any of those could regulate hepatic CYP7a. But Applicant’s Spec. doesn’t discuss any of those regulators, using them in the claimed composition, or a structure responsible for the “regulating” function.
Similarly, the art of Dawson (et al. 2009. Bile acid transporters. J. Lipid Res. 50:2342, “Dawson”) teaches (Fig. 1) there are at least 4 “major” bile transport proteins, and an artisan would recognize that the claims encompass any agent that inhibits any of them, as well as agents that inhibit their synthesis or induce their degradation. The claims also encompass any other agents upstream of those agents. Nothing in the Spec. defines any structure responsible for the function of inhibiting a bile acid transporter.
Regarding enzyme inhibitors, Wikipedia (“Enzyme inhibitors”. Available online at Wikipedia.org. Accessed on 10 September 2026, “Wikipedia”) teaches (§Structural classes) enzyme inhibitors are a chemically diverse set of substances and include small molecules, proteins, primary and secondary metabolites, and drugs. Wikipedia teaches (§Reversible inhibitors, §Irreversible inhibitors, and §Applications) enzyme inhibitors work through diverse mechanisms and comprise diverse structures because the targets comprise diverse structures. Nothing in the Spec. defines any structure responsible for the function of inhibiting any enzyme.
Furthermore, the art of Wang (2026. Strategies for overcoming multiple barriers of oral administration of protein and peptide therapeutics. Mater. Today Bio. 7[37]:102763, “Wang”) discusses oral drug delivery. Wang is directed to protein/peptide therapeutics but there is no reason their teachings no not also apply to ASO therapeutics. Wang teaches (§3. Strategies for overcoming barriers of orally administered protein and peptide therapeutics-3.1.2.1. Addition of enzyme inhibitor ¶2) using enzyme inhibitors presents several complications in terms of supplying an adequate concentration of an agent, agents’ toxic properties, disruption to endogenous pathways that impact on absorption, and compensatory responses. Wang teaches (§3.4. Comparative analysis and integration of strategies ¶2) no single strategy can effectively address all GI barriers and indicates (§5. Challenges of current strategies ¶1) available strategies do not address the complexity of the GI environment comprehensively to prevent enzymatic degradation.
Regarding what structure is encompassed by the inhibitor of bile transporters, regulator of hepatic CYP7a, and enzyme-inhibiting agents that preven[t] enzymatic degradation…in the stomach/small intestine, the Spec. does not provide information describing their features. The Spec. does not disclose what physical structures are responsible for the claimed functions.
Applicant’s examples do not disclose any inhibitor of bile transporters, regulator of hepatic CYP7a, or enzyme-inhibiting agents that preven[t] enzymatic degradation…in the stomach/small intestine, so the Spec. as a whole fails to provide written description support for the huge genera of inhibitors of bile transporters, regulators of hepatic CYP7a, and enzyme-inhibiting agents that preven[t] enzymatic degradation…in the stomach/small intestine. Although the claims claim the functional characteristics (i.e., inhibiting bile transporters, regulating hepatic CYP7a, and inhibiting any enzyme and preventing any enzymatic degradation in the stomach/small intestine), each functional characteristic is not coupled with any known structure.
The Spec. does not identify a core structure necessary for performing the claimed function(s) of inhibiting bile transporters, regulating hepatic CYP7a, and inhibiting any enzyme to prevent enzymatic degradation in the stomach/small intestine. 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 inhibiting bile transporters, regulating hepatic CYP7a, and inhibiting any enzyme in such a way to demonstrate possession of the full invention as claimed at time of filing. As explained above, the art teaches members of each claimed genus do not share a core structure.
The specification disclose only the two species within the claimed genus/genera, as discussed above. But those are only a paltry number compared with the breadth of what is claimed. Altogether, the number of species disclosed by complete structure is not sufficient to provide the written description support for the huge genera and subgenera that are encompassed by the claims.
While none of these elements is specifically required to demonstrate possession, in combination their absence means that one skilled in the art at the time of filing would conclude that the inventors lacked possession of the full breadth of the invention claimed. Claims 142, 144, and 148 are rejected for failing to demonstrate possession of the claimed invention. Claims 143 and 150-152 are rejected because they depend from Claim(s) 142 or 148 and do not remedy the issues.
112(b)
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 132-134, 137-138, 140-141, 146-152 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A claim may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173. In the present instance, Claim 132 recites …and does not substantially disintegrate or dissolved in the stomach. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. It is not clear how much disintegration or dissolution is or is not “substantial”.
Claim 132 is rejected for those reasons. Claims 133-134 are rejected because they depend from Claim 132 and do not remedy the issues. In the interest of compact prosecution, the claim is interpreted as requiring that the enteric coating is a pH sensitive enteric coating. Note that a pH sensitive enteric coating inherently possesses the property of protecting a drug from the acidity of the stomach and releasing the drug in the intestine. See Wikipedia (“Enteric coating”, ¶1).
Claim 132 recites the limitation "the composition of claim 129, wherein the pH sensitive coating…" in L1. There is insufficient antecedent basis for this limitation in the claim because neither Claim 129 nor any claim from which Claim 129 depends mentions any “pH sensitive coating”. Claim 132 is rejected for those reasons. Claims 133-134 are rejected because they depend from Claim 132 and do not remedy the issues. In the interest of compact prosecution, the claim is interpreted as depending from Claim 131.
The term “about” in Claims 134 and 146-148 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The Spec. discloses (¶88) the term "about" is used herein to mean approximately, roughly, around, or in the regions of When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth, but that “definition” doesn’t provide any guidance about the actual amounts that are acceptable to use in the invention.
Claims 134 and 146-148 are rejected for those reasons. Claims 149-152 are rejected because they depend from Claims 146 and/or 148 and do not remedy the issues. In the interest of compact prosecution, the term “about” is interpreted as ±50% of the stated value.
In the present instance, Claims 139-140 recite methacrylmethacrylate. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. It is not clear what is “methacrylmethacrylate”. A search of the CAS database for that term yielded no hits.
Claims 139-140 are rejected for those reasons. Claim 140 is rejected because it depends from Claim 139 and does not remedy the issues. In the interest of compact prosecution, the claim is interpreted as if it recites methyl methacrylate. The claims are interpreted that way because Evonik (2015. Technical Information for “EUDRAGIT® FS 30 D”. Available online at pharmacompass.com. Accessed on 15 September 2026, “Evonik 2015”) teaches (§2) EUDRAGIT® FS 30 D comprises methyl acrylate, methyl methacrylate, and methacrylic acid.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claim 134 recites the broad recitation the pH value is between about 5.5 and about 7.5, and the claim also recites between about 7.2 and about 7.3 which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
In the interest of compact prosecution, the claim is interpreted as requiring only the broader range and the narrower range is interpreted as merely exemplary.
In the present instance, Claim 146 recites the broad recitation the dosage form comprises about 1 mg to about 100 mg, and the claim also recites: [or the dosage form comprises] about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 20 mg to about 100 mg, or about 20 mg [to] about 50 mg of the ASO, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
In the interest of compact prosecution, the claim is interpreted as requiring only the broader range and the narrower ranges are interpreted as merely exemplary.
Claim 144 recites the limitations “the ASO and/or one or more additional therapeutic agents” and "the stomach" in L3. There is insufficient antecedent basis for the limitations “the… one or more additional therapeutic agents” and “the stomach” in the claim because Claim 144 depends from Claim 124 and neither of those claims mentions any additional therapeutic agents or any stomach.
In the interest of compact prosecution, the claim is interpreted as reciting the composition of Claim 124, further comprising one or more additional therapeutic agents and an enzyme-inhibiting agent that inhibits enzymatic degradation of the ASO and/or one or more additional therapeutic agents in the subject’s stomach and/or small intestine.
Claims 137-138 and 140-141 contain the trademark/trade names AQOAT®, AQOAT®-HF, EUDRAGIT®, and EUDRAGIT®FS30D.
Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name.
