DETAILED ACTION
Receipt of Arguments/Remarks filed on October 13 2025 is acknowledged. Claims 3-9, 14-17, 24-25, 31, 34-35, 37-69 and 72-86 were/stand cancelled. Claims 1-2, 20-22, 70-71 and 87 were amended. Claims 1-2, 10-13, 18-23, 26-30, 32-33, 36, 70-71 and 87 are pending.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Withdrawn Objections/Rejections
The amendments filed October 13 2025 to the specification are sufficient to overcome the objections to the specification. Specifically the trademark is now accompanied by the generic terminology.
The amendments filed October 13 2025 are sufficient to overcome the rejection of claims 20-22, 70-71 and 87 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. The amendments have removed the trademarks from the claims. The product by process and method of making now at least recite a producing step.
Claim 87 now makes it clear these are additional cytidines.
The amendments filed October 13 2025 limit the scope of the ASO to only include the recited 31P-NMR spectrum. Since not all ASO necessarily possess this spectrum as evidenced by, for example, Figure 7C, the rejection of claim(s) 1-2, 10-11, 18-23, 26-30, 32-33, 36 and 70 under 35 U.S.C. 102(a)(1) as being anticipated by Baroni (USPGPUB No. 20120015033) is withdrawn.
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:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Specifically, Fig. 1 is a specifically enumerated nucleic acid with more than 10 nucleotides. Therefore, the sequence in Fig. 1 must be associated with a specific SEQ ID No.
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.
Response to Arguments
Applicants’ arguments filed October 13 2025 have been fully considered but they are not persuasive.
It is noted that neither an amendment to Fig. 1 or an amendment to the brief description of the drawings for Fig. 1 indicate the SEQ ID No: of the sequence. Therefore, the identified deficiency is maintained. The examiner further notes that the response does not specifically address this deficiency.
New/Modified Objections/Rejections Necessitated by the Amendments filed October 13 2025
Claim Objections
Claim 1 is objected to because of the following informalities: the claim is ungrammatical. Specifically the amendments to claim 1 cause the claim to recite “the PC2 score that below 0.00” in the last line of the claim. The recitation “score that below” needs to be corrected. Appropriate correction is required.
Claim 2 is objected to because of the following informalities: the claim is ungrammatical. Specifically the amendments to claim 2 cause the claim to recite “consists of a PC2 score is below 0.00” in lines 1-2 of page 4. The “a PC2 score is below” needs to be corrected. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 70 is 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.
Claim 70 as currently written is vague and indefinite. In the second to last line of the claim it recites “a PC2 score that is below 0.00 to 0.20”. This recitation renders the claim indefinite. The scope of the PC2 score is unclear. Is the score required to be below 0.00 or below 0.2. A score below 0.2 is not necessarily below 0.00. Therefore, metes and bounds of the claimed score are unclear. The examiner notes claim 1 and 71 were amended to recite the PC2 score is below 0.00 (i.e. deleting to 0.20) but that same amendment was not made in claim 70.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 10-13, 18-23, 26-30, 32-33, 36 and 70-71 are rejected under 35 U.S.C. 103 as being unpatentable over Baroni (USPGPUB No. 20120015033) in view of Iwamoto et al. (Nature Biotechnology, 2017, cited on PTO Form 1449), Aartsma-Rus et al. (Molecular Therapy, 2009) and Shibahara et al. (EP0339842).
Applicant Claims
The instant application claims a pharmaceutical composition comprising a SMAD7 antisense oligonucleotide (ASO), wherein the SMAD7 ASO consists of a plurality of diastereomers of a SMAD7 antisense oligonucleotide (ASO) having a sequence according to SEQ ID NO: 1 (5'- GTXGCCCCTTCTCCCXGCAGC-3') in which all internucleoside linkages are 0,0-linked phosphorothioate linkages and X is 5-methyl 2'-deoxycytidine, wherein the plurality of diastereomers has a phosphorus-31 nuclear magnetic resonance (31P-NMR) spectrum consisting of: a) one or more resonances between 54.8 to 55.5 ppm; and b) a first principal component 1 (PC 1) score and a second principal component 2 (PC2) score, wherein:(i) the PC1 score is below about -0.20 or above about 0.25 and the PC2 score is below about 0.00; or (ii) the PCI score is below -0.32 or above 0.30 and the PC2 score that is below 0.00.
The instant application claims a method of treating or preventing an inflammatory bowel disease in a subject in need thereof, comprising administering to the subject the pharmaceutical composition
The instant application claims a pharmaceutical composition comprising a SMAD7 antisense oligonucleotide (AS)), wherein the SMAD7 ASO consists of a plurality of diastereomers of a SMAD7 antisense oligonucleotide (ASO) that is pharmacologically and/or clinically efficacious, made by a method comprising: a) producing a plurality of diastereomers of a SMAD7 antisense oligonucleotide (AS) having a sequence according to SEQ ID NO: 1 in which all internucleotide linkages are O,O-linked phosphorothioate linkages and X is 5-methyl 2’-deoxycytidine; b) confirming a 31P-NMR spectrum for the plurality of diastereomers consists of one or more resonances between 54.8 to 55.5 ppm; and c) confirming the 31P-NMR spectrum consists of:(i) a first principal component 1 (PC1) score that is below about -0.20 or above about 0.25 and a second principal component 2 (PC2) score that is below about 0.00, or (ii) a PC1 score that is below -0.32 or above 0.30 and a PC2 score that is below 0.00 ,as determined by principal component analysis (PCA).
