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 .
Priority
This Application is a National Entry Application under 35 U.S.C. §371. Applicant’s claim to priority from PCT/EP2021/075548 filed 09/16/2021 and from Provisional Applications Nos. 63/114,232 filed 11/16/2020 and 63/079,941 filed 09/17/2020 is hereby acknowledged.
Election/Restrictions
Applicant’s election without traverse of Invention Group I (claims 1-9 and 14-16, drawn to a pharmaceutical composition wherein the one or more ASO or a pharmaceutically acceptable salt thereof) in the reply filed on 07/15/2026 is acknowledged.
Applicant’s election of Species Group B (1) (ION 975616; claims 1, 2, 5-9 and 14-16 ) in the reply filed on 07/15/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 3-4, 9-13 and 17-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/15/2026.
Application Status
This Office Action is in response to Applicant’s communication filed 07/15/2026.
Claims 1-20 filed 03/16/2023 are pending. Claims 3-4, 9-13 and 17-20 are withdrawn. Therefore, claims 1-2, 5-8 and 14-16 are under consideration in this Office Action.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 06/07/2023 (1 IDS), 10/09/2023 (4 IDSs) and 07/15/2026 (1 IDS) are hereby acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description:
Figure 2 is labeled “Dissolution AZD6615 gastro resistant table Phosphate buffer pH 6/8 EB18-374204 (40mg)”. AZD 6615 is not described in the “Brief Description of the Drawings” section. EB18-374204 does not exist in the Specification.
Figure 4 presents data for ION-704361, this oligonucleotide is not described in the “Brief Description of Drawings”. The terms “SC” and “IJ” are not described either.
Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) 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. 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
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
This application contains sequence disclosures in accordance with the definitions
for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834.
The examiner has noted that the sequences SEQ ID NO: 1 and SEQ ID NO: 2
are presented in the Specification with chemical modifications and are not in agreement with the sequences in the listing. SEQ ID Nos 1 and 2 are presented in § [0047], as listed without chemical modifications. However, the § [0055]-[0061] present the same SEQ ID Nos with structures that bear chemical modifications.
MPEP § 2412.05(b) teaches “Representation and Symbols of nucleotide sequence data”. Each modified oligonucleotide’s description must comply with the requirements of WIPO Standard ST.26. Each modified oligonucleotide must have a SEQ ID NO.
Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2., as well as
• A statement that identifies the location of all additions, deletions, or replacements of sequence information in the “Sequence Listing XML” as required by 1.835(b)(3);
• A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4);
• A statement that the “Sequence Listing XML” includes no new matter in accordance with 1.835(b)(5); and
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The use of the terms “Comil” ([00120]), “Avicel” ([00121], [00124]), “Turbula” ([00121], [00124]), “Perlitol” ([00123]), “Syloid” ([00124]), which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 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 8 and 16 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.
Regarding claims 8 and 16, they both recite “Form A sodium caprate”. Applicant does not provide a written description on how different the “Form A” is from the commercially available sodium caprate at the molecular level.
In the Specification ( [0011], [0065]-[0071]), Applicant states: “As understood
herein, "Form A sodium caprate" is understood to mean sodium caprate characterized by at least one of the following:
i) a wide-angle X-ray scattering (WAXS) spectrum which includes a peak at a region of 0. 1 to 0. 15 Å-1;
ii) a wide-angle X-ray scattering (W AXS) spectrum which includes a peak at 0.12 and 0.23 Å -1 ;
iii) a small-angle X-ray scattering (SAXS) spectrum which includes a peak at 0.12 and 0.23 A-1;
iv) an X-ray powder diffraction (XRPD) spectrum which includes a peak at 4° 28; or
v) a water content of less than about 3.5% as measured by Karl Fischer titration.”
Applicant gives the characteristics of the molecule without providing a clear method of obtaining/isolating the “Form A”.
If the chemical structure of Form A sodium caprate is an entity different from the commercially obtainable by one of ordinary skills, there is no mention in the Specification of a specific chemical structure, or on how to procure the “Form A”, or on how to specifically prepare it.
