DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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 specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Table on pages 134-135 has sequences without sequence identifiers (SEQ ID NOs).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, 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.
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.
There are sequences in Figures 9B and 10B without sequence identifiers (SEQ ID NOs).
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.
Claim 43 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.
Regarding claim 43, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claims 44-59 are indefinite as well because they depend from claim 43 but do not clarify the issue.
Claim 43 is indefinite because it recites “the further internucleoside linkages” without proper antecedent basis. It is unclear if “the further internucleoside linkages” refers to some unspecified subset of further internucleoside linkages or to all other internucleoside linkages in the oligonucleotide. Claims 44-59 are indefinite as well because they depend from claim 43 but do not clarify the issue.
Claim Interpretation
Claims 43-59 are interpreted as product-by-process claims, therefore they are limited by structure implied by manufacturing steps, but not limited to the manipulation of recited steps (see MPEP 2113).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 43-53, 57-59 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hossbach et al (US 2017/0319614, November 2017, cited from IDS).
Hossbach teach antisense oligonucleotides of at least 10 nucleotides wherein at least two of the nucleotides are LNAs, and pharmaceutical compositions comprising the oligonucleotides (see Abstract). The oligonucleotides may contain 1 to 5 LNA units at the 5' terminal end and 1 to 5 LNA units at the 3' terminal end and so may be gapmers, a type of antisense oligonucleotide (see paragraphs [0039 and 0095]). The antisense oligonucleotides may also contain phosphorothioate (PS) or phosphorodithioate (P2S) instead of phosphate bridges (see paragraph [0040]). Such modifications may be present only in the LNA segments or only in the non-LNA segment of the antisense oligonucleotide (see paragraph [0040]). PS and P2S linkages may be present in either the gap or flanking segments, and may also connect the two types of segments (see paragraph [0447]). The oligonucleotides may be formulated as salts and the internucleotide linkage preferably contains a negatively charged oxygen or sulfur atom which form salts like the sodium, lithium or potassium salt (see paragraphs [0375-0376]). The LNA residues may be beta-D-oxy-or beta-D-thio-LNAs (see paragraphs [0367, 0536, and 0541]). It is noted that the P2S linkages of Hossbach have non-bridging sulfur atoms, and Hossbach satisfies the limitations of instant formulas so are of formulas (IA) and (IB) (see paragraph [0448]). Hossbach also teach that the oligonucleotides could comprise modifications such as 2’-alkoxy and substituted alkoxy groups (see paragraph [0462]).
Hossbach exemplified numerous antisense gapmer oligonucleotides comprising beta-D-oxy-LNA residues flanking a deoxynucleotide gap region and comprising 5- methylcytosine and/or 2-aminoadenine residues: see, for example, SEQ D NOs: 238h, 152aa, and 251h (Table 4 at page 70, and Table 5 at pages 72and 73). However, each of these exemplified oligonucleotides differ from the oligonucleotide of instant claim 1 in that each internucleoside linkage was a P2S linkage. Similarly, Hossbach teach numerous antisense gapmer oligonucleotides comprising 5-methylcytosine and/or 2- aminoadenine residues wherein each internucleoside linkage was a PS linkage: see, for example, SEQ ID NOs: 234d-234f in Table 4 at page 68. These oligonucleotides differ from the instant claims by lacking any P2S linkages.
The instantly claimed patterns of P2S and PS internucleoside linkages are considered to have been prima facie obvious over the disclosure of Hossbach because Hossbach teach that in LNA gapmer oligomers, all of the linkages in the LNA portions could be P2S linkages, all of the linkages in the gap region could be PS linkages (see paragraphs [0040 and 0447]) and the linkages joining the gap and flanking sequences could be either PS or P2S. In view of that disclosure, one of ordinary skill could have immediately envisioned gapmer oligonucleotides with LNA flanking sequences where all linkages were P2S linkages and gaps where all linkages were PS linkages. Accordingly, instant claims 43-46, 48-53, 57-59 are prima facie obvious.
Claim 47 requires a P2S linkage between a LNA nucleoside and a DNA nucleoside. This is considered to have been obvious because Hossbach teach that P2S linkages could join the flank and gap regions (see paragraph [0447]) and because the flank regions consist of LNA residues and the gap regions consist of DNA residues (see paragraph [0551]).
The structure of the oligomers rendered obvious by Hossbach is indistinguishable from those recited in claims 43-53, 57-59, and so the oligomers rendered obvious by Hossbach are identical to instantly claimed ones irrespectively of the method of manufacturing them (see MPEP 2113).
Claims 54-56 stand rejected under 35 U.S.C. 103 as being unpatentable over Hossbach et al, above, as applied to claims 43-53, 57-59 above, and further in view of Prakash et al (US 20150126720, May 2015, cited from IDS).
The teachings of Hossbach are summarized above and render obvious LNA gapmer oligonucleotides in which the flanking nucleotides are joined to each other and to the gap section by P2S linkages, and the gap nucleotides are joined by PS linkages. Hossbach also teach that nucleotides in the oligomers could comprise other modifications such as 2’-alkoxy and -substituted alkoxy groups (see paragraph [0462]).
Hossbach does not teach a P2S linkage between a LNA residue and a 2 - methoxy-RNA residue or 2’ -methoxyethoxy-RNA residue.
Prakash provide guidance regarding the structural characteristics of gapmer oligonucleotides and teach that flanking sequences could have mixtures of different types of 2’-modifications. For example, Prakash teach that the 3'-wing of a gapmer could comprise at least one LNA nucleoside and at least one non-bicyclic modified nucleoside, such as at least one 2'-MOE nucleoside at least one 2'-OMe nucleoside (where 2’-MOE is 2’-methoxyethyl, also known as 2'-methoxyethoxy, and 2’-OMe is 2-O-methyl, also known as 2’-methoxy), (see paragraph [0631]). Prakash teach that such modifications have desirable properties, such as enhanced nuclease stability or increased binding affinity with a target nucleic acid relative to an oligonucleotide comprising only nucleosides (see paragraphs [0577-0578]).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time of the invention to have substituted 2' -methoxyethoxy or 2’-methoxy residues into the flanking sequence of Hossbach such that the flanking sequence comprised a mixture of LNA and 2’-MOE or -OMe residues (as taught by Prakash) linked by P2S linkages (as taught by Hossbach). One of the ordinary skill of the art would be motivated to do that to achieve desirable properties of gapmers as taught by Prakash.
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 43-59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-66 of copending Application No. 18/618,900. Claims from ‘900 recite gapmer oligonucleotides comprising LNAs connected by phosphorodithioate bonds same as instantly claimed with other bonds being phosphorothioate, anticipating instant claims.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EKATERINA POLIAKOVA whose telephone number is (571)270-5257. The examiner can normally be reached Mon-Fri 8-5.
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/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637