The instant application claims method of manufacturing a pharmaceutical composition comprising a plurality of diastereomers of a SMAD7 antisense oligonucleotide (ASO), the method comprising a) producing a plurality of diastereomers of a SMAD7 antisense oligonucleotide (AS) having a sequence according to SEQ ID NO: 1 in which all internucleotide linkages are O,O-linked phosphorothioate linkages and X is 5-methyl 2’-deoxycytidine; b) confirming a 31P-NMR spectrum for the plurality of diastereomers consists of one or more resonances between 54.8 to 55.5 ppm; and c) confirming the 31P-NMR spectrum consists of:(i) a first principal component 1 (PC1) score that is below about -0.20 or above about 0.25 and a second principal component 2 (PC2) score that is below about 0.00, or (ii) a PC1 score that is below -0.32 or above 0.30 and a PC2 score that is below 0.00 ,as determined by principal component analysis (PCA).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Baroni et al. is directed to antisense compositions and methods and using same. Claimed is a pharmaceutical tablet formulation for oral administration of an antisense oligonucleotide comprising: an intra-granular phase comprising an antisense oligonucleotide represented by SEQ ID NO 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable filler; and an extra-granular phase comprising a disintegrant (claim 1) wherein the internucleotide linkages of SEQ ID NO. 1 are O,O-linked phosphorothioates (claim 2). As taught SEQ ID NO: 1 GTC*GCC CCT TCT CCC C*GC AGC, where C* represents 5-methyl-2'-deoxycytidine. An exemplary antisense oligonucleotide is shown in Fig. 1 which is the same as instant Fig. 1.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Baroni et al. teach the same antisense oligonucleotide, Baroni et al. is silent to the 31P NMR and principal component analysis. However, this deficiency is cured by Iwamoto et al., Aartsma-Rus et al. and Shibahara et al.
Iwamoto et al. teaches the control of phosporothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides. Phosphorothioate (PS) substitution converts the achiral phosphodiester linkage into a chiral PS center having two distinct stereochemical configurations. Because there has existed no practical means to control the geometry of PS installation, all PS-substituted ASOs comprise mixtures of up to 2n individual drug molecules, where n equals the number of PS linkages. It is well-established that stereochemical variation at even a single stereogenic center in small molecules can profoundly affect their pharmacologic properties. Hence it seemed possible that stereoisomeric ASOs might exhibit distinct behaviors in vitro and in vivo (page 845). Our work provides evidence that stability and activity can be rationally engineered into the same molecule. These findings demonstrate that PS stereochemistry affects the measurable biophysical and biochemical properties of ASOs, and in certain cases, for example, with regards to nucleolytic stability, the observed impact is substantial. It is reasonable, therefore, to expect that precise control over the stereochemistry of ASOs will enable the development of drugs with improved clinical efficacy, and perhaps safety, compared with those comprising complex mixtures, each component of which exhibits its own pharmacologic properties (page 850, right column).
Aartsma-Rus et al. is directed to the guidelines for antisense oligonucleotide design and insight into splice-modulating mechanisms. Taught is using principal component analysis to extract parameters that are largely independent and would yield optimal classification of effective and ineffective ASO. The first three principal components appear most important for explaining the variance (page 551, Classification of effective and ineffective AONs). It is taught that after principal component analysis, parameters can be selected to correctly classify effective and ineffective AONs (page 552, last paragraph).
Shibahara et al. is directed to novel oligoribonucleotide derivatives and application thereof to antiviral agents. 31P-NMR for compounds with multiplet phosphorothioates give a characteristic signal at 51-55ppm (paragraph 0078).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claims 1-2, 10-11, 70 and 87, SEQ ID No. 1 is exactly the same as instantly claimed and as shown in Fig. 1 contains the O,O-linked phosphorothioates and the sequence contains 2 cytidines that are 5-methyl 2’-deoxycytidine. Therefore, Baroni et al. expressly teaches a pharmaceutical composition with the same SMAD7 antisense oligonucleotide.
Regarding the claimed 31P-NMR spectrum and principal component analysis and claim 71, Baroni et al. is silent. However, Shibahara et al. recognizes31P-NMR (i.e. phosphorous NMR) for compounds with multiplet phosphorothioates give a characteristic signal at 51-55 ppm. Iwamoto et al. teaches phosphorothioate (PS) substitution converts the achiral phosphodiester linkage into a chiral PS center having two distinct stereochemical configurations and all PS-substituted ASOs comprise mixtures of up to 2n individual drug molecules, where n equals the number of PS linkages. Iwamoto et al. teaches it is well-established that stereochemical variation at even a single stereogenic center in small molecules can profoundly affect their pharmacologic properties and their findings demonstrate that PS stereochemistry affects the measurable biophysical and biochemical properties of ASOs, and in certain cases, for example, with regards to nucleolytic stability, the observed impact is substantial. Aartsma-Rus et al. teaches that using principal component analysis to extract parameters that are largely independent and would yield optimal classification of effective and ineffective AOS and after principal component analysis, parameters can be selected to correctly classify effective and ineffective AONs. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Baroni et al., Iwamoto et al., Aartsma-Rus et al. and Shibahara et al. and measure the 31P-NMR and perform principal component analysis (PCA) on the ASOs produced in order to classify the ASOs into effective and ineffective compounds. Since Aartsma-Rus et al. expressly teaches using PCA on antisense oligonucleotides and the compounds of Baroni et al. are antisense oligonucleotides there is a reasonable expectation of success. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize known ways of classifying compounds such as 31P-NMR and principal component analysis in order to determine the identification of effective compounds. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to confirm a phosphorothioates signal at 51-55 ppm. The instant claims are merely claiming the particular 31P-NMR and principal component analysis possessed by the compounds and claim those which are effective. Since Baroni et al. teaches that the oligonucleotides need to be used to treat Crohn’s disease, one skilled in the art would have been motivated to identify ways of determining which oligonucleotides are effective.