In the art, Tong ( Tong, H.H.Y. et al. “Spray freeze drying with polyvinylpyrrolidone and sodium caprate for improved dissolution and oral bioavailability of oleanolic acid, a BCS Class IV compound”. International Journal of Pharmaceutics, Vol. 404 (2011), pp: 148-158) teaches the use of sodium caprate for enhancing dissolution and oral bioavailability of oleanolic acid (see title and abstract). Tong teaches using Spray freeze drying of the compound to be transformed into powder (see page 149, section 2.2). Tong does not teach a specific form obtained from sodium caprate.
The only reference in the art where the “Form A” is mentioned is in Matic (Matic, H. et al. WO 2023/161792 A1; published August 31, 2023). Therefore, in the art, the terms “Form A” are not widely used.
Fan (Fan, W. et al. “Overcoming poor tabletability of bulky absorption enhancers by Spray Drying Technology”. Journal of Pharmaceutical Sciences, Vol. 108 (2019), pp: 2128-2135) teaches spray drying absorption enhancers to provide with better compression and absorption (see abstract).
Fan teaches that Spray drying is a one-step continuous process that provides the possibility of optimizing the physicochemical characteristics such as particle size, density, shape, and solid state of the resulting dry powders (see “Introduction” section, right column, second paragraph). Fan teaches “high bonding excipients for coating” (same paragraph). Fan teaches that high amount of absorption enhancers would improve the tabletability of the formulations.
Although there is no mention of different forms of the absorption enhancers molecules after the spray drying treatment, Fan provides with steps and specific method to alter the compressibility of a formulation.
In summary, there is a lack of concrete description of a “Form A”. Applicant points to specific physicochemical characteristics of the product without specifying whether the molecule is altered, and without presenting the method of obtaining this specific form or pointing out a specific commercial source.
Applicant also states: “Methods of preparing a XRPD experimental set-up are known to the skilled artisan”. If the methods are known by the skilled artisan, Examiner interprets that there is no novelty, but the use of the terms “Form A” in claims points to something specific that is not clearly described.
Claim Rejections - 35 USC § 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 14, 15 and 16 are rejected under 35 U.S.C. §112(b) or 35 U.S.C. §112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 14-16, it is unclear which structure corresponds to SEQ ID NO: 2, to ION 975616 and to ION 916333. There is no chemical structure corresponding to ION 91633 described and no SEQ ID NO corresponding to any modified oligonucleotide. The description of SEQ ID NO: 2 is inconsistent with the presence of chemical modifications.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. §102 and §103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. §102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 5-8 are rejected under 35 U.S.C. §102(a)(1) as being anticipated by Raoof (Raoof, A.A. et al. “Oral bioavailability and multiple dose tolerability of an antisense oligonucleotide tablet formulated with sodium caprate”. Journal of Pharmaceutical Sciences, Vol. 93, No. 6 (2004), pp: 1431-1439).
Regarding claim 1, it recites “C) one or more optional pharmaceutically acceptable excipient; and D) one or more optional coating.”
Examiner interprets the limitation in C) and D) as optional, therefore, not absolutely required by the claim. However, Raoof teaches all the limitations.
Regarding claim 1, Raoof teaches an ASO (ISIS 104838) in a pharmaceutical composition as a salt, i.e., a 19 sodium salt of ribonucleotide oligomer (see abstract; “Materials and Methods” section, page 1432, “Materials” paragraph).
Raoof teaches the ASO being prepared as a tablet with a permeation enhancer, sodium caprate (see abstract; see page 1433, left column, “Table preparation and characterization” paragraphs).
Raoof teaches a tablet made of mannitol, aerosol, and magnesium stearate as excipients, and Opadry® as a subcoat, then coated with an enteric coating solution of hydroxypropylmethylcellulose (HPMC-50) (see page 1433, left column, “Table preparation and characterization” paragraphs).
Regarding claims 5-7, Raoof teaches sodium caprate as the permeation enhancer (see title and abstract).
Regarding claim 8, Examiner interprets that the physical form of sodium caprate is different, since Applicant claims something specific, however, Examiner interprets that the molecule is the same. Therefore, Raoof teaches the molecule being used in the formulation (see title and abstract).
Claims 1, 2 and 5-8 are rejected under 35 U.S.C. §102(a)(1) as being anticipated by Hinkle (Hinkle, G. US 2018/0201936 A1, published July 19, 2018; cited previously and cited on IDS filed 06/07/2023).
Regarding claim 1, Hinkle teaches an ASO within a composition for treatment of disease associated with PNPLA3 ( see [0007], [0403]-[0405]).