In the present case, each trademark/trade name is used to identify/describe, respectively, hypromellose acetate succinate, hypromellose acetate succinate-fine grade, a portfolio of functional polymers produced by Evonik, and Evonik 2015 teaches “Eudragit® FS 30 D” is (§1 and 2) an aqueous dispersion with 30% dry substance, the dry substance comprising an anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid and the aqueous dispersion comprising purified water and 0.3 % Sodium Laurilsulfate Ph. Eur. / NF and 1.2 % Polysorbate 80 Ph. Eur. / NF on solid substance, as emulsifiers. Accordingly, the identification/description is indefinite.
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) 124-126, 129-132, 135, 142-143, and 145-152 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent No. 9364495 (published 14 June 2016, “US495”), International Publication No. WO2014/207232 (published 31 December 2014, “WO232”, of record on IDS), and International Publication No. WO 2018/033927 (published 22 February 2018, “WO927”) as evidenced by Jones (2016. “Hard capsules”. Chapter 33 in Basic Medical Key. Available at basicmedicalkey.com. Accessed on 14 September 2026, “Jones”).
All references to WO document p# refer to the PDF p#.
US495 (§Abstract) discloses LNA oligomers for treating a metabolic disorder, wherein the LNA oligomer is administered orally and in the presence of a permeation enhancer.
US495 teaches (Col 13 L19-22, Col 43 L10-61) LNA oligomers that target PCSK9 are effective for treating hypercholesterolemia. US495 teaches (Col 1-2 L19-20) modification of oligont has produced molecules stable enough to survive the intestinal environment and their LNA oligos provide stability to deliver an oligont to the GI tract, and bioavailability is enhanced when used in conjunction with a permeation enhancer.
Regarding Claims 124, 131-132: US495 teaches (Col 5-6 L40-50, Col 37-38 L20-40) their oral medication can be encapsulated or coated in an enteric material which improves the delivery of oligomer through the stomach into the site of absorption in the small intestine.
As discussed in §Claim interpretation, an enteric formulation is, by definition, one that protects a drug from degradation in the stomach and allows the drug to be released in the small intestine.
Regarding Claims 135-136 and 137-140: US495 teaches (Col 5-6 L40-50, Col 37-38 L20-40) hydroxypropyl methylcellulose acetate succinate and copolymers of methacrylic acid and methyl methacrylate including EUDRAGIT®.
Regarding Claims 125-126: US495 teaches (Col 5 L20-50) including pharmaceutically acceptable excipients including a diluent or preservative.
Regarding Claims 130 and 145: US495 teaches (Col 5 L35-40) tablets and capsules.
Regarding Claims 142-143 and the optional limitations of Claims 148(b) and 149): US495 teaches (Col 8 L5-10) including an additional therapeutic agent that is a statin including (Col 47 L1-15) simvastatin.
Regarding Claim 144: US495 teaches including chelating agents that can act as enzyme inhibitors, including DNase inhibitors. That indicates a chelating agent would inhibit DNase in any tissue where it’s released.
Regarding the dosage forms of Claims 146-148: US495 teaches (Col 5-6 L50-36) each unit dose (i.e., a capsule or tablet) can comprise 1-500 mg oligomer or 20-100 mg oligomer. US495 teaches (same §) a penetration enhancer is included at a ratio of at least 5 : 1, 10 : 1, or 20 : 1. If an oligomer is included in a tablet at 20 mg, a ratio of 10 : 1 would mean the tablet also comprises about 200 mg of penetration enhancer.
Regarding Claims 150-152: US495 teaches (Col 34 L10-20, Col 37-38 L30-50) doses formulated in a powder and capsules filled with powder. A unit dose formulated in a powder constitutes a dry blend. US495 teaches (Col 5 L35-50, Col 37-38 L30-50) capsules that comprise gelatin as well as hard capsules and soft capsules and caplets, and that capsules for oral delivery are well known in the art. Hard and soft capsules comprising gelatin constitute hard-shell and soft gelatin capsules.
Regarding penetration enhancers: US495 teaches (Col 6 L1-45) formulations comprising generic penetration enhancers and (Col 32-33 L50-10) penetration enhancers that are fatty acid derivatives including caprylic acid and salts thereof.
US495 does not teach the PCSK9-targeting ASO that comprises 100% complementarity to claimed SEQ ID NO 31 (UGGGUUUUGUAGCAUU).
However, WO232, drawn to ASOs for targeting PCSK9, teaches a GalNAc-conjugated 16-mer ASO that comprises 100% complementarity to SEQ ID NO 31 (UGGGUUUUGUAGCAUU), as shown by the following alignment:
RESULT 1
US-18-256-632-31/c
Query Match 100.0%; Score 16; DB 1; Length 16;
Best Local Similarity 100.0%;
Matches 16; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AATGCTACAAAACCCA 16 WO232 SEQ ID NO 19
||||||||||||||||
Db 16 AATgctacaaaacCCA 1 Reverse complement of claimed SEQ ID NO 31
That compound is shown here in a modified excerpt of WO232’s Fig. 5:
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WO232 teaches (Table 1 on p. 10, p. 11 L5-20) SEQ ID NO 19 comprises LNA gapmer oligont and the lowercase letters are DNA units, and the capital letters are LNA units. WO232 describes (pp. 34-36 L6-17) gapmer design: a gapmer has a X’-Y’-Z’ structure wherein Y’ comprises at least 4-5 consecutive DNA nt and each of X’ and Z’ comprise 1-6 nt analogs that can be LNA. Therefore, WO232 teaches the limitations of Claim 124(i).
WO232 teaches (Figs. 16-17) the ASO comprising that nucleobase or nucleotide sequence (i.e., WO232’s SEQ ID NO 19) is highly effective at inhibiting PCSK9 expression.
WO232 also teaches (pp. 46-47 L3-19) using lipophilic conjugate moieties, including caprylic acid, that enhance cellular penetration and delivery to hepatocytes, indicating delivery to that tissue is desirable.
Regarding Claims 142-143 and the optional limitations of Claims 148(b) and 149: WO232 teaches (p. 60 L21-34) combination treatments that use the ASO in combination with another therapeutic agent that can be other cholesterol lowering compounds (including various bile salt sequestering resins, e.g., cholestyramine, colestipol, and colesevelam hydrochloride), HMGCoA-reductase inhibitors (i.e., statins; e.g., lovastatin, cerivastatin, pravastatin, atorvastatin, simvastatin, rosuvastatin, and fluvastatin), nicotinic acid, fibric acid derivatives, probucol, neomycin, dextrothyroxine, plant-stanol esters, cholesterol absorption inhibitors, implitapide, inhibitors of bile acid transporters, regulators of hepatic CYP7a, estrogen replacement therapeutics, and anti-inflammatories. Therefore, WO232 teaches limitations of Claims 142-143 and the optional limitations of Claims 148(b) and 149.
WO232 teaches (pp. 4-5 L20-30) pharmaceutical compositions comprising their ASO and a pharmaceutically acceptable diluent, carrier, salt or adjuvant. WO232 teaches (same §) those pharmaceutical compositions can be used to treat various PCSK9-related diseases and disorder.
US495 and WO232 do not teach using the specific cellular penetration enhancer 5-CNAC or a salt thereof (Claim 124[ii]), or that the salt is a monosodium or disodium salt thereof (Claim 129).
However, WO927, generally drawn to formulations for oral administration of active agents, teaches (§Abstract) pharmaceutical composition comprising a therapeutically effective amount of a therapeutically active agent and an effective amount of the absorption enhancer 5-CNAC.
Although WO927 uses the term “absorption enhancer” and US495 uses the term “penetration enhancer”, it is clear that both terms refer to the same phenomenon because WO927 teaches (p. 63 L10-16) their compositions are particularly suitable for enhancing the absorption of therapeutically active agents whose absorption upon oral administration is limited by a molecular weight and hydrophilicity (which inhibit crossing of lipid membranes in the gastrointestinal tract).