Regarding claims 12-13, 100 millimoles to 5 moles of SMAD7 ASO corresponds to 658.4 g to 32920 g based on an ASO molecular weight of 6584 g/mol (C200H261N69O107P20S20). Baroni et al. generally teaches a tablet comprising 35 to 500 mg (paragraph 0010). Example 4 which is directed to a 40 mg tablet uses 188.66 g of the active. Based on example 4, a 500 mg tablet would use 2358.25 g (when scaled up from a 40 mg tablet). Therefore, Baroni et al. suggest amounts which overlap the range of millimoles claimed. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Regarding claims 18-23, example 4 of Baroni et al. is directed to a 40 mg tablet:
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This example contains the same claimed components in an amount falling within the scope claimed for claims 18-22 when about is taken into consideration.
Regarding claims 26-29, 33, 36, firstly claims 26-29 are directed to the intended use of the composition and do not structurally distinguish the pharmaceutical composition of Baroni et al. from the instant claims. Furthermore, Baroni et al. claims a method of treating Crohn’s disease comprising orally administering the tablet rendering obvious instant claims 33 and 36.
Regarding claim 30, example 4 teaches a 40 mg oral tablet.
Regarding claim 32, Baroni et al. generally teaches a tablet comprising 35 to 500 mg (paragraph 0010). Exemplary formulations include 100 mg, 150 mg, 200 mg, etc. (paragraph 0035). Therefore, Baroni et al. teaches concentrations which overlap the instant claims. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Claim 87 is rejected under 35 U.S.C. 103 as being unpatentable over Baroni in view of Iwamoto et al., Aartsma-Rus et al. and Shibahara et al. as applied to claims 1-2, 10-13, 18-23, 26-30, 32-33, 36 and 70-71 above and in further view of Cicala (USPGPUB NO. 20170247695).
Applicant Claims
The instant application claims one or more additional cytidines are a 5-methyl 2’-deoxycytidine.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Baroni, Iwamoto et al., Aartsma-Rus et al. and Shibahara et al.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Baroni teaches two C which are 5-methyl-2’-deoxycytidine, Baroni does not expressly teach additional 5-methyl-2’-deoxycytidine. However, this deficiency is cured by Cicala.
Cicala is directed to isotopologues of SMAD7 antisense oligonucleotides. Taught is an SMAD7 antisense oligonucleotide which is a phosphorothioate and has SEQ ID No: 8 which is the same as instantly claimed SEQ ID NO: 1 (paragraph 0022). As claimed the oligonucleotide comprises a mixture of diastereomers (claim 56). It is taught that the SMAD7 antisense oligonucleotide includes at least one unnatural nucleoside, e.g. 5-methyl-2’-deoxycytidine-5-monophosphate/monophosphorothioate. It is taught that the oligonucleotides include 2 up to 25 or more deoxycytidine and/or 5-methyl-2’-deoxycytidines (paragraph 0130).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Caroni, Iwamoto et al., Aartsma-Rus et al., Shibahara et al. and Cicala and utilize more than 2 5-methyl-2’-deoxycytidines. One skilled in the art would have been motivated to utilize more than 2 as Cicala which teach SMAD7 antisense oligonucleotides which include diastereomers and suggest that they can include more than 2 5-methyl-2-doexycytidines. Therefore, all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Note: MPEP 2143 KSR International Co. v. Teleflex Inc., 550 US 398, 82 USPQ 2d 1385 (2007).
Response to Arguments
Applicants’ arguments filed October 13 2025 have been fully considered but they are not persuasive.
Applicants argue (page 13) that (1) Baroni fails to anticipate the presently claimed pharmaceutical composition because Baroni does not inherently teach an SMAD7 ASO consisting of the claimed 31P-NMR spectrum and PC1 and PC2.
Regarding Applicants first argument, Baroni does teach the same SMAD7 ASO structure. The specification at paragraph 0045 states Fig. 1 is an illustration showing the structure of exemplary SMAD7 antisense oligonucleotides. Baroni teaches the same structure as instant Fig. 1 in Fig.1. Looking to the instant specification, it does not appear that the 31P-NMR differentiates one ASO from another as all the batches have at least one intensity between 54.8 to 55.5 ppm (see for example Fig. 5B of the instant specification). While the intensity might be different, the claims merely require one or more resonances between this range. Therefore, this limitation cannot be said to differentiate the instantly claimed ASOs from those taught in Baroni. However, the instant claims require a particular PC1 and PC2 which the instant specification shows in Figure 7C and 7D are not necessarily possessed by all ASOs. This is why the rejection under 102 has been withdrawn.