Hinkle teaches a pharmaceutical composition comprising an ASO and a pharmaceutically acceptable salt, excipient and coating (see [0334]), as well as a permeation enhancer agent (see [0217]-[0222]).
Regarding claim 2, Hinkle teaches that the ASO can be conjugated to a ligand that is N-acetylgalactosamine (GalNAc) derivative, or a trivalent GalNAc ligand (see [0032]-[0033]).
Regarding claim 5, Hinkle teaches one or more permeation enhancer chosen from medium fatty acids and their salts, i.e., their derivatives (see [0334], [0357], [0359], [0361]).
Regarding claims 6 and 8, Hinkle teaches one or more permeation enhancer chosen from lauric acid, capric acid, myristic acid, palmitic acid, stearic acid, caprylic acid, and their derivatives, and/or esters or salts thereof (see [0334], [0361]).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 14, 15 and 16 are rejected under 35 U.S.C. §103 as being unpatentable over Hinkle (Hinkle, G. US 2018/0201936 A1, published July 19, 2018; cited previously; cited on IDS filed 06/07/2023) as applied to claim 1 above, and further in view of Freier (Freier, S.M. et al. US 10, 774,333 B2, published September 15, 2020, with priority from US2020/0140869 A1, filed 09/18/2019, published 05/07/2020, and from Provisional Application No. 62/733,152 filed September 19, 2018; cited on IDS filed 10/09/2023 (27 pages; ref#105).
It is noted that claim 1 is anticipated by Hinkle. The rejection of claim 1 is described above, and as follows:
Regarding claim 1, Hinkle teaches an ASO within a composition for treatment of disease associated with PNPLA3 ( see [0007], [0403]-[0405]).
Hinkle teaches a pharmaceutical composition comprising an ASO and a pharmaceutically acceptable salt, excipient and coating (see [0334]), as well as a permeation enhancer agent (see [0217]-[0222]).
Therefore, Hinkle teaches ASO agents that target and inhibit PNPLA3 gene expression (title and abstract).
However, regarding claims 14, 15 and 16, Hinkle does not teach an ASO that has a nucleobase sequence comprising SEQ ID NO: 2, nor an ASO with the commercial name ION 975616.
A search for instant SEQ ID NO: 2 (Qy (Query)) leads to the alignment below with 100% match:
RESULT 1
US-16-574-407-1089
(NOTE: this sequence has 1 duplicate in the database searched.
See complete list at the end of this report)
Sequence 1089, US/16574407
Patent No. 10774333
GENERAL INFORMATION
APPLICANT: Ionis Pharmaceuticals, Inc.
TITLE OF INVENTION: MODULATORS OF PNPLA3 EXPRESSION
FILE REFERENCE: BIOL0317US.L
CURRENT APPLICATION NUMBER: US/16/574,407
CURRENT FILING DATE: 2019-09-18
NUMBER OF SEQ ID NOS: 2172
SEQ ID NO 1089
LENGTH: 16
TYPE: DNA
ORGANISM: Artificial sequence
FEATURE:
OTHER INFORMATION: Synthetic oligonucleotide
Query Match 100.0%; Score 16; Length 16;
Best Local Similarity 100.0%; Matches 16; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CTTTATTCAATGTGGC 16
||||||||||||||||
Db 1 CTTTATTCAATGTGGC 16
The alignment shows that the sequence was used previously and patented in US Patent No. 10, 774, 333 B2 under SEQ ID NO: 1089; and was publicly available since May 7, 2020.
Freier also teaches the use of the ASO named ION 975616 (see column 11, lines 45-51; column 36, lines 23-28; column 37, line 2; column 38, line 33). Freier teaches this particular ASO as one of 9 that are efficient and well tolerated (see column 97, lines 8-13).
Freier specifically claims SEQ ID NO: 1089 and the compound with the same modifications presented in instant Specification §[0058] as one possible ION 975616 (see Freier’s claims 1-9; columns 967-969).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have substituted the composition used by Hinkle to inhibit PNPLA3 gene expression, with the specific ASO claimed by Freier, comprising the sequence SEQ ID NO: 1089, with the modifications as claimed in Freier’s claim 1. One with ordinary skills in the art motivated in using a composition that is effective and well tolerated for oral administration of a medicament for treating a PNPLA3-associated disease, could have performed this modification with a reasonable expectation of success and would have arrived at the claimed invention.