Regarding Claim 124: WO927 teaches (p. 7 L1-12) a pharmaceutical composition comprising a therapeutically active agent and an absorption enhancer wherein the absorption enhancer is 5-CNAC. WO927 teaches (p. 96 L25-31) their invention encompasses formulations of many relevant therapeutically active agents yet to be developed.
Regarding Claim 129: WO927 teaches (p. 37 L3-10) the 5-CNAC can be in monosodium or disodium form.
Regarding the dose of Claims 146-148: WO927 teaches (pp. 41-42 L30-25) using the absorption enhancer in a range of a total of 10-200 mg or 10-500 mg per dose.
Regarding the limitations of Claims 151-152: WO927 teaches (p. 86 L11-21) dosage forms for oral use that include push-fit gelatin capsules and soft gelatin capsules.
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 oral formulations comprising a PCSK9-targeting ASO of US495 with the specific PCSK9-targeting ASO of WO232, and WO927’s specific penetration/absorption enhancer 5-CNAC. They would have done so for the benefit of determining whether a formulation for oral delivery comprising 5-CNAC is a suitable alternative to or offers improvements over the penetration enhancers disclosed in US495. One would have been motivated to do so with a reasonable expectation of success because WO232 teaches their PCSK9-inhibiting ASOs are highly effective, and because WO927 teaches 5-CNAC is an absorption/penetration enhancer that can be used with any therapeutically active ingredient. It would have been a simple matter to use WO927’s 5-CNAC in the tablet/capsule formulations of US495 and one would have done so for the benefit of determining which penetration enhancer optimizes bioavailability.
Regarding the dosage forms comprising about 1-100 mg ASO and about 200 mg of 5-CNAC (Claims 146-148): formulating capsules or tablets with different amounts of ASO and 5-CNAC would have been obvious in view of the art because WO927 teaches (cited above) a quantity of about 10-200 mg of 5-CNAC is an appropriate amount and US495 teaches various ratios of penetration enhancer : oligont.
It would have been a simple matter to swap WO232’s PCSK9-targeting ASO for that of US495 and it would have been a simple matter to swap WO927’s 200 mg of 5-CNAC for the 200 mg of generic penetration enhancer of US495. Doing so would have produced all the limitations of Claim 146.
Since US495 teaches 20 mg oligont and a ratio of 10 : 1 per dose, the tablets/capsules comprising 20 mg ASO and 200 mg 5-CNAC would have been obvious. One would have been motivated to do so with a reasonable expectation of success because US495 and WO927 disclose acceptable ranges of compound to be used in oral formulations. It also would have been obvious to vary the amount of active ingredient (i.e., ASO) for the benefits of optimizing bioavailability and cost-effectiveness (by minimizing the amount of ASO in each dosage formulation).
Regarding the hard-shell gelatin capsule of Claim 152: Jones describes (§Introduction) there are two types of capsule: hard and soft but better adjectives would be ‘two-piece’ in place of ‘hard’ and ‘one-piece’ in place of ‘soft’. The hard capsule consists of two pieces in the form of cylinders closed at one end; the shorter piece, called the ‘cap’, fits over the open end of the longer piece, called the ‘body’. That evidence indicates that the push-fit gelatin capsules of WO927 are hard-shell gelatin capsules.
Obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). The motivation to combine falls under an “obvious to try” rationale; see MPEP 2143(I)(E):
To reject a claim based on this rationale, Office personnel must resolve the Graham factual inquiries. Then, Office personnel must articulate the following:
(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; and
(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.
The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense.
Regarding (1): US495 teaches PCSK9-targeting ASOs were of interest in the art and WO232 teaches (Figs. 16-17) ASOs comprising the nucleobase and nt sequence of SEQ ID NO 19 were highly effective at inhibiting PCSK9 expression. US495 teaches oral formulations for nt delivery comprising a generic penetration enhancer. WO927 then teaches species of penetration enhancer including 5-CNAC.
Regarding (2): US495 and WO927 teach using penetration enhancers to enhance uptake of orally administered drugs. WO927 teaches 5 penetration enhancers, including 5-CNAC, that can be used for enteric delivery of any drug. That is clearly a finite number. It would have been obvious to use any of them.
Regarding (3): As discussed in the rejection, it would have been a simple matter to include WO232’s PCKS9-targeting ASO together with any of WO927’s five penetration enhancers in the oral formulation of US495 and one would have done so to determine which one optimizes bioavailability.
Therefore, the limitations of Claims 124-126, 129-132, 135-136, 139-140, and 142-152 would have been obvious in view of US495, WO232, and WO927.
Claim(s) 124-152 are rejected under 35 U.S.C. 103 as being unpatentable over US495, WO232, and WO927 as applied to claims 124-126, 129-132, 135-136, 139-140, and 142-152 in the 103 rejection above, and further in view of Wikipedia (“Enteric coating”. Page saved 27 August 2020. Available online at Wikipedia.org. Accessed on 10 September 2026, “Wikipedia”, of record on IDS), Evonik (2019. Eudragit®: Functional polymers to take control of your release profile Versatility and reliability for oral solid dosage forms. Available online at pharmaexcipients.com. Accessed on 14 September 2026, “Evonik”), Shin-Etsu (January 2020. Shin-Etsu AQOAT®. Page archived on 20 January 2020 and accessed via The Wayback Machine on 15 September 2026, “ShinEtsu”), and Stillhart (et al. 2020. Impact of gastrointestinal physiology on drug absorption in special populations––An UNGAP review. European J. Pharmaceut. Sci. 147:105280, “Stillhart”).
The teachings of US495, WO232, and WO927 as applicable to Claim(s) 124-126, 129-132, 135-136, 139-140, and 142-152 have been described above.
US495, WO232, and WO927 teach a composition for oral administration comprising (1) a 16-mer PCSK9-targeting ASO that is 100% complementary to claimed SEQ ID NO 31 and is a gapmer and (2) 5-CNAC; wherein the ASO and 5-CNAC are in a dosage form comprising an enteric coating. As discussed above, an enteric coating on a drug protects the drug from disintegration in the gastric environment so it is absorbed in the intestine.
US495, WO232, and WO927 do not teach that the enteric coating releases in the duodenum or distal jejunum of the small intestine (Claims 127-128). WO232, US495, WO232, and WO927 do not teach that the pH sensitive coating dissolves at a pH greater than 4.5 (Claim 133) or that the pH sensitive coating dissolves at a pH between about 5.5 and about 7.5 (Claim 134). US495, WO232, and WO927 do not teach that the pH sensitive coating comprises AQOAT® or AQOAT®-HF (Claims 137-138); or that the pH sensitive coating comprises EUDRAGIT® FS 30 D (Claim 141).
However, Wikipedia teaches (§Main text) an enteric coating is a polymer barrier applied to oral medication that prevents its dissolution or disintegration in the gastric environment and is used to obtain drug targeting, including to a specific part of the intestine. Wikipedia teaches (§Description):
Most enteric coatings work by presenting a surface that is stable at the intensely acidic pH found in the stomach, but breaks down rapidly at a higher pH (alkaline pH). For example, they will not dissolve in the gastric acids of the stomach (pH ~3), but they will in the alkaline (pH 7–9) environment present in the small intestine.
Therefore, the enteric coating of US495 would have possessed the property of dissolving in intestinal juices that have a higher pH value than that of the stomach. Wikipedia discloses that an exemplary pH sensitive enteric coating dissolves at pH 7-9 (which is greater than pH 4.5 [i.e., Claim 133] and encompasses pH between about 5.5 and about 7.5 or between about 7.2 and about 7.3 [i.e., Claim 134].
As discussed, US495 teaches a list of enteric coatings that includes methyl methylacrylate-methacrylic acid copolymers and hydroxypropyl methyl cellulose acetate succinate.
Brand name products comprising those enteric coatings were known in the art:
Evonik teaches (p. 2) a methyl methylacrylate-methacrylic acid copolymer product called EUDRAGIT® FS 30 D that is soluble above pH 7.0. ShinEtsu teaches (p. 1) various AQOAT® products, including LF that is soluble above pH 5.5, MF that is soluble above pH 6.0, and HF that is soluble above pH 6.8.
