DETAILED CORRESPONDENCE
Application Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Claims 1-20 are pending.
Election/Restrictions
3. Applicant’s election of Group I, claims 1-7, 10, 12, 14 and 15 in the reply filed on 06/22/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
4. Claims 8-9, 11, 13, and 16-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/22/2026.
Claims 1-7, 10, 12, 14 and 15 are pending and examined on the merits.
Priority
5. Acknowledgement is made of applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d) to Europe Patent Application No. 21163793.9, filing date 03/19/2021. The certified copy has been electronically retrieved by the USPTO on 03/18/2022.
Information Disclosure Statement
6. The IDSs filed on 09/18/2023 and 12/02/2024 have been considered by the examiner and copies of the Form PTO/SB/08 are attached to the office action.
Specification
7. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
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. See Figure 6.
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(b)
8. 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.
9. Claims 1-7, 10, 12, and 14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1 (claims 2-7, 10, 12, and 14 dependent therefrom), there is insufficient antecedent basis for the limitation “said polynucleotide” in part iii of claim 1.
Further regarding claims 1-7, 10, 12, and 14, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Further regarding claim 5, the parenthesis renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 7, there is insufficient antecedent basis for “said one or more produced POIs”.
It is suggested that applicants clarify the meaning of the claims.
Claim Rejections - 35 USC § 102
10. 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.
11. Claim(s) 1-3, 6, 10, and 12 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wen et al. (Biochemical and Biophysical Research Communications, 2008; cited on IDS filed on 12/02/2024).
12. Claims 1-3, 6, 10 and 12 are drawn to a method for expressing or producing one or more proteins of interest in a eukaryotic cell by a. introducing into a eukaryotic cell a nucleic acid molecule comprising a polynucleotide encoding a protein of interest (POI), wherein said nucleic acid molecule is targeted to the nucleolar DNA, preferably to a nucleolar organizer region, of said organism to insert or form upon integration of said nucleic acid molecule a chimeric gene comprising the following operably-linked elements: i. a polymerase I promoter; ii. a polynucleotide encoding an internal ribosomal entry site (IRES); iii. said polynucleotide encoding said POI; iv. optionally, a 3’ end region/transcription terminator.
13. With respect to claim 1, Wen et al. teach a method for expressing a human coagulation factor IX in a human cell by introducing into said eukaryotic cell a nucleic acid molecule targeted to the rDNA locus (nucleolar DNA) that upon integration of said nucleic acid molecule a chimeric gene comprising a polymerase I promoter, a IRES, polynucleotide encoding said Factor IX, and 3’ terminator [see Abstract; p. 847, Figures 1-2].
With respect to claim 2, Wen et al. teach the method wherein said nucleic acid molecule already comprises said polymerase I promoter [see Abstract; p. 847, Figures 1-2].
With respect to claim 3, Wen et al. teach the method wherein said nucleic acid molecule is flanked with one or more flanking sequences for allowing integration of said nucleic acid molecule at a predefined site in said nucleolar DNA by homologous recombination [see Abstract; Figure 2].
With respect to claim 6, Wen et al. teach the method wherein expression of said POI is enhanced compared to expression driven by a strong PolII promoter [see Abstract].
With respect to claim 10, Wen et al. teach the method wherein said chimeric gene is integrated into the 18S rDNA locus (cistron) [see Abstract].
With respect to claim 12, Wen et al. teach the method wherein the cell is a HT1080 cell (human cell) [see p. 847, column 1].
Claim Rejections - 35 USC § 103
14. 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.
15. Claim(s) 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wen et al. (Biochemical and Biophysical Research Communications, 2008; cited on IDS filed on 12/02/2024) in view of Rozov et al. (Molecular Biology, 2019; examiner cited).
16. The relevant teachings of Wen et al. as applied to claims 1-3, 6, 10 and 12 are set forth in the 102(a)(1) rejection above.
However, Wen et al. does not teach the method wherein said chimeric gene further comprises a polynucleotide encoding an translational enhancer or a cap-independent translation enhancer (CITE).