Applicants argue (page 14-16) that (2) the presently claimed subject is not obvious because the cited references either alone or in combination fail to produce what is presently claimed or provide any reason for one skill in the art to modify the reference to produce what is claimed. It is argued that ASOs with the recited NMR spectrum, PC1 and PC2 scores demonstrate in vitro and/or clinic efficacy. The references alone or in combination fail to teach or suggest the effects of a SMAD7 antisense oligonucleotide with the recited physical characteristics that can reduce SMAD7 expression level. Applicants point to example 7 and Fig. 7D and that the instantly claimed subject matter encompasses clusters 2 and 3. It is argued that samples that fell within clusters 2 and 3 were able to decrease SMAD7 expression levels in vitro. It is argued that Iwamoto fails to teach or suggest using PCA to classify ASOs, let alone ASOs which reduce expression of SMAD7. Aartsma-Rus et al. does not teach or suggest how to apply PCA to any ASO and does not teach SMAD7. Shibahara is for a different gene that is not SMAD7. It is argued that Shibahara does not teach a 21-mer ASO that targets SMAD7 the office is making assumptions about equivalence that are not supported by evidence in the record.
Regarding Applicants’ second argument, as set forth above, the 31P NMR does not appear to distinguish any of the ASOs as all the ASOs have at least one resonance within the claimed range. Additionally, Baroni expressly claims that the pharmaceutical formulation which comprises the SMAD7 ASO is used for treating Crohn’s disease. Therefore, the ASO taught by Baroni has clinic efficacy. Baroni teaches that antisense oligodeoxynucleotide drugs are short chains of DNA nucleotides that inhibit protein translation by specifically binding to a small segment of mRNA responsible for driving the production of disease-causing proteins (paragraph 0006). Therefore, Baroni already suggests the desire to form antisense oligonucleotides which reduces expression of SMAD7 (i.e. a disease-causing protein). Applicants are merely selecting the optimal ASO to achieve the desired effect. While Iwamoto et al. and Aartsma-Rus et al.do not expressly teach ASOs for SMAD7, it is not a requirement for obvious as the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Iwamoto et al. teaches that control of phosphorothioate stereochemistry increases the efficacy of antisense oligonucleotides. Since all phosphorothioate ASOs comprise mixtures of drugs due to the chiral PS center, it is well-established within the art that stereochemical variation can affect pharmacological properties. This suggests that understanding which stereochemistry of ASOs which provide for the desired pharmacological effect would improve clinical efficacy. Aartsma-Rus et al. teaches that principal component analysis can be used to extract parameters that are independent to classify ASO Therefore, the state of the art recognizes that principal component analysis can be used to classify ASOs into effective and non-effective and this can be done through the phosphorothioate stereochemistry which is known to have an effect on the clinical efficacy. This is not limited to only the ASOs taught in Iwamoto et al. or Aartsma-Rus et al. but to ASOs in general. The instant specification merely classifies the various ASOs which are made into effect and ineffective and is claiming those as effective. While this realization is valuable it does not establish a patentable difference from the prior art and state of the art since the prior art already recognizes the desirability of ASOs which treat Crohn’s disease. Regarding the arguments of Shibahara et al., firstly, as set forth above, the instant specification shows that all ASOs (whether effective or not, e.g. all batches) have at least one intensity in the claimed range. The 31P-NMR is measuring the phosphorothioate signals. Therefore, it would be expected that a compound with the same number of phosphorothioates would have the same signal. Since Baroni teaches the same structure, it would be expected to have the same 31P-NMR. While Shibahara et al. might teach different oligonucleotide sequences, it still recognizes that oligonucleotides with phosphorothioates have signals in the 51-55 ppm range. The examiner cannot agree that extrapolation of this information to other oligonucleotides with phosphorothioates is not supported.
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, 10-13, 18-23, 26-30, 32-33, 36, 70-71 and 87 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10337004 in view of Baroni et al. and in further view of Iwamoto et al. (Nature Biotechnology, 2017), Aartsma-Rus et al. (Molecular Therapy, 2009) and Shibahara et al. (EP0339842). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims a pharmaceutical composition comprising a SMAD7 antisense oligonucleotide (ASO), wherein the SMAD7 ASO consists of a plurality of diastereomers of a SMAD7 antisense oligonucleotide (ASO) having a sequence according to SEQ ID NO: 1 (5'- GTXGCCCCTTCTCCCXGCAGC-3') in which all internucleoside linkages are 0,0-linked phosphorothioate linkages and X is 5-methyl 2'-deoxycytidine, wherein the plurality of diastereomers has a phosphorus-31 nuclear magnetic resonance (31P-NMR) spectrum consisting of: a) one or more resonances between 54.8 to 55.5 ppm; and b) a first principal component 1 (PC 1) score and a second principal component 2 (PC2) score, wherein:(i) the PC1 score is below about -0.20 or above about 0.25 and the PC2 score is below about 0.00; or (ii) the PCI score is below -0.32 or above 0.30 and the PC2 score that is below 0.00.
The instant application claims a pharmaceutical composition comprising a SMAD7 antisense oligonucleotide (AS)), wherein the SMAD7 ASO consists of a plurality of diastereomers of a SMAD7 antisense oligonucleotide (ASO) that is pharmacologically and/or clinically efficacious, made by a method comprising: a) producing a plurality of diastereomers of a SMAD7 antisense oligonucleotide (AS) having a sequence according to SEQ ID NO: 1 in which all internucleotide linkages are O,O-linked phosphorothioate linkages and X is 5-methyl 2’-deoxycytidine; b) confirming a 31P-NMR spectrum for the plurality of diastereomers consists of one or more resonances between 54.8 to 55.5 ppm; and c) confirming the 31P-NMR spectrum consists of:(i) a first principal component 1 (PC1) score that is below about -0.20 or above about 0.25 and a second principal component 2 (PC2) score that is below about 0.00, or (ii) a PC1 score that is below -0.32 or above 0.30 and a PC2 score that is below 0.00 ,as determined by principal component analysis (PCA).