In addition, Stillhart teaches (§2. GI tract physiology in healthy adults ¶2) luminal fluids in the duodenum have pH 5-6 and those in the distal jejunum have pH 7-8.
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 composition of US495, WO232, and WO927 with the teachings about enteric coatings and various enteric coatings of Wikipedia, Evonik, and ShinEtsu and the teachings about the intestinal pH of Stillhart. One would have done so for the benefit of determining which enteric coating optimizes bioavailability of the PCSK9 inhibitor (i.e., concentration in plasma) and maximizes PCKS9 inhibition. One would have been motivated to do so with a reasonable expectation of success because US495 teaches (Col 6 L35-42) enteric coating improves delivery of an oligomer through the stomach and into the site of absorption in the small intestine, Stillhart teaches different parts of the small intestine (i.e. the duodenum and distal jejunum/ileum) have different pH ranges, and the art teaches different enteric coatings that are soluble at each pH. The enteric coatings of Evonik and ShinEtsu would have made it feasible to determine whether bioavailability changes depending on absorption by different parts of the small intestine. Therefore, all the limitations of Claims 127-128 and 132-141 (and Claims 124-126, 129-132, 135-136, 139-140, and 142-152) would have been obvious in view of US495, WO232, WO927, Wikipedia, Evonik, ShinEtsu, and Stillhart.
Claim(s) 124-126, 129-132, 135, 142-143, and 145-152 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication No. WO2014/207232 (published 31 December 2014, “WO232”, of record on IDS), Shapiro (et al. 2018. PCSK9: From basic science discoveries to clinical trials. Circ. Res. 122:1420, “Shapiro”), International Publication No. WO 99/60012 (published 25 November 1999, “WO012”), and International Publication No. WO 2018/033927 (published 22 February 2018, “WO927”) as evidenced by Jones (2016. “Hard capsules”. Chapter 33 in Basic Medical Key. Available at basicmedicalkey.com. Accessed on 14 September 2026, “Jones”).
All references to WO document p# refer to the PDF p#.
WO232, drawn to ASOs for targeting PCSK9, teaches a GalNAc-conjugated 16-mer ASO that comprises 100% complementarity to SEQ ID NO 31 (UGGGUUUUGUAGCAUU), as shown by the following alignment:
RESULT 1
US-18-256-632-31/c
Query Match 100.0%; Score 16; DB 1; Length 16;
Best Local Similarity 100.0%;
Matches 16; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AATGCTACAAAACCCA 16 WO232 SEQ ID NO 19
||||||||||||||||
Db 16 AATgctacaaaacCCA 1 Reverse complement of claimed SEQ ID NO 31
That compound is shown here in a modified excerpt of WO232’s Fig. 5:
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Greyscale
WO232 teaches (Table 1 on p. 10, p. 11 L5-20) SEQ ID NO 19 comprises LNA gapmer oligont and the lowercase letters are DNA units, and the capital letters are LNA units. WO232 describes (pp. 34-36 L6-17) gapmer design: a gapmer has a X’-Y’-Z’ structure wherein Y’ comprises at least 4-5 consecutive DNA nt and each of X’ and Z’ comprise 1-6 nt analogs that can be LNA. Therefore, WO232 teaches the limitations of Claim 124(i).
WO232 teaches (pp. 46-47 L3-19) using lipophilic conjugate moieties, including caprylic acid, that enhance cellular penetration and delivery to hepatocytes, indicating delivery to that tissue is desirable.
Regarding Claims 142-143 and the optional limitations of Claims 148(b) and 149: WO232 teaches (p. 60 L21-34) combination treatments that use the ASO in combination with another therapeutic agent that can be other cholesterol lowering compounds (including various bile salt sequestering resins, e.g., cholestyramine, colestipol, and colesevelam hydrochloride), HMGCoA-reductase inhibitors (i.e., statins; e.g., lovastatin, cerivastatin, pravastatin, atorvastatin, simvastatin, rosuvastatin, and fluvastatin), nicotinic acid, fibric acid derivatives, probucol, neomycin, dextrothyroxine, plant-stanol esters, cholesterol absorption inhibitors, implitapide, inhibitors of bile acid transporters, regulators of hepatic CYP7a, estrogen replacement therapeutics, and anti-inflammatories. Therefore, WO232 teaches limitations of Claims 142-143 and the optional limitations of Claims 148(b) and 149.
WO232 teaches (pp. 4-5 L20-30) pharmaceutical compositions comprising their ASO and a pharmaceutically acceptable diluent, carrier, salt or adjuvant. WO232 teaches (same §) those pharmaceutical compositions can be used to treat various PCSK9-related diseases and disorder.
WO232 does not teach the exact body tissues where PCSK9 is expressed.
However, Shapiro teaches (§PCSK9 Biology-Regulation of PCSK9 Levels and Function ¶1) human PCSK9 is expressed in multiple tissues and that liver, small intestine, and kidney are the major sources of its plasma levels. Shapiro teaches (§Cost, Cost-Effectiveness, and Barriers to Access ¶2) PCSK9 inhibition with oligont may be a cost-effective treatment strategy.
That would have motivated an artisan to formulate a delivery system that would deliver the PCKS9-inhibiting ASO drug of WO232 to the tissues where PCSK9 is most highly expressed. They would have done so for the benefit of producing a cost-effective treatment strategy that reaches tissues where PCSK9 is most highly expressed.
WO232 and Shapiro do not teach that the pharmaceutical composition is comprised in a dosage form comprising an enteric coating (Claim 124), that the composition comprises at least one excipient (Claim 125) wherein the excipient can be a preservative or lubricant (Claim 126), that the composition is formulated into a tablet or capsule dosage form (Claims 130 and 145), comprises a pH sensitive coating (Claim 131) that is resistant to stomach acid (Claim 132) and can comprise hydroxypropyl methylcellulose (Claim 135), or that the dosage form comprises about 1-100 mg of the ASO and about 200 mg of the penetration enhancer (Claims 146-148).
However, WO012, drawn to pharmaceutical compositions comprising oligonucleotides for systemic delivery and oral dosage formulations, teaches those limitations. WO012 teaches (§Abstract) pharmaceutical compositions of oligont that include one or more penetration enhancers so an oligont is transported across mucosal membranes.
WO012 teaches (p. 4 L15-30) oral delivery offers easier, less injurious, and less expensive administration of oligont drugs, but that it requires compositions that enhance the availability of the drug. WO012 teaches (p. 7 L1-15) bioavailability studies determine the degree of intestinal absorption of a drug by measuring peripheral blood levels after an oral dose. That indicates that an orally administered drug’s bioavailability depends on intestinal absorption.
Regarding Claims 124, 130-132, 135, and 145: WO012 teaches (pp. 54-56 L36-6; pp. 97-102 L32-20) oral formulations that are capsules or tablets that are coated with enteric materials and formulated to provide slow release of the active ingredients. WO012 teaches (same §) formulation in an acid-resistant enteric material that protects the nucleic acid from the pH extremes of the stomach to optimize its delivery to a particular mucosal site.
As discussed in §Claim interpretation, an enteric formulation is, by definition, one that protects a drug from degradation in the stomach and allows the drug to be released in the small intestine. Although WO012 teaches acid-resistant tablets and doesn’t use the same terminology as what is claimed (i.e., pH sensitive coating), the text makes clear that WO012 is talking about pH sensitive coating because it says the formulation can contain an enteric material effective in protecting the nucleic acid from pH extremes of the stomach [emphasis added].
WO012 teaches (pp. 54-56 L36-6; pp. 97-102 L32-20) enteric materials, including hydroxypropyl methyl cellulose phthalate (known in the art as a pH sensitive coating) that can be used to produce acid-resistant tablets, capsules, and caplets. WO012 teaches (same §) an example of an oral formulation of tablets comprising ASO and the penetration enhancer sodium caprate wherein the tablets are dipped in an enteric coating solution. WO012 teaches (same §) administering the oral formulation to beagle dogs and finding (Table 21) the enteric coating provided the highest bioavailability and plasma concentration of the ASO.