Claim 16 is rejected under 35 U.S.C. §103 as being unpatentable over Hinkle (Hinkle, G. US 2018/0201936 A1, published July 19, 2018; cited previously and cited on IDS filed 06/07/2023) as applied to claim 1 above, and further in view of Freier (Freier, S.M. et al. US 10, 774,333 B2, published September 15, 2020, with priority from US2020/0140869 A1, filed 09/18/2019, published 05/07/2020, and from Provisional Application No. 62/733,152 filed September 19, 2018; cited on IDS filed 10/09/2023 (27 pages; ref#105) and Raoof (Raoof, A.A. et al. “Oral bioavailability and multiple dose tolerability of an antisense oligonucleotide tablet formulated with sodium caprate”. Journal of Pharmaceutical Sciences, Vol. 93, No. 6 (2004), pp: 1431-1439).
It is noted that claim 1 is anticipated by Hinkle. The rejection of claim 1 is described above, and as follow:
Regarding claim 1, Hinkle teaches an ASO within a composition for treatment of disease associated with PNPLA3 ( see [0007], [0403]-[0405]).
Hinkle teaches a pharmaceutical composition comprising an ASO and a pharmaceutically acceptable salt, excipient and coating (see [0334]), as well as a permeation enhancer agent (see [0217]-[0222]).
Therefore, Hinkle teaches ASO agents that target and inhibit PNPLA3 gene expression (title and abstract).
However, regarding claim 16, Hinkle does not teach an ASO that has a nucleobase sequence comprising SEQ ID NO: 2, nor an ASO with the commercial name ION 975616.
Regarding claim 16, Freier teaches an ASO comprising the sequence SEQ ID NO: 1089, with the modification present in ION 975616 or an pharmaceutically acceptable salt (claim 1, column 967).
The alignment above shows that the sequence was used previously and patented in US Patent No. 10, 774, 333 B2 under SEQ ID NO: 1089.
Freier also teaches the use of the ASO named ION 975616 (see column 11, lines 45-51; column 36, lines 23-28; column 37, line 2; column 38, line 33). Freier teaches this particular ASO as one of 9 that are efficient and well tolerated (see column 97, lines 8-13).
Freier specifically claims SEQ ID NO: 1089 and the compound with the same modifications presented in instant Specification §[0058] as one possible ION 975616 (see Freier’s claims 1-9; columns 967-969).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have substituted the composition used by Hinkle to inhibit PNPLA3 gene expression, with the specific ASO claimed by Freier, comprising the sequence SEQ ID NO: 1089, with the modifications as claimed in Freier’s claim 1. One with ordinary skills in the art motivated in using a composition that is effective and well tolerated for oral administration of a medicament for treating a PNPLA3-associated disease, could have performed this modification with a reasonable expectation of success and would have arrived at the claimed invention.
However, the combination of Hinkle and Freier does not teach an ASO present in the composition in an amount ranging from about 1 to about 100 mg, nor sodium caprate in an amount ranging from about 10 to about 1000 mg, nor a pharmaceutically acceptable excipient present in an amount ranging from about 0 to 600 mg, nor an optional coating present in an amount within range from about 0 mg to about 100 mg.
However, Raoof teaches enteric coated tablets each containing 80 mg of the drug (ASO) and 330 mg of sodium caprate (see Table 2, page 1436).
Raoof also teaches excipients such as mannitol, aerosol and magnesium stearate. Raoof teaches a subcoat of Opadry® and a coating of HPMC-50 (see page 1433, left column, “Table preparation and characterization” section). However, Raoof is silent on the amount of these excipients and coating chemicals. Raoof only states that each tablet has a total weight of 644 mg (same paragraph). Therefore, the amount of excipients and coating must be 234 mg altogether ( 644 – (330 +80)); these amounts fall within the instant’s claim requirements.
Raoof also teaches that the coated formulation is stable in acidic conditions (see page 1434, left column, “Table dissolution” section). Raoof teaches that the formulation is well tolerated without obvious effects on food consumption or body weight (see page 1435, right column, “Clinical chemistry and tolerability” section). Raoof teaches the essential use of permeation enhancers to achieve successful delivery of antisense oligonucleotides following oral administration (see page 1436, left column, “Discussion” section”.