The instant application claims a method of treating or preventing an inflammatory bowel disease in a subject in need thereof, comprising administering to the subject the pharmaceutical composition
The instant application claims specific concentrations or excipients.
Patent ‘004 claims a SMAD7 antisense oligonucleotide comprising the nucleotide sequence of SEQ ID NO:13 (5′-GTXGCCCCTTCTCTCXGCAGC-3′), wherein X is a nucleotide comprising 5-methyl-2′-deoxycytidine and wherein all internucleotide linkages are phosphorothioate linkages. A pharmaceutical composition is claimed.
While patent ‘004 claims a pharmaceutical composition, patent ‘004 does not claim concentrations nor specific excipients nor a method of use. However, these deficiencies are cured by Baroni et al.
Baroni et al. is directed to antisense compositions and methods and using same. Claimed is a pharmaceutical tablet formulation for oral administration of an antisense oligonucleotide comprising: an intra-granular phase comprising an antisense oligonucleotide represented by SEQ ID NO 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable filler; and an extra-granular phase comprising a disintegrant (claim 1) wherein the internucleotide linkages of SEQ ID NO. 1 are O,O-linked phosphorothioates (claim 2). As taught SEQ ID NO: 1 GTC*GCC CCT TCT CCC C*GC AGC, where C* represents 5-methyl-2'-deoxycytidine. An exemplary antisense oligonucleotide is shown in Fig. 1 which is the same as instant Fig. 1 and the same as patent ‘004
Patent ‘004 does not claim a particular 31P NMR and principal component analysis.
However, this deficiency is cured by Iwamoto et al., Aartsma-Rus et al. and Shibahara et al.
Iwamoto et al. teaches the control of phosporothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides. Phosphorothioate (PS) substitution converts the achiral phosphodiester linkage into a chiral PS center having two distinct stereochemical configurations. Because there has existed no practical means to control the geometry of PS installation, all PS-substituted ASOs comprise mixtures of up to 2n individual drug molecules, where n equals the number of PS linkages. It is well-established that stereochemical variation at even a single stereogenic center in small molecules can profoundly affect their pharmacologic properties. Hence it seemed possible that stereoisomeric ASOs might exhibit distinct behaviors in vitro and in vivo (page 845). Our work provides evidence that stability and activity can be rationally engineered into the same molecule. These findings demonstrate that PS stereochemistry affects the measurable biophysical and biochemical properties of ASOs, and in certain cases, for example, with regards to nucleolytic stability, the observed impact is substantial. It is reasonable, therefore, to expect that precise control over the stereochemistry of ASOs will enable the development of drugs with improved clinical efficacy, and perhaps safety, compared with those comprising complex mixtures, each component of which exhibits its own pharmacologic properties (page 850, right column).
Aartsma-Rus et al. is directed to the guidelines for antisense oligonucleotide design and insight into splice-modulating mechanisms. Taught is using principal component analysis to extract parameters that are largely independent and would yield optimal classification of effective and ineffective AOS. The first three principal components appear most important for explaining the variance (page 551, Classification of effective and ineffective AONs). It is taught that after principal component analysis, parameters can be selected to correctly classify effective and ineffective AONs (page 552, last paragraph).
Shibahara et al. is directed to novel oligoribonucleotide derivatives and application thereof to antiviral agents. 31P-NMR for compounds with multiplet phosphorothioates give a characteristic signal at 51-55ppm (paragraph 0078).
Since Baroni et al. teaches the same antisense oligonucleotide as claimed in patent ‘004, it would have been obvious to one of ordinary skill before the effective filing date to use the antisense oligonucleotide of patent ‘004 in the pharmaceutical composition of Baroni et al. with a reasonable expectation of success. Since patent ‘004 claims a pharmaceutical composition, it would have been obvious to one skilled in the art to utilize known compositions for delivering the antisense oligonucleotide.
Regarding the claimed 31P-NMR spectrum and principal component analysis and claim 71, Patents ‘004 is silent. However, Shibahara et al. recognizes31P-NMR (i.e. phosphorous NMR) for compounds with multiplet phosphorothioates give a characteristic signal at 51-55 ppm. Iwamoto et al. teaches phosphorothioate (PS) substitution converts the achiral phosphodiester linkage into a chiral PS center having two distinct stereochemical configurations and all PS-substituted ASOs comprise mixtures of up to 2n individual drug molecules, where n equals the number of PS linkages. Iwamoto et al. teaches it is well-established that stereochemical variation at even a single stereogenic center in small molecules can profoundly affect their pharmacologic properties and their findings demonstrate that PS stereochemistry affects the measurable biophysical and biochemical properties of ASOs, and in certain cases, for example, with regards to nucleolytic stability, the observed impact is substantial. Aartsma-Rus et al. teaches that using principal component analysis to extract parameters that are largely independent and would yield optimal classification of effective and ineffective AOS and after principal component analysis, parameters can be selected to correctly classify effective and ineffective AONs. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘004, Baroni et al., Iwamoto et al., Aartsma-Rus et al. and Shibahara et al. and measure the 31P-NMR and perform principal component analysis (PCA) on the ASOs produced in order to classify the ASOs into effective and ineffective compounds. Since Aartsma-Rus et al. expressly teaches using PCA on antisense oligonucleotides and the compounds of Patent ‘004, are antisense oligonucleotides there is a reasonable expectation of success. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize known ways of classifying compounds such as 31P-NMR and principal component analysis in order to determine the identification of effective compounds. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to confirm a phosphorothioates signal at 51-55 ppm. The instant claims are merely claiming the particular 31P-NMR and principal component analysis possessed by the compounds and claim those which are effective. Patent ‘004 teaches that the oligonucleotides need to be used to treat Crohn’s disease, one skilled in the art would have been motivated to identify ways of determining which oligonucleotides are effective.