Therefore, WO012 teaches some limitations of Claims 124, 130-132, 135, and 145.
Regarding Claims 125-126: WO012 teaches (pp. 8-10 L22-13, p. 20 L4-25, p. 46 L7-10) penetration enhancers facilitate drug transport across mucus membranes without interfering with oligont activity and allow an oligont to be introduced to an animal’s body without side effects. WO012 teaches (same §) excipients that can be (p. 8, pp. 20-21 L25-5) preservatives, (p. 20) lubricants, and (p. 56 L1-5) plasticizers.
Regarding the liposome of Claim 130: WO012 teaches (p. 10 L21-33) their compositions can comprise liposomes.
Regarding the dosage form that comprises about 100 mg ASO and about 200 mg of penetration enhancer (some limitations of Claims 146-148): WO012 teaches (p. 56 L5-35) various formulations are known in the art and the therapeutically active compound should be present in each in a concentration of about 0.5% to about 95% by weight of the total mixture. WO012 teaches (pp. 57-58 L9-16) dosage formulations vary depending on a patient’s needs and those of ordinary skill can easily determine optimum dosages and dosing methodologies. WO012 describes (p. 98 L1-20) 1100 mg tablets comprising 124 mg ASO and 200 mg of the penetration enhancer sodium caprate.
Regarding the dry blend of Claim 150: WO012 teaches (p. 98) an example describing the composition and preparation of oral dosage formulations wherein the ASO was passed through a mesh screen and other ingredients, including the penetration enhancer, were added. WO012 teaches the powder was then mixed thoroughly, compressed into tablets, and some of them were used that way and others were dipped in enteric coating. Therefore, WO012 teaches formulating ingredients in a dry blend.
WO012 teaches (pp. 15-16 L31-35) penetration enhancers that are fatty acid derivatives and can include caprylic acid.
WO232, Shapiro, and WO012 do not teach using the specific cellular penetration enhancer 5-CNAC (Claim 124[ii]), that the salt is a monosodium or disodium salt thereof (Claim 129), that 5-CNAC is included in a formulation in a dose of 200 mg (Claims 146-148), or that the composition can be formulated in a gelatin capsule (Claim 151) or a hard-shell gelatin capsule (Claim 152).
However, WO927, generally drawn to formulations for oral administration of active agents, teaches (§Abstract) pharmaceutical composition comprising a therapeutically effective amount of a therapeutically active agent and an effective amount of the absorption enhancer 5-CNAC.
Although WO927 uses the term “absorption enhancer” and WO012 uses the term “penetration enhancer”, it is clear that both terms refer to the same phenomenon because WO927 teaches (p. 63 L10-16) their compositions are particularly suitable for enhancing the absorption of therapeutically active agents whose absorption upon oral administration is limited by a molecular weight and hydrophilicity (which inhibit crossing of lipid membranes in the gastrointestinal tract). Similarly, WO012 discussed improving transport of oligont across mucosa.
Regarding Claim 124: WO927 teaches (p. 7 L1-12) a pharmaceutical composition comprising a therapeutically active agent and an absorption enhancer wherein the absorption enhancer is 5-CNAC. WO927 teaches (p. 96 L25-31) their invention encompasses formulations of many relevant therapeutically active agents yet to be developed.
Regarding Claim 129: WO927 teaches (p. 37 L3-10) the 5-CNAC can be in monosodium or disodium form.
Regarding the dose of Claims 146-148: WO927 teaches (pp. 41-42 L30-25) using absorption enhancer in a range of a total of 10-200 mg or 10-500 mg per dose.
Regarding the limitations of Claims 151-152: WO927 teaches (p. 86 L11-21) dosage forms for oral use that include push-fit gelatin capsules and soft gelatin capsules.
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 PCSK9-targeting ASO of WO232 with Shapiro’s teachings about where PCKS9 is expressed, WO012’s formulations for oral delivery (including the enteric coating comprising hydroxypropylmethyl cellulose and the penetration/absorption enhancer), and WO927’s specific penetration/absorption enhancer 5-CNAC. They would have done so for the benefit of determining whether a formulation for oral delivery comprising 5-CNAC is a suitable alternative to or offers improvements over sodium caprate (which was used in WO012’s tablets for oral delivery of ASOs). One would have been motivated to do so with a reasonable expectation of success because WO232 teaches PCSK9-inhibiting ASOs, because Shapiro teaches PCSK9 is highly expressed in the intestine, because WO012 teaches (cited above) administering an active substance to the intestine using penetration enhancers and an enteric coating, and because WO927 teaches 5-CNAC is an absorption/penetration enhancer that can be used with any therapeutically active ingredient.
Regarding the dosage forms comprising about 1-100 mg ASO and about 200 mg of 5-CNAC (Claims 146-148): formulating capsules or tablets with different amounts of ASO and 5-CNAC would have been obvious in view of the art because WO927 teaches (cited above) a quantity of about 10-200 mg 5-CNAC is an appropriate amount. WO012 teaches (cited above) tablets comprising 124 mg of an ASO (which is “about 100 mg”) and 200 mg of the penetration enhancer sodium caprate (SC).
It would have been a simple matter to swap WO232’s PCSK9-targeting ASO for that of WO012 and it would have been a simple matter to swap WO927’s 200 mg of 5-CNAC for the 200 mg SC of WO012. Doing so would have produced all the limitations of Claim 146.
It also would have been obvious to vary the amount of active ingredient (i.e., ASO) from 0.5-95% of the total dosage weight for the benefits of optimizing bioavailability and cost-effectiveness (by minimizing the amount of ASO in each dosage formulation). One would have been motivated to do so with a reasonable expectation of success because WO012 teaches (p. 57) various factors determine a dosage formulation and accounting for those is well within the purview of a person of ordinary skill. It would have been obvious to an artisan optimizing the dosage formulations to produce compositions with different amounts of active ingredients, including tablets or capsules comprising 200 mg 5-CNAC and 100 mg, 50 mg, 25 mg, 10 mg, 5 mg, or 1 mg ASO, thereby producing the limitations of Claim 147. The enteric formulation would have ensured release of the ASO and any other active ingredient (including the statin of WO232) in a small intestine, thereby producing the limitations of Claims 148-149.
Regarding the dry blend of Claim 150: it would have been obvious to produce dosage formulations comprising a dry blend of WO232’s ASO and WO927’s 5-CNAC because WO012 discussed producing tablets from a dry blend and it would have been a simple matter to use WO927’s 5-CNAC in the formulation preparation method of WO012.
Regarding the hard-shell gelatin capsule of Claim 152: Jones describes (§Introduction) there are two types of capsule: hard and soft but better adjectives would be ‘two-piece’ in place of ‘hard’ and ‘one-piece’ in place of ‘soft’. The hard capsule consists of two pieces in the form of cylinders closed at one end; the shorter piece, called the ‘cap’, fits over the open end of the longer piece, called the ‘body’. That evidence indicates that the push-fit gelatin capsules of WO927 are hard-shell gelatin capsules.
Obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). The motivation to combine falls under an “obvious to try” rationale; see MPEP 2143(I)(E):
To reject a claim based on this rationale, Office personnel must resolve the Graham factual inquiries. Then, Office personnel must articulate the following:
(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; and
(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.
The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense.
Regarding (1): WO232 teaches that PCSK9-targeting ASOs were of interest in the art and (Figs. 16-17) ASOs comprising the nucleobase and nt sequence of SEQ ID NO 19 were highly effective at inhibiting PCSK9 expression. Shapiro teaches that PCSK9 is highly expressed in the intestine. WO012 teaches artisans were interested in formulations for oral delivery and that absorption by the small intestine influences bioavailability. WO012 teaches they administered to beagle dogs tablets comprising an enteric coating encasing penetration enhancers + ASO, and the formulation was available in plasma, indicating it passed through the stomach and was absorbed by the intestine.