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have substituted the composition used by Hinkle to inhibit PNPLA3 gene expression, with the specific ASO claimed by Freier, comprising the sequence SEQ ID NO: 1089, with the modifications as claimed in Freier’s claim 1, and added the excipients, permeation enhancer and coating chemicals needed for a tablet formulation as taught by Raoof . One with ordinary skills in the art motivated in using a composition that is effective and well tolerated for oral administration of a medicament for treating a PNPLA3-associated disease, could have performed this modification with a reasonable expectation of success and would have arrived at the claimed invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 5-8 and 14-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 10,774,333 B2 in view of Raoof (Raoof, A.A. et al. “Oral bioavailability and multiple dose tolerability of an antisense oligonucleotide tablet formulated with sodium caprate”. Journal of Pharmaceutical Sciences, Vol. 93, No. 6 (2004), pp: 1431-1439).
Regarding claim 1, claim 1 of Freier claims an ASO within a pharmaceutical composition, or in the form of a pharmaceutically acceptable salt.
Regarding claim 2, Claims 1-2 of Freier are drawn to an ASO conjugated to a ligand that is a trivalent GalNAc.
Regarding claims 14, 15 and 16, a search for instant SEQ ID NO: 2 (Qy (Query)) leads to the alignment below with 100% match:
RESULT 1
US-16-574-407-1089
(NOTE: this sequence has 1 duplicate in the database searched.
See complete list at the end of this report)
Sequence 1089, US/16574407
Patent No. 10774333
GENERAL INFORMATION
APPLICANT: Ionis Pharmaceuticals, Inc.
TITLE OF INVENTION: MODULATORS OF PNPLA3 EXPRESSION
FILE REFERENCE: BIOL0317US.L
CURRENT APPLICATION NUMBER: US/16/574,407
CURRENT FILING DATE: 2019-09-18
NUMBER OF SEQ ID NOS: 2172
SEQ ID NO 1089
LENGTH: 16
TYPE: DNA
ORGANISM: Artificial sequence
FEATURE:
OTHER INFORMATION: Synthetic oligonucleotide
Query Match 100.0%; Score 16; Length 16;
Best Local Similarity 100.0%; Matches 16; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CTTTATTCAATGTGGC 16
||||||||||||||||
Db 1 CTTTATTCAATGTGGC 16
The alignment shows that the sequence was used previously and patented in US Patent No. 10, 774, 333 B2 under SEQ ID NO: 1089 claimed in Freier’s claims 1-9.
Freier specifically claims SEQ ID NO: 1089 and the compound with the same modifications presented in instant Specification §[0058] as one possible ION 975616 (see Freier’s claims 1-9; columns 967-969).
Freier does not teach one or more permeation enhancer, or an optional pharmaceutically acceptable excipient or one or more optional coating.
However, Raoof teaches compressing an ASO into a tablet. Raoof teaches the ASO being prepared as a tablet with a permeation enhancer, sodium caprate (see abstract; see page 1433, left column, “Table preparation and characterization” paragraphs).
Raoof teaches a tablet made of mannitol, aerosol, and magnesium stearate as excipients, and Opadry® as a subcoat, then coated with an enteric coating solution of hydroxypropylmethylcellulose (HPMC-50) (see page 1433, left column, “Table preparation and characterization” paragraphs).
Regarding claims 5-7 and 16, Raoof teaches sodium caprate as the permeation enhancer (see title and abstract).
Raoof teaches that the coated formulation is stable in acidic conditions (see page 1434, left column, “Table dissolution” section). Raoof teaches that the formulation is well tolerated without obvious effects on food consumption or body weight (see page 1435, right column, “Clinical chemistry and tolerability” section). Raoof teaches the essential use of permeation enhancers to achieve successful delivery of antisense oligonucleotides following oral administration (see page 1436, left column, “Discussion” section”.
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have used the ASO taught by Freier and adapted the formulation of the ASO for oral administration using the method as taught by Raoof. One with ordinary skills in the art motivated in enhanced stability of a formulation of ASO and an enhanced intestinal permeability provided by sodium caprate as taught by Raoof, could have performed this modification with a reasonable expectation of success and would have arrived at the claimed invention.
Conclusion
No claim is allowed.
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/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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