Regarding claims 12-13, 100 millimoles to 5 moles of SMAD7 ASO corresponds to 658.4 g to 32920 g based on an ASO molecular weight of 6584 g/mol (C200H261N69O107P20S20). Baroni et al. generally teaches a tablet comprising 35 to 500 mg (paragraph 0010). Example 4 which is directed to a 40 mg tablet uses 188.66 g of the active. Based on example 4, a 500 mg tablet would use 2358.25 g (when scaled up from a 40 mg tablet). Therefore, Baroni et al. suggest amounts which overlap the range of millimoles claimed. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Regarding claims 18-23, example 4 is directed to a 40 mg tablet:
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This example contains the same claimed components in an amount falling within the scope claimed for claims 18-22 when about is taken into consideration.
Regarding claims 26-29, 33, 36, firstly claims 26-29 are directed to the intended use of the composition and do not structurally distinguish the pharmaceutical composition of Baroni et al. from the instant claims. Furthermore, Baroni et al. claims a method of treating Crohn’s disease comprising orally administering the tablet rendering obvious instant claims 33 and 36.
Regarding claim 30, example 4 teaches a 40 mg oral tablet.
Regarding claim 32, Baroni et al. generally teaches a tablet comprising 35 to 500 mg (paragraph 0010). Exemplary formulations include 100 mg, 150 mg, 200 mg, etc. (paragraph 0035). Therefore, Baroni et al. teaches concentrations which overlap the instant claims. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Claims 1-2, 10-13, 18-23, 26-30, 32-33, 36, 70-71 and 87 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 10473669 in view of Baroni et al., by Iwamoto et al., Aartsma-Rus et al. and Shibahara et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
Patent ‘669 claims a method for treating or managing an inflammatory bowel disease in a patenting comprising administering to the patient an initial dose of an SMAD7 antisense oligonucleotide. As claimed (claim 23) the SMAD7 antisense oligonucleotide is an antisense oligonucleotide phosphorothioate against SMAD7 comprising the following sequence: 5′-GTXGCCCCTTCTCCCXGCAGC-3′ (SEQ ID NO: 1), wherein X is 5-methyl -2′-deoxycytidine and wherein the internucleoside linkages are phosphorothioate linkages.
While patent ‘669 claims the same SMAD7 antisense oligonucleotide, patent ‘669 does not claim a pharmaceutical composition. However, this deficiency is cured by Baroni et al.
The teachings of Baroni et al. are set forth above.
Patent ‘669 does not claim a particular 31P NMR and principal component analysis.
However, this deficiency is cured by Iwamoto et al., Aartsma-Rus et al. and Shibahara et al.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of patent ‘669, Baroni et al., Iwamoto et al., Aartsma-Rus et al. and Shibahara et al. and utilize the pharmaceutical composition of Baroni et al. to deliver the SMAD7 antisense oligonucleotide. One skilled in the art would have been motivated to utilize the pharmaceutical composition of Baroni et al. as Baroni et al. teaches the same antisense oligonucleotide and patent ‘669 claims administering the oligonucleotide. Therefore, one skilled in the art would have found it obvious to utilize any known pharmaceutical composition known to deliver SMAD7 antisense oligonucleotides with a reasonable expectation of success.
Regarding the claimed 31P-NMR spectrum and principal component analysis and claim 71, Patents ‘669 is silent. However, Shibahara et al. recognizes31P-NMR (i.e. phosphorous NMR) for compounds with multiplet phosphorothioates give a characteristic signal at 51-55 ppm. Iwamoto et al. teaches phosphorothioate (PS) substitution converts the achiral phosphodiester linkage into a chiral PS center having two distinct stereochemical configurations and all PS-substituted ASOs comprise mixtures of up to 2n individual drug molecules, where n equals the number of PS linkages. Iwamoto et al. teaches it is well-established that stereochemical variation at even a single stereogenic center in small molecules can profoundly affect their pharmacologic properties and their findings demonstrate that PS stereochemistry affects the measurable biophysical and biochemical properties of ASOs, and in certain cases, for example, with regards to nucleolytic stability, the observed impact is substantial. Aartsma-Rus et al. teaches that using principal component analysis to extract parameters that are largely independent and would yield optimal classification of effective and ineffective AOS and after principal component analysis, parameters can be selected to correctly classify effective and ineffective AONs. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘669, Baroni et al., Iwamoto et al., Aartsma-Rus et al. and Shibahara et al. and measure the 31P-NMR and perform principal component analysis (PCA) on the ASOs produced in order to classify the ASOs into effective and ineffective compounds. Since Aartsma-Rus et al. expressly teaches using PCA on antisense oligonucleotides and the compounds of Patent ‘004, are antisense oligonucleotides there is a reasonable expectation of success. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize known ways of classifying compounds such as 31P-NMR and principal component analysis in order to determine the identification of effective compounds. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to confirm a phosphorothioates signal at 51-55 ppm. The instant claims are merely claiming the particular 31P-NMR and principal component analysis possessed by the compounds and claim those which are effective. Patent ‘669 teaches that the oligonucleotides need to be used to treat Crohn’s disease, one skilled in the art would have been motivated to identify ways of determining which oligonucleotides are effective.