Regarding (2): WO012 and WO927 teach using penetration enhancers to enhance uptake of orally administered drugs. WO927 teaches 5 penetration enhancers, including 5-CNAC, that can be used for enteric delivery of any drug.
Regarding (3): As discussed in the rejection, it would have been a simple matter to include WO232’s PCKS9-targeting ASO together with any of WO927’s five penetration enhancers in the oral formulation of WO012.
Therefore, the limitations of Claims 124-126, 129-132, 135, 142-143, and 145-152 would have been obvious in view of WO232, Shapiro, WO012, and WO927.
Claim(s) 124-143 and 145-152 are rejected under 35 U.S.C. 103 as being unpatentable over WO232, Shapiro, WO012, and WO927 as applied to claims 124-126, 129-132, 135, 142-143, and 145-152 in the 103 rejection above, and further in view of Wikipedia (“Enteric coating”. Page saved 27 August 2020. Available online at Wikipedia.org. Accessed on 10 September 2026, “Wikipedia”, of record on IDS), Evonik (2019. Eudragit®: Functional polymers to take control of your release profile Versatility and reliability for oral solid dosage forms. Available online at pharmaexcipients.com. Accessed on 14 September 2026, “Evonik”), Shin-Etsu (January 2020. Shin-Etsu AQOAT®. Page archived on 20 January 2020 and accessed via The Wayback Machine on 15 September 2026, “ShinEtsu”), and Stillhart (et al. 2020. Impact of gastrointestinal physiology on drug absorption in special populations––An UNGAP review. European J. Pharmaceut. Sci. 147:105280, “Stillhart”).
The teachings of WO232, Shapiro, WO012, and WO927 as applicable to Claim(s) 124-126, 129-132, 135, 142-143, and 145-152 have been described above.
WO232, Shapiro, WO012, and WO927 teach a composition for oral administration comprising (1) a 16-mer PCSK9-targeting ASO that is 100% complementary to claimed SEQ ID NO 31 and is a gapmer and (2) 5-CNAC; wherein the ASO and 5-CNAC are in a dosage form comprising an enteric coating. As discussed above, an enteric coating on a drug protects the drug from disintegration in the gastric environment so it is absorbed in the intestine.
WO232, Shapiro, WO012, and WO927 do not teach that the enteric coating releases in the duodenum or distal jejunum of the small intestine (Claims 127-128). WO232, Shapiro, WO012, and WO927 do not teach that the pH sensitive coating dissolves at a pH greater than 4.5 (Claim 133) or that the pH sensitive coating dissolves at a pH between about 5.5 and about 7.5 (Claim 134). WO232, Shapiro, WO012, and WO927 do not teach that the pH sensitive coating comprises hydroxypropylmethyl cellulose acetate succinate (Claim 136), AQOAT® or AQOAT®-HF (Claims 137-138); or that the pH sensitive coating comprises methyl methylacrylate-methacrylic acid copolymers (Claim 139), that the copolymer is a EUDRAGIT® polymer (Claims 140), or that the EUDRAGIT® polymer is EUDRAGIT® FS 30 D (Claim 141).
However, Wikipedia teaches (§Main text) an enteric coating is a polymer barrier applied to oral medication that prevents its dissolution or disintegration in the gastric environment and is used to obtain drug targeting, including to a specific part of the intestine. Wikipedia teaches (§Description):
Most enteric coatings work by presenting a surface that is stable at the intensely acidic pH found in the stomach, but breaks down rapidly at a higher pH (alkaline pH). For example, they will not dissolve in the gastric acids of the stomach (pH ~3), but they will in the alkaline (pH 7–9) environment present in the small intestine.
Therefore, the enteric coating of WO012 would have possessed the property of dissolving in intestinal juices that have a higher pH value than that of the stomach. Wikipedia discloses that an exemplary pH sensitive enteric coating dissolves at pH 7-9 (which is greater than pH 4.5 [i.e., Claim 133] and encompasses pH between about 5.5 and about 7.5 or between about 7.2 and about 7.3 [i.e., Claim 134].
Wikipedia teaches (§Composition) a list of enteric coatings that includes methyl methylacrylate-methacrylic acid copolymers and hydroxypropyl methyl cellulose acetate succinate.
Brand name products comprising those enteric coatings were known in the art:
Evonik teaches (p. 2) a methyl methylacrylate-methacrylic acid copolymer product called EUDRAGIT® FS 30 D that is soluble above pH 7.0. ShinEtsu teaches (p. 1) various AQOAT® products, including LF that is soluble above pH 5.5, MF that is soluble above pH 6.0, and HF that is soluble above pH 6.8.
In addition, Stillhart teaches (§2. GI tract physiology in healthy adults ¶2) luminal fluids in the duodenum have pH 5-6 and those in the distal jejunum have pH 7-8.
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 composition of WO232, Shapiro, WO012, and WO927 with the teachings about enteric coatings and various enteric coatings of Wikipedia, Evonik, and ShinEtsu and the teachings about the intestinal pH of Stillhart. One would have done so for the benefit of determining which enteric coating optimizes bioavailability of the PCSK9 inhibitor (i.e., concentration in plasma) and maximizes PCKS9 inhibition. One would have been motivated to do so with a reasonable expectation of success because WO012 teaches (p. 7) bioavailability depends on intestinal absorption, Stillhart teaches different parts of the small intestine (i.e. the duodenum and distal jejunum/ileum) have different pH ranges, and the art teaches different enteric coatings that are soluble at each pH. The enteric coatings of Evonik and ShinEtsu would have made it feasible to determine whether bioavailability changes depending on absorption by different parts of the small intestine. Therefore, all the limitations of Claims 127-128 and 132-141 (and Claims124-126, 129-132, 135, 142-143, and 145-152) would have been obvious in view of WO232, Shapiro, WO012, WO927, Wikipedia, Evonik, ShinEtsu, and Stillhart.
Claim(s) 124-126, 129-132, 135, and 142-152 are rejected under 35 U.S.C. 103 as being unpatentable over WO232, Shapiro, WO012, and WO927 as applied to claims 124-126, 129-132, 135, 142-143, and 145-152 in the 103 rejection above, and further in view of Laukova (et al. 2020. Deoxyribonucleases and Their Applications in Biomedicine. Biomolecules 1:1036, “Laukova”).
The teachings of WO232, Shapiro, WO012, and WO927 as applicable to Claim(s) 124-126, 129-132, 135, 142-143, 145-149, and 151-152 have been described above.
WO232, Shapiro, WO012, and WO927 teach a composition for oral administration comprising (1) a 16-mer PCSK9-targeting ASO that is 100% complementary to claimed SEQ ID NO 31 and is a gapmer and (2) 5-CNAC; wherein the ASO and 5-CNAC are in a dosage form comprising an enteric coating. As discussed above, an enteric coating on a drug protects the drug from disintegration in the gastric environment so it is absorbed in the intestine.
WO012 teaches (p. 18 L11-25) incorporating to the ASO formulations chelating agents which have an added advantage of serving as DNase inhibitors. A chelating agent that is a DNase inhibitor is a kind of enzyme-inhibiting agent that prevents enzymatic degradation of an nucleic acid. WO012 teaches (same §) chelating agents sequester metallic ions, thereby functioning as DNase inhibitors because DNA nucleases require a divalent metal ion for catalysis.
WO232, Shapiro, WO012, and WO927 do not teach that the chelating agent prevents degradation of the ASO in the small intestine.
However, Laukova teaches (2. DNase I ¶2) DNase I is secreted into the small intestine and (same § and ¶) other DNase I enzymes are active even in the stomach.
