DETAILED ACTION
Claims 3-9, 13-17, 24-25, 31, 34-35, 37-69 and 72-86 were/stand cancelled. 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 .
Priority
This application is a 371 of PCT/IB2021/000272 (04/23/2021) which claims benefit of 63/135,283 (01/08/2021) and claims benefit of 63/030,818 (05/27/2020) and claims benefit of 63/015,120 (04/24/2020) as reflected in the filing receipt issued March 28 2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June 20 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The use of the term Opadry®, Acryl-EZE® and Eudragit® (paragraph 0018, 0154, 0157) which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears 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.
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.
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.
Claims 20-22, 70-71 and 87 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 20-22 contain the trademark/trade name Opadry® AMB and Acryl-EZE®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name (Opadry AMB) is used to identify/describe a combination of Polyvinyl alcohol - part hydrolyzed, Titanium dioxide, Talc, Lecithin. (soya), Xanthan gum, iron oxide yellow (see for example page 10 of WO2011018185) and, accordingly, the identification/description is indefinite. In the present case, the trademark/trade name (Acryl-EZE) is used to identify/describe Poly [methacrylic acid, ethyl acrylate] with the ratio 1:1 (see for example Gupta et al., page 35 d)) and, accordingly, the identification/description is indefinite.
Claims 70-71 as currently written is vague and indefinite. The claims are directed to a method of manufacturing a pharmaceutical composition (or the product made by the method) comprising a plurality of diastereomers of a SMAD7 antisense oligonucleotide, the method comprising 1) confirming a 31P-NMR…;and confirming the 31P-NMR. The claim is confusing because the method steps are not to manufacturing but to characterizing the oligonucleotides that are produced. None the claimed steps actually recite making the oligonucleotides but to confirming a particular spectrum of the made compound. Furthermore, the claim never indicates what to do if the 31P-NMR spectrum doesn’t have one of the claimed resonance or principal components claimed. Therefore, it isn’t clear how the method steps practice the method of manufacturing as claimed.
Claim 87 as currently written is vague and indefinite. Claim 87 recites wherein one or more cytidines are 5-methyl 2’-deoxycytidine. Claim 87 depends from claim 1 and already requires 2 of the cytidines to be 5-methyl 2’-deoxycytidine (as X). It is unclear if these one or more cytidines are referring to the non-X cytidines and are in addition to the two 5-methyl 2’-deoxycytidine already required or if Applicants are attempting to redefine the number of 5-methyl 2’-deoxycytidine present in the sequence.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1-2, 10-11, 18-23, 26-30, 32-33, 36, 70 and 87 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Baroni (USPGPUB No. 20120015033).
The instant application claims a pharmaceutical composition, comprising 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 comprising: 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 outside of the range of -0.32 to 0.30 and/or the PC2 score that is outside the range of 0.00 to 0.20.
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 plurality of diastereomers of a SMAD7 antisense oligonucleotide (ASO) that is pharmacologically and/or clinically efficacious, made by a method comprising: a) confirming a 31P-NMR spectrum for the plurality of diastereomers of one or more resonances between 54.8 to 55.5 ppm; and b) confirming the 31P-NMR spectrum has:(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 outside of the range of -0.32 to 0.30 and/or a PC2 score that is outside the range of 0.00 to 0.20,as determined by principal component analysis (PCA).
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.
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. Baroni et al. is silent. However, the spectrum as claimed is the result of the structure. Since the instant claims recite comprising and the structure of sequence 1 includes a plurality of diastereomers, it is inherent that at some of the ASO would have a 31P-NMR as claimed. Note MPEP 2112.01: "Products of identical chemical composition cannot have mutually exclusive properties." A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705,709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). The instant specification (example 1, page 49) which is the only example directed to actually making the oligonucleotides does not indicate any particular method is utilized to make the oligonucleotides. Therefore, there is no structural difference between the oligonucleotides of Baroni et al. and the instant claims.
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.