Regarding claims 12-13, 100 millimoles to 5 moles of SMAD7 ASO corresponds to 658.4 g to 32920 g based on an ASO molecular weight of 6584 g/mol (C200H261N69O107P20S20). Baroni et al. generally teaches a tablet comprising 35 to 500 mg (paragraph 0010). Example 4 which is directed to a 40 mg tablet uses 188.66 g of the active. Based on example 4, a 500 mg tablet would use 2358.25 g (when scaled up from a 40 mg tablet). Therefore, Baroni et al. suggest amounts which overlap the range of millimoles claimed. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Regarding claims 18-23, example 4 is directed to a 40 mg tablet:
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This example contains the same claimed components in an amount falling within the scope claimed for claims 18-22 when about is taken into consideration.
Regarding claims 26-29, 33, 36, firstly claims 26-29 are directed to the intended use of the composition and do not structurally distinguish the pharmaceutical composition of Baroni et al. from the instant claims. Furthermore, Baroni et al. claims a method of treating Crohn’s disease comprising orally administering the tablet rendering obvious instant claims 33 and 36.
Regarding claim 30, example 4 teaches a 40 mg oral tablet.
Regarding claim 32, Baroni et al. generally teaches a tablet comprising 35 to 500 mg (paragraph 0010). Exemplary formulations include 100 mg, 150 mg, 200 mg, etc. (paragraph 0035). Therefore, Baroni et al. teaches concentrations which overlap the instant claims. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Claims 1-2, 10-13, 18-23, 26-30, 32-33, 36, 70-71 and 87 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 8912154; claims 1-9 of U.S. Patent No. 9314434; claims 1-28 of U.S. Patent No. 9499819; claims 1-19 of U.S. Patent No. 9982264; or claims 1-23 of U.S. Patent No. 10272047 in view of Baroni et al., Iwamoto et al., Aartsma-Rus et al. and Shibahara et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
Patent ‘154 claims a pharmaceutical tablet formulation for oral administration of an antisense oligonucleotide comprising: an intra-granular phase comprising an antisense oligonucleotide represented by SEQ ID NO 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable filler; an extra-granular phase comprising a disintegrant; and an enteric coating comprising an ethylacrylate-methacrylic acid copolymer. Mannitol, sodium starch glycolate are also claimed. Treating Crohn’s disease is claimed. O,O-linked phosphorothioates are claimed.
Patent ‘434 claims an oral dosage form comprising an amount of anti-SMAD7 antisense oligonucleotide comprising the nucleotide sequence of SEQ ID NO:1, wherein all internucleoside linkages in the anti-SMAD7 antisense oligonucleotide are O,O-linked phosphorothioates, or a pharmaceutically acceptable salt thereof, wherein about 10% to about 30% of the amount of the anti-SMAD7 antisense oligonucleotide is released in an environment of pH of 6.6 from the oral dosage form over a period of 30 minutes in an HPLC dissolution method and substantially none of the amount of anti-SMAD7 antisense oligonucleotide is released from the oral dosage form in an environment of pH of 1.0 over a period of 120 minutes in an HPLC dissolution method. As claimed all internucleoside linkages in the anti-SMAD7 antisense oligonucleotide are O,O-linked phosphorothioates. Enteric coatings are claimed. Tablets are claimed.
Patent ‘819 claims a method of treating inflammatory bowel disease comprising orally administering to a patient in need thereof an oral dosage form comprising an amount of anti-SMAD7 antisense oligonucleotide or a pharmaceutically acceptable salt thereof, wherein about 10% to about 30% of the amount of the anti-SMAD7 antisense oligonucleotide is released in an environment of pH of 6.6 from the oral dosage form over a period of 30 minutes in an HPLC dissolution method and substantially none of the amount of anti-SMAD7 antisense oligonucleotide is released from the oral dosage form in an environment of pH of 1.0 over a period of 120 minutes in an HPLC dissolution method. As claimed the anti-SMAD7 antisense oligonucleotide comprises the nucleotide sequence of SEQ ID NO:1, wherein all internucleoside linkages in the anti-SMAD7 oligonucleotide are O,O-linked phosphorothioates. Enteric coating is claimed. Dosage forms comprising from about 35 to about 500 mg antisense oligonucleotide is claimed. Crohn’s disease is claimed.
Patent ‘264 claims a method for confirming topical delivery of an oligonucleotide of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, substantially to the terminal ileum and/or right colon of a human following administration to the human of an oral dosage form comprising the oligonucleotide of SEQ ID NO: 1 or the pharmaceutically acceptable salt thereof, and an enteric coating, wherein the method comprises measuring plasma concentration of the oligonucleotide, or a pharmaceutically acceptable salt thereof, in the human; wherein minimal or absent plasma concentration of the oligonucleotide, or a pharmaceutically acceptable salt thereof, confirms topical delivery of the oligonucleotide, or a pharmaceutically acceptable salt thereof, substantially to the terminal ileum and/or right colon of the human. As claimed all internucleoside linkages in the oligonucleotide or the pharmaceutically acceptable salt thereof are O,O-linked phosphorothioates. Chron’s disease is claimed. Oral dosage form being a tablet is claimed. Oral dosage form comprises about 35 mg to about 500 mg of the oligonucleotide.