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 composition of WO232, Shapiro, WO012, and WO927 with the chelating agent of WO012 and teachings of Laukova for the benefit of inhibiting DNase in the gastrointestinal environment. One would have been motivated to do so with a reasonable expectation of success because Laukova teaches DNases exist and function in the stomach and small intestine, and WO012 teaches formulating an ASO compound with enzyme inhibitors that are chelating agents and teaches doing so is beneficial because chelating agents inhibit DNase. Therefore, the limitations of Claim 144 would have been obvious in view of WO232, Shapiro, WO012, WO927, and Laukova.
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 124-152 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12291708 (“US708”) in view of Wikipedia (“Enteric coating”. Page saved 27 August 2020. Available online at Wikipedia.org. Accessed on 10 September 2026, “Wikipedia”, of record on IDS), Evonik (2019. Eudragit®: Functional polymers to take control of your release profile Versatility and reliability for oral solid dosage forms. Available online at pharmaexcipients.com. Accessed on 14 September 2026, “Evonik”), Shin-Etsu (January 2020. Shin-Etsu AQOAT®. Page archived on 20 January 2020 and accessed via The Wayback Machine on 15 September 2026, “ShinEtsu”), and Stillhart (et al. 2020. Impact of gastrointestinal physiology on drug absorption in special populations––An UNGAP review. European J. Pharmaceut. Sci. 147:105280, “Stillhart”).
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are directed to pharmaceutical compositions for oral administration of an ASO to a subject, the compositions comprising (1) a 16-mer ASO comprising (US708) the sequence of SEQ ID NO 19 or (instant claims) a sequence 100% complementary to claimed SEQ ID NO 31 and (2) 5-CNAC; wherein the two components are formulated in an enteric coating that releases in the small intestine. US708 SEQ ID NO 19 is 100% complementary to claimed SEQ ID NO 31.
The instant claims recite additional components not recited in the patented claims but those are taught by the prior art of Wikipedia (§Main text, §Description, §Composition), Evonik (p. 2), ShinEtsu (p. 1), and Stillhart (§2. GI tract physiology in healthy adults ¶2).
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 composition of the US708 claims with the teachings and various enteric coatings of Wikipedia, Evonik, and ShinEtsu and the teachings about the intestinal pH of Stillhart. One would have done so for the benefit of determining which enteric coating optimizes bioavailability of the PCSK9 inhibitor (i.e., concentration in plasma) and maximizes PCKS9 inhibition. One would have been motivated to do so with a reasonable expectation of success because the US708 claims recite any enteric coating and Wikipedia, Evonik, and ShinEtsu teach enteric coatings known in the art to dissolve at different pH, and because Stillhart teaches different parts of the small intestine (i.e. the duodenum and distal jejunum/ileum) have different pH ranges. The enteric coatings of Evonik and ShinEtsu would have made it feasible to determine whether bioavailability changes depending on absorption by different parts of the small intestine. Therefore, the instant claims would have been obvious in view of the US708 claims and Wikipedia, Evonik, ShinEtsu, and Stillhart.
Claims 124-152 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 9364495 (“US495”) in view of International Publication No. WO2014/207232 (published 31 December 2014, “WO232”, of record on IDS), International Publication No. WO 99/60012 (published 25 November 1999, “WO012”), Laukova (et al. 2020. Deoxyribonucleases and Their Applications in Biomedicine. Biomolecules 1:1036, “Laukova”), International Publication No. WO 2018/033927 (published 22 February 2018, “WO927”), Wikipedia, Evonik, ShinEtsu, and Stillhart .
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are directed to pharmaceutical compositions for oral administration of an ASO to a subject, or to methods for using them.
The instant claims recite compositions comprising (1) a 16-mer ASO comprising a sequence 100% complementary to claimed SEQ ID NO 31 and (2) 5-CNAC; wherein the two components are formulated in an enteric coating that releases in the small intestine.
The US495 claims recite methods of treating certain disorders by administering a composition comprising an LNA oligomer that targets APOB and a penetration enhancer, wherein the ratio between the LNA oligo and the penetration enhancer is at least 5 : 1 (w/w), and wherein the oligomer can be 16 nt long.
The instant claims recite additional components not recited in the patented claims, including that the ASO comprises a sequence 100% complementary to claimed SEQ ID NO 31, but those are taught by the prior art of WO232 (Table 1 on p. 10, p. 11 L5-20; pp. 34-36 L6-17, pp. 46-47 L3-19, p. 60 L21-34, pp. 4-5 L20-30), WO012 (p. 7 L1-15, pp. 54-56 L36-6; pp. 97-102 L32-20; pp. 54-56 L36-6; pp. 97-102 L32-20; pp. 8-10 L22-13, p. 20 L4-25, p. 46 L7-10; p. 8, pp. 20-21 L25-5; p. 20, p. 56 L1-5, p. 10 L21-33, p. 56 L5-35, pp. 57-58 L9-16, p. 98 L1-20, p. 98, pp. 15-16 L31-35, p. 18 L11-25), Laukova (2. DNase I ¶2), WO927 (§Abstract, p. 63 L10-16, p. 7 L1-12, p. 96 L25-31, p. 37 L3-10, pp. 41-42 L30-25, p. 86 L11-21), Wikipedia (§Main text, §Description, §Composition), Evonik (p. 2), ShinEtsu (p. 1), and Stillhart (§2. GI tract physiology in healthy adults ¶2).
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 composition used in the methods of the US495 claims with the ASO of WO232, the enzyme inhibitor of WO012 and Laukova, the 5-CNAC of WO927, and the teachings and various enteric coatings of Wikipedia, Evonik, and ShinEtsu and the teachings about the intestinal pH of Stillhart. One would have done so for the benefits of inhibiting PCSK9 expression and treating additional disorders. One would have done so for the benefits of optimizing absorption (by trying additional penetration enhancing agents) and of determining which enteric coating optimizes bioavailability of the PCSK9 inhibitor (i.e., concentration in plasma) and maximizes PCKS9 inhibition. One would have been motivated to do so with a reasonable expectation of success because the US495 claims recite oral formulations, WO232 teaches ASOs that target PCSK9, WO012 and Laukova teach enzyme inhibitors, WO012 and WO927 teach ASO oral formulations and WO927 teaches oral formulations comprising 5-CNAC, and Wikipedia, Evonik, and ShinEtsu teach enteric coatings known in the art to dissolve at different pH, and because Stillhart teaches different parts of the small intestine (i.e. the duodenum and distal jejunum/ileum) have different pH ranges. Therefore, the instant claims would have been obvious in view of the US495 claims, WO232, WO012, Laukova, WO927, Wikipedia, Evonik, ShinEtsu, and Stillhart.
Claims 124-152 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 9566293 (“US293”) in view of WO232, WO012, Laukova, WO927, Wikipedia, Evonik, ShinEtsu, and Stillhart .
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are directed to pharmaceutical compositions for oral administration of an LNA oligomer to a subject, or to methods for using them.
The instant claims recite compositions comprising (1) a 16-mer ASO comprising a sequence 100% complementary to claimed SEQ ID NO 31 and (2) 5-CNAC; wherein the two components are formulated in an enteric coating that releases in the small intestine.
The US293 claims recite methods of inhibiting a target miR in the liver by administering a composition comprising an LNA oligomer that targets the miR and a penetration enhancer, wherein the ratio between the LNA oligo and the penetration enhancer is at least 5 : 1 (w/w), and wherein the oligomer can be 16 nt long.
The instant claims recite additional components not recited in the patented claims, including that the ASO comprises a sequence 100% complementary to claimed SEQ ID NO 31, but those are taught by the prior art of WO232 (Table 1 on p. 10, p. 11 L5-20; pp. 34-36 L6-17, pp. 46-47 L3-19, p. 60 L21-34, pp. 4-5 L20-30), WO012 (p. 7 L1-15, pp. 54-56 L36-6; pp. 97-102 L32-20; pp. 54-56 L36-6; pp. 97-102 L32-20; pp. 8-10 L22-13, p. 20 L4-25, p. 46 L7-10; p. 8, pp. 20-21 L25-5; p. 20, p. 56 L1-5, p. 10 L21-33, p. 56 L5-35, pp. 57-58 L9-16, p. 98 L1-20, p. 98, pp. 15-16 L31-35, p. 18 L11-25), Laukova (2. DNase I ¶2), WO927 (§Abstract, p. 63 L10-16, p. 7 L1-12, p. 96 L25-31, p. 37 L3-10, pp. 41-42 L30-25, p. 86 L11-21), Wikipedia (§Main text, §Description, §Composition), Evonik (p. 2), ShinEtsu (p. 1), and Stillhart (§2. GI tract physiology in healthy adults ¶2).
