DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Receipt is acknowledged of Applicants’ preliminary amendment, filed on 01/29/2024, in which claims 21-28 and 46-52 are amended and claims 1-20, 29-45, and 53-59 are cancelled.
Claims 21-28 and 46-52 are pending and are examined on the merits herein.
Priority
The instant application is a CON of 17/870,551 filed on 07/21/2022 which is a CON of PCT/CN2021/095036 filed on 05/21/2021, which claims foreign priority from CN PCT/CN2020/091643 filed on 05/21/2020.
Information Disclosure Statement
The information disclosure statements (IDS) dated 11/20/2023 and 09/23/2024 comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, the information disclosure statements have been considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
The instant specification recites “Size: 4 kilobytes” on page 1. The size of the text file should be in bytes.
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 - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
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 incorporation-by-reference paragraph, 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 Objections
Claims 22-23 are objected to because of the following informalities: the phrase “determined whether a test substantially pure dichloroacetic acid comprises” on lines 2-3 of each of claims 22-23 appears to be missing a word. This should be corrected to “determined whether a test of substantially pure dichloroacetic acid comprises”. Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 21, 24-28, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Krotz et al. (US 2005/0075490 A1; IDS 11/20/2023) in view of Yang et al. (Synthetic Metals, 2006; PTO-892).
Krotz teaches process of manufacturing oligonucleotides includes a 5'-deblocking step in which the 5-blocking group is removed with dichloroacetic acid that is essentially free of chloral. The process is useful for making oligonucleotides that are substantially free of chloral adducts (abstract).
Krotz describes a typical oligonucleotide synthesis using phosphoramidite chemistry is paragraphs [0007]-[0022]:
First, a primer support is provided in a standard synthesizer column. The primer support is typically a solid support having a linker covalently bonded thereto. It is common to purchase the primer support with a first 5'-protected nucleoside bonded thereto.
The 5'-blocking group is removed, (e.g. by exposing the 5'-blocked primer-support bound nucleoside to an acid) thereby producing a support-bound nucleoside.
The column is washed with acetonitrile, which acts to both push the reagent (acid) onto the column, and to wash unreacted reagent and the removed 5'-blocking group from the column.
The primer support is then reacted with a phosphitylation reagent (amidite), which is dissolved in acetonitrile.
The support-bound dimer is then typically washed with acetonitrile.
A capping reagent in acetonitrile is then added to the column, thereby capping unreacted nucleoside.
The column is then washed again with acetonitrile.
Steps (A)-(F) are then repeated, if necessary, a sufficient number of times to prepare a support-bound, blocked oligonucleotide [0022]. A typical blocking group for 5'-protection of nucleotides is the dimethoxytrityl group (DMT). The DMT group is acid labile, and may be removed with relatively weak acid, Such as dichloroacetic acid [0027].
Krotz teaches that it is important that the oligonucleotide be produced in both good yield and excellent purity [0027]. During normal oligonucleotide synthesis a significant impurity arises out of the coupling of chloral or its derivatives to the nascent oligonucleotide during deblocking of 5'-OH groups. Such deblocking is generally referred to as detritylation, because the trityl group, or DMT, is the most commonly used group for protecting the 5'-OH of the nucleoside during coupling of the nucleoside to the oligonucleotide. The most commonly used reagent for detritylation is dichloroacetic acid (DCA) [0033]. Even very small amounts of chloral impurity in DCA can lead to significant impurities arising from coupling of chloral to or within the oligonucleotide chain [0034].
The teachings of Krotz differ from that of the instantly claimed invention in that Krotz is silent regarding the glyoxylic level of the reagents.
Yang discusses the synthesis of polyaniline nanofibers (page 1225, paragraph 1) and the effect of water concentration on the solubility of the nanofibers (page 1226, paragraph 1). Specifically, Yang investigates the impact of hydrogen bonds on polyaniline nanofiber chain conformation in solutions of 2-acrylamido-2-methyl-l-propanesulfonic acid/dichloroacetic acid (DCAA) (abstract). In the materials section, Yang discloses that the DCAA used was of high purity and so has a negligible amount of water. The DCAA used was purchased from Sigma–Aldrich and was of 99.9% purity (page 1226, paragraph 2). Yang teaches that dichloroacetic acid is hygroscopic to some extent (paragraph bridging pages 1228-1229).
It would have been prima facie obvious before the effective filing date of the claimed invention to use the dichloroacetic acid of Yang in the oligonucleotide synthesis method described by Krotz to arrive at the instantly claimed invention because it would have been prima facie obvious to select the known and commercially available dichloroacetic acid for use in the known method of Krotz to achieve the predictable result of a method of oligonucleotide synthesis. Furthermore, one of ordinary skill in the art would have been motivated to use the high purity dichloroacetic acid of Yang as a reagent in the method of Krotz because Krotz teaches that even very small amounts of chloral impurity in DCA can lead to significant impurities and that it is important that the oligonucleotide be produced in both good yield and excellent purity, and Yang teaches that the 99.9% pure dichloroacetic used was of high purity.