Patent ‘047 claims an oral dosage form comprising: An intra-granular phase comprising an oligonucleotide comprising the nucleotide sequence of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof; an extra-granular phase comprising a disintegrant; and an enteric coating comprising an ethylacrylate-methacrylic acid copolymer, wherein the oligonucleotide is released from the oral dosage form in an environment of pH 6.6 over a period of 30 minutes in an HPLC dissolution method. As claimed, all of the internucleoside linkages of SEQ ID NO: 1 are O,O-linked phosphorothioates. Tablets are claimed. Treating Chron’s disease is claimed.
The difference between Patent ‘154, ‘434, ‘819, ‘264 or ‘047 is the patents are silent to the 31P-NMR spectrum and principal component analysis as well as specifics of the pharmaceutical composition. However, this deficiency is cured by Baroni et al., Iwamoto et al., Aartsma-Rus et al. and Shibahara et al.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘154, ‘434, ‘819, ‘264 or ‘047 and Baroni et al., Iwamoto et al., Aartsma-Rus et al. and Shibahara et al. and utilize the pharmaceutical composition of Baroni et al. to deliver the SMAD7 antisense oligonucleotide. One skilled in the art would have been motivated to utilize the pharmaceutical composition of Baroni et al. as Baroni et al. teaches the same antisense oligonucleotide and Patent ‘154, ‘434, ‘819, ‘264 or ‘047 claim administering the oligonucleotide. Therefore, one skilled in the art would have found it obvious to utilize any known pharmaceutical composition known to deliver SMAD7 antisense oligonucleotides with a reasonable expectation of success.
Regarding the claimed 31P-NMR spectrum and principal component analysis and claim 71, Patents ‘66 Patent ‘154, ‘434, ‘819, ‘264 or ‘047 are silent. However, Shibahara et al. recognizes31P-NMR (i.e. phosphorous NMR) for compounds with multiplet phosphorothioates give a characteristic signal at 51-55 ppm. Iwamoto et al. teaches phosphorothioate (PS) substitution converts the achiral phosphodiester linkage into a chiral PS center having two distinct stereochemical configurations and all PS-substituted ASOs comprise mixtures of up to 2n individual drug molecules, where n equals the number of PS linkages. Iwamoto et al. teaches it is well-established that stereochemical variation at even a single stereogenic center in small molecules can profoundly affect their pharmacologic properties and their findings demonstrate that PS stereochemistry affects the measurable biophysical and biochemical properties of ASOs, and in certain cases, for example, with regards to nucleolytic stability, the observed impact is substantial. Aartsma-Rus et al. teaches that using principal component analysis to extract parameters that are largely independent and would yield optimal classification of effective and ineffective AOS and after principal component analysis, parameters can be selected to correctly classify effective and ineffective AONs. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘669, Baroni et al., Iwamoto et al., Aartsma-Rus et al. and Shibahara et al. and measure the 31P-NMR and perform principal component analysis (PCA) on the ASOs produced in order to classify the ASOs into effective and ineffective compounds. Since Aartsma-Rus et al. expressly teaches using PCA on antisense oligonucleotides and the compounds of Patent ‘004, are antisense oligonucleotides there is a reasonable expectation of success. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize known ways of classifying compounds such as 31P-NMR and principal component analysis in order to determine the identification of effective compounds. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to confirm a phosphorothioates signal at 51-55 ppm. The instant claims are merely claiming the particular 31P-NMR and principal component analysis possessed by the compounds and claim those which are effective. Patent ‘669 teaches that the oligonucleotides need to be used to treat Crohn’s disease, one skilled in the art would have been motivated to identify ways of determining which oligonucleotides are effective.
Regarding claims 12-13, 100 millimoles to 5 moles of SMAD7 ASO corresponds to 658.4 g to 32920 g based on an ASO molecular weight of 6584 g/mol (C200H261N69O107P20S20). Baroni et al. generally teaches a tablet comprising 35 to 500 mg (paragraph 0010). Example 4 which is directed to a 40 mg tablet uses 188.66 g of the active. Based on example 4, a 500 mg tablet would use 2358.25 g (when scaled up from a 40 mg tablet). Therefore, Baroni et al. suggest amounts which overlap the range of millimoles claimed. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Regarding claims 18-23, example 4 is directed to a 40 mg tablet:
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This example contains the same claimed components in an amount falling within the scope claimed for claims 18-22 when about is taken into consideration.
Regarding claims 26-29, 33, 36, firstly claims 26-29 are directed to the intended use of the composition and do not structurally distinguish the pharmaceutical composition of Baroni et al. from the instant claims. Furthermore, Baroni et al. claims a method of treating Crohn’s disease comprising orally administering the tablet rendering obvious instant claims 33 and 36.
Regarding claim 30, example 4 teaches a 40 mg oral tablet.
Regarding claim 32, Baroni et al. generally teaches a tablet comprising 35 to 500 mg (paragraph 0010). Exemplary formulations include 100 mg, 150 mg, 200 mg, etc. (paragraph 0035). Therefore, Baroni et al. teaches concentrations which overlap the instant claims. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Response to Arguments
Applicants’ arguments filed October 13 2025 have been fully considered but they are not persuasive.
Applicants argue (pages 19-20) that claim 1 has been amended and the claims are not obvious for the reasons provided herein.
These arguments are not persuasive for the reasons set forth above.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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