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 composition used in the methods of the US293 claims with the ASO of WO232, the enzyme inhibitor of WO012 and Laukova, the 5-CNAC of WO927, and the teachings and various enteric coatings of Wikipedia, Evonik, and ShinEtsu and the teachings about the intestinal pH of Stillhart. One would have done so for the benefits of inhibiting PCSK9 expression and treating additional disorders. One would have done so for the benefits of optimizing absorption (by trying additional penetration enhancing agents) and of determining which enteric coating optimizes bioavailability of the PCSK9 inhibitor (i.e., concentration in plasma) and maximizes PCKS9 inhibition. One would have been motivated to do so with a reasonable expectation of success because the US293 claims recite oral formulations, WO232 teaches ASOs that target PCSK9, WO012 and Laukova teach enzyme inhibitors, WO012 and WO927 teach ASO oral formulations and WO927 teaches oral formulations comprising 5-CNAC, and Wikipedia, Evonik, and ShinEtsu teach enteric coatings known in the art to dissolve at different pH, and because Stillhart teaches different parts of the small intestine (i.e. the duodenum and distal jejunum/ileum) have different pH ranges. Therefore, the instant claims would have been obvious in view of the US293 claims, WO232, WO012, Laukova, WO927, Wikipedia, Evonik, ShinEtsu, and Stillhart.
Claims 124-152 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3-4, 9, 11-13, 15-16, 18-33 of copending Application No. 17726371 (“App371”) in view of WO232, Wikipedia, Evonik, ShinEtsu, and Stillhart.
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are directed to pharmaceutical compositions for oral administration of an ASO to a subject, the compositions comprising (1) an ASO that can be (App371, Claims 18-19) CIVI008 or (instant claims) a sequence 100% complementary to claimed SEQ ID NO 31 and (2) an oral delivery agent that can be 5-CNAC; wherein the two components are formulated in an enteric coating that releases in the small intestine. App371’s CIVI008 comprises a sequence that is 100% complementary to claimed SEQ ID NO 31.
The instant claims recite additional components not recited in the copending claims but those are taught by the prior art of WO232 (p. 60 L21-34), Wikipedia (§Main text, §Description, §Composition), Evonik (p. 2), ShinEtsu (p. 1), and Stillhart (§2. GI tract physiology in healthy adults ¶2).
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 composition of the App371 claims with the additional agent of WO232, the teachings and various enteric coatings of Wikipedia, Evonik, and ShinEtsu; and the teachings about the intestinal pH of Stillhart. One would have done so for the benefits of treating additional conditions in patients and determining which enteric coating optimizes bioavailability of the PCSK9 inhibitor (i.e., concentration in plasma) and maximizes PCKS9 inhibition. One would have been motivated to do so with a reasonable expectation of success because WO232 teaches using additional therapeutic agents with their ASO and because the App371 claims recite any enteric coating and Wikipedia, Evonik, and ShinEtsu teach enteric coatings known in the art to dissolve at different pH, and because Stillhart teaches different parts of the small intestine (i.e. the duodenum and distal jejunum/ileum) have different pH ranges. The enteric coatings of Evonik and ShinEtsu would have made it feasible to determine whether bioavailability changes depending on absorption by different parts of the small intestine. Therefore, the instant claims would have been obvious in view of the App371 claims and WO232, Wikipedia, Evonik, ShinEtsu, and Stillhart.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 124-152 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18, 20-21, 23-35 of copending Application No. 18555229 (“App229”) in view of International Publication No. WO2014/207232 (published 31 December 2014, “WO232”, of record on IDS), Wikipedia, Evonik, ShinEtsu, and Stillhart.
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are directed to (instant claims) pharmaceutical compositions for oral administration of an ASO to a subject, or to methods of making the compositions in a tablet or capsule form, the compositions comprising (1) an ASO that can be (App229, Claim 23) CIVI008 or (instant claims) a sequence 100% complementary to claimed SEQ ID NO 31 and (2) an oral delivery agent that can be 5-CNAC; wherein the two components are formulated in an enteric coating that releases in the small intestine. App229’s CIVI008 consists of a sequence that is 100% complementary to claimed SEQ ID NO 31. Both claim sets are directed to the same subject matter because the instant claims are directed to compositions and the App229 claims are directed to methods of making those exact compositions.
The instant claims recite additional components not recited in the copending claims but those are taught by the prior art of WO232 (p. 60 L21-34), Wikipedia (§Main text, §Description, §Composition), Evonik (p. 2), ShinEtsu (p. 1), and Stillhart (§2. GI tract physiology in healthy adults ¶2).
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 composition of the App229 claims with the additional agent of WO232, the teachings and various enteric coatings of Wikipedia, Evonik, and ShinEtsu; and the teachings about the intestinal pH of Stillhart. One would have done so for the benefits of treating additional conditions in patients and determining which enteric coating optimizes bioavailability of the PCSK9 inhibitor (i.e., concentration in plasma) and maximizes PCKS9 inhibition. One would have been motivated to do so with a reasonable expectation of success because WO232 teaches using additional therapeutic agents with their ASO. One would have been motivated to do so with a reasonable expectation of success because the App229 claims recite any enteric coating and Wikipedia, Evonik, and ShinEtsu teach enteric coatings known in the art to dissolve at different pH, and because Stillhart teaches different parts of the small intestine (i.e. the duodenum and distal jejunum/ileum) have different pH ranges. The enteric coatings of Evonik and ShinEtsu would have made it feasible to determine whether bioavailability changes depending on absorption by different parts of the small intestine. Therefore, the instant claims would have been obvious in view of the App229 claims and WO232, Wikipedia, Evonik, ShinEtsu, and Stillhart.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 124-152 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 124-143 of copending Application No. 19090296 (reference application, “App296”) in view of Wikipedia, Evonik, ShinEtsu, and Stillhart.
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are directed to pharmaceutical compositions for oral administration of an ASO to a subject, the compositions comprising (1) a 16-mer ASO comprising (App296) the sequence of SEQ ID NO 19 or (instant claims) a sequence 100% complementary to claimed SEQ ID NO 31 and (2) an oral delivery agent that can be 5-CNAC; wherein the two components are formulated in an enteric coating that releases in the small intestine. App296 SEQ ID NO 19 is 100% complementary to claimed SEQ ID NO 31.
The instant claims recite additional components not recited in the copending claims but those are taught by the prior art of Wikipedia (§Main text, §Description, §Composition), Evonik (p. 2), ShinEtsu (p. 1), and Stillhart (§2. GI tract physiology in healthy adults ¶2).
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 composition of the App296 claims with the teachings and various enteric coatings of Wikipedia, Evonik, and ShinEtsu and the teachings about the intestinal pH of Stillhart. One would have done so for the benefit of determining which enteric coating optimizes bioavailability of the PCSK9 inhibitor (i.e., concentration in plasma) and maximizes PCKS9 inhibition. One would have been motivated to do so with a reasonable expectation of success because the App296 claims recite any enteric coating and Wikipedia, Evonik, and ShinEtsu teach enteric coatings known in the art to dissolve at different pH, and because Stillhart teaches different parts of the small intestine (i.e. the duodenum and distal jejunum/ileum) have different pH ranges. The enteric coatings of Evonik and ShinEtsu would have made it feasible to determine whether bioavailability changes depending on absorption by different parts of the small intestine. Therefore, the instant claims would have been obvious in view of the App296 claims and Wikipedia, Evonik, ShinEtsu, and Stillhart.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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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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