Claim Interpretation
As set forth above, Baroni et al. exemplifies a SMAD7 antisense oligonucleotide which has the exact same structure as instantly claimed but is silent to the 31P NMR and principal component analysis. It is the examiner’s position that at least some of the compounds that are formed when making the oligonucleotide would have the 31P NMR and principal component analysis as claimed and the instant claims do not exclude other diastereomers from being present. In the event the claims are limited to diastereomers which ONLY possess the instantly claimed 31P NMR and principal component analysis, the claims are obvious for the reasons set forth below.
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, 70-71 and 87 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), Aarttsma-Rus (Molecular Therapy, 2009) and Shibahara et al. (EP0339842).
Applicant Claims
The instant claims are set forth above.
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) confirming a 31P-NMR spectrum for the plurality of diastereomers of one or more resonances between 54.8 to 55.5 ppm; and b) confirming the 31P-NMR spectrum has:(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 outside of the range of -0.32 to 0.30 and/or a PC2 score that is outside the range of 0.00 to 0.20,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 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).
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 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.
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, 10-11 and 70 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10337004. 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 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 comprising: 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 outside of the range of -0.32 to 0.30 and/or the PC2 score that is outside the range of 0.00 to 0.20.
The instant application claims a pharmaceutical composition comprising a plurality of diastereomers of a SMAD7 antisense oligonucleotide (ASO) that is pharmacologically and/or clinically efficacious, made by a method comprising: a) confirming a 31P-NMR spectrum for the plurality of diastereomers of one or more resonances between 54.8 to 55.5 ppm; and b) confirming the 31P-NMR spectrum has:(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 outside of the range of -0.32 to 0.30 and/or a PC2 score that is outside the range of 0.00 to 0.20,as determined by principal component analysis (PCA).
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.
Regarding the claimed 31P-NMR spectrum and principal component analysis. Patent ‘004 is silent. However, the spectrum as claimed is the result of the structure. Since the instant claims recite comprising and the structure of sequence 1 includes a plurality of diastereomers, it is inherent that at some of the ASO would have a 31P-NMR as claimed. Note MPEP 2112.01: "Products of identical chemical composition cannot have mutually exclusive properties." A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705,709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). The instant specification (example 1, page 49) which is the only example directed to actually making the oligonucleotides does not indicate any particular method is utilized to make the oligonucleotides. Therefore, there is no structural difference between the oligonucleotides of Patent ‘004 and the instant claims.
Claims 1-2, 10-13, 18-23, 26-30, 32-33, 36, 70 and 87 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10337004 as applied to claims 1-2, 10-11 and 70 in view of Baroni 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 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.
The teachings of patent ‘004 are set forth above.
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
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 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 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. 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.
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 and Baroni 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. Patent ‘004 is silent. However, the spectrum as claimed is the result of the structure. Since the instant claims recite comprising and the structure of sequence 1 includes a plurality of diastereomers, it is inherent that at some of the ASO would have a 31P-NMR as claimed. Note MPEP 2112.01: "Products of identical chemical composition cannot have mutually exclusive properties." A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705,709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). The instant specification (example 1, page 49) which is the only example directed to actually making the oligonucleotides does not indicate any particular method is utilized to make the oligonucleotides. Therefore, there is no structural difference between the oligonucleotides of Patent ‘669 and the instant claims.
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 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. 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.
Patent ‘154, 434, 819, 264 and ‘047 all claim the same antisense oligonucleotide and pharmaceutical compositions comprising the oligonucleotide. 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.
The teachings of Baroni et al. are set forth above.
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. 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. Patent ‘154, 434, 819, 264 or ‘047 are silent. However, the spectrum as claimed is the result of the structure. Since the instant claims recite comprising and the structure of sequence 1 includes a plurality of diastereomers, it is inherent that at some of the ASO would have a 31P-NMR as claimed. Note MPEP 2112.01: "Products of identical chemical composition cannot have mutually exclusive properties." A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705,709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). The instant specification (example 1, page 49) which is the only example directed to actually making the oligonucleotides does not indicate any particular method is utilized to make the oligonucleotides. Therefore, there is no structural difference between the oligonucleotides of Patent ‘154, 434, 819, 264 or ‘047 and the instant claims.
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 exa