Regarding the limitation “selecting or identifying a substantially pure dichloroacetic acid that comprises less than 1,000 ppm glyoxylic acid”, one of ordinary skill in the art would have understood that the 99.9% pure dichloroacetic of Yang has at most 0.1% impurity present. A 0.1% impurity is equivalent to 1,000 ppm of impurity. Thus, even if the only impurity present in the dichloroacetic acid of Yang has at most 1,000 ppm glyoxylic acid. MPEP 2144.05(I) states that a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. “In re Brandt, 886 F.3d 1171, 1177, 126 USPQ2d 1079, 1082 (Fed. Cir. 2018) the court found a prima facie case of obviousness had been made in a predictable art wherein the claimed range of "less than 6 pounds per cubic feet" and the prior art range of "between 6 lbs./ft3 and 25 lbs./ft3" were so mathematically close that the difference between the claimed ranges was virtually negligible absent any showing of unexpected results or criticality.” Thus the prior art teaching of dichloroacetic acid with at most a 1,000 ppm impurity renders prima facie obvious the claimed range of less than 1,000 ppm glyoxylic acid.
Furthermore, the instant disclosure does not demonstrate the criticality of the claimed range. The instant disclosure in Example 1.2 (Specification, beginning page 33) describes the synthesis of Oligodeoxyribonucleotide Tl1 using DCA sample-01 and states that the main product was 10mer dT product, which indicates that the synthesis failed. The glyoxylic acid content of DCA sample-01 is indicated in Table 2 on page 35 as 2142.7 ppm.
Example 5 (Specification, beginning page 36) details the synthesis of oligonucleotides using the 10% DCA reagents of Table 4, which is reproduced below, in the detritylation step (Specification, page 37, paragraph 5).
PNG
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362
482
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Greyscale
However, the instant specification does not provide data showing whether the synthesis using these reagents was successful, nor does it provide a comparison of oligonucleotide synthesis using a DCA reagent within the claimed range of less than 1,000 ppm glyoxylic acid to a DCA reagent that is outside of the claimed range of glyoxylic acid. MPEP 716.02(d) states that to establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range, and that the objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support. Furthermore, MPEP 716.02(d) states that the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. Thus the instant specification does not provide evidence that this claimed glyoxylic acid concentration is critical.
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 21-28 and 46-52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5-16 of U.S. Patent No. 11873318. Although the claims at issue are not identical because ‘318 claims a method comprising a pure dichloroacetic acid having less than 50 ppm glyoxylic acid and thus a smaller range of glyoxylic acid content, they are not patentably distinct from each other because claim 5 of ‘318 is directed to a method of synthesizing an oligonucleotide, comprising mixing the substantially pure dichloroacetic acid with a protected oligonucleotide having an acid labile protecting group under conditions suitable to remove the acid labile protecting group, thereby producing a deprotected oligonucleotide wherein the substantially pure dichloroacetic acid is prepared from a starting dichloroacetic acid composition having glyoxylic acid by reducing the level of glyoxylic acid to less than 50 ppm. The disclosure of ‘318 indicates that conditions suitable to remove the acid labile protecting group encompass detritylation conducted using 10% DCA reagents in toluene (col. 30, lines 47-48). Claim 7 further limits wherein prior to the mixing, the pure dichloroacetic acid is determined to comprise less than 50 ppm glyoxylic acid by ion chromatography. Claim 9 further limits wherein the protected oligonucleotide comprises a 5'-hydroxyl protected with the acid labile protecting group. Claim 10 further limits wherein the acid labile protecting group is a trityl group. Claim 11 further limits wherein the protected oligonucleotide is bound to a solid support.
MPEP 2131.03(I) states that “if the prior art discloses a point within the claimed range, the prior art anticipates the claim.” If the claims of ‘318 were available as prior art, the instantly claimed method would have been anticipated and thus the instant claims are rejected on the ground of nonstatutory double patenting.
Allowable Subject Matter
Claims 22-23 and 47-52 contain allowable subject matter. The following is a statement of reasons for the indication of allowable subject matter.
Claims 22-23 and 47-52 are drawn to methods of synthesizing an oligonucleotide, comprising a step of determining or having determined whether a test substantially pure dichloroacetic acid comprises less than 1,000 ppm glyoxylic acid. Thus the instantly claimed invention requires determination of the glyoxylic acid concentration in the dichloroacetic acid.
The closest prior art is Krotz et al. (US 2005/0075490 A1; IDS 11/20/2023) which discloses methods of oligonucleotide synthesis comprising dichloroacetic acid. However, neither Krotz nor the prior art recognizes glyoxylic acid as an impurity of dichloroacetic acid. Thus one of ordinary skill in the art would not have been motivated to test for the presence glyoxylic acid in dichloroacetic acid as a part of the method of oligonucleotide synthesis taught by Krotz, and claims 22-23 and 47-52 are not obvious over the prior art.
Conclusion
No claims are allowed.
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/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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