Rozov et al. teach similar methods and constructs for expressing a recombinant protein in eukaryotic cells and teach that the presence of 3’-CITE in the transient expression system based on CMV virus increases translation level by 30% [see Abstract; p. 159, column 2]. Furthermore, Rozov et al. teach that the nucleolus containing 35S rRNA is the most active part of the genome, and therefore site-specific insertion of the target recombinant genes in the active nucleolus organizer region can lead to a stable and high expression level [see p. 167, column 2, bottom], and RNA polymerase I transcripts can be further translated if the expression cassette contains IRES or 3’-CITES that provide a cap-independent attraction of the translation factors and binding to the ribosome [see p. 167, column 2 bridging to p. 168, column 1].
Before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill in the art to combine the teachings of Wen et al. and Rozov et al. to include a CITE in the nucleic acid molecule of Wen et al. because both Wen et al. and Rozov et al. teach the expression of recombinant proteins in eukaryotic cells by targeted integration into the nucleolar DNA of the cell. Rozov et al. teach that the presence of CITE in the construct increases translation level and RNA polymerase I transcripts can be further translated if the expression cassette contains IRES or 3’-CITES that provide a cap-independent attraction of the translation factors and binding to the ribosome. One of ordinary skill in the art would have had a reasonable expectation of success, a reasonable level of predictability and would have been motivated to combine the teachings of Wen et al. and Rozov et al. because Rozov et al. acknowledges that the presence of CITE in the construct increases translation level and RNA polymerase I transcripts can be further translated if the expression cassette contains IRES or 3’-CITES that provide a cap-independent attraction of the translation factors and binding to the ribosome. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
17. Claims 5, 7, and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Wen et al. (Biochemical and Biophysical Research Communications, 2008; cited on IDS filed on 12/02/2024) in view of Schneider et al. (US Patent Application Publication 2013/0323780 A1; examiner cited).
18. The relevant teachings of Wen et al. as applied to claims 1-3, 6, 10 and 12 are set forth in the 102(a)(1) rejection above.
With respect to claim 15, Wen et al. teach a method for expressing a human coagulation factor IX in a human cell by introducing into said eukaryotic cell a nucleic acid molecule targeted to the rDNA locus (nucleolar DNA) that upon integration of said nucleic acid molecule a chimeric gene comprising a polymerase I promoter, a IRES, polynucleotide encoding said Factor IX, and 3’ terminator [see Abstract; p. 847, Figures 1-2].
However, Wen et al. does not teach the method of claim 5, wherein said chimeric gene further comprises a polynucleotide encoding a second IRES sequence operably linked to a second polynucleotide encoding a second protein of interest; the method of claims 7 and 15, comprising a further step of isolating and optionally purifying said one or more produced POIs, protein or polypeptide; and the method of claim 14, wherein said cell is from a Nannochloropsis sp.
Schneider et al. teach similar methods for expressing proteins and purifying heterologous expressed proteins from eukaryotic cells, particularly algae such as Nannochloropsis comprising expression constructs comprising one or more IRES elements and polynucleotides encoding one or more proteins [see Abstract; paragraphs 0024, 0062, 0100, 0108-0115].
Before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill in the art to combine the teachings of Wen et al. and Schneider et al. to include additional IRES, genes encoding polypeptides and purifying the expressed protein because Wen et al. and Schneider et al. both teach the expression of recombinant proteins in eukaryotic cells. Schneider et al. teach similar methods for expression in algae comprising one or more IRES elements in addition to one or more polynucleotides encoding one or more proteins. One of ordinary skill in the art would have had a reasonable expectation of success and would have a reasonable level of predictability to combine the teachings of Wen et al. and Schneider et al. because Schneider et al. acknowledges that you can include additional IRES elements for expression of one or more proteins in eukaryotic cells. Therefore, the above invention would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
19. Status of the claims:
Claims 1-20 are pending.
Claims 8-9, 11, 13, and 16-20 stand withdrawn pursuant to 37 CFR 1.142(b).
Claims 1-7, 10, 12, 14 and 15 are rejected.
No claims are in condition for an allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PAUL J HOLLAND whose telephone number is (571)270-3537. The examiner can normally be reached Monday to Friday from 8AM to 5PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached at 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL J HOLLAND/Primary Examiner, Art Unit 1656
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