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 .
Election/Restrictions
Applicant’s election without traverse of Group II, claims 57 and 59, in the reply filed on 06/18/2026 is acknowledged.
Amendments to claims 57 and 59 are acknowledged.
Claims 1-56, 58, and 60-64 are canceled in the claim set filed on 06/18/2026.
New claims 65-81 are acknowledged.
Claims 57, 59, and 65-81 are pending and under examination on the merits.
Priority
This application 18/320,187 filed on 05/18/2023 is a continuation of U.S. Patent Application No. 15/195,524, filed on 06/28/2016, which is a continuation of International Application No. PCT/EP2014/003481, filed on 12/30/2014 and claims the benefit of International Application No. PCT/EP2013/003948, filed on 12/30/2013.
The priority date of claim 57 and its dependent claims 59, and 65-81 is determined to be 12/30/2013, the filing date of International Application No. PCT/EP2013/003948.
It is also noted that the elected claims of the instant application correspond to the non-elected Group IV of the parent U.S. Patent Application No.15/195,524 and as such is considered a divisional application.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.831-1.834 because the “Sequence Listing XML,” as a separate part of the disclosure, is defective, damaged or unreadable.
Refer to document “Sequence Listing in Computer Readable Format is Defective” dated 05/18/2023.
The specification is objected to because of the following deficiencies in the Sequence Listing:
SEQ ID NO:2 in the Sequence Listing does not match the sequence provided for SEQ ID NO:2 in the specification but is instead identical to SEQ ID NO. 1. The sequence provided for SEQ ID NO:2 in the Sequence Listing is not an RNA sequence.
SEQ ID NO:4 in the Sequence Listing does not match the sequence provided for SEQ ID NO:4 in the specification but is instead identical to SEQ ID NO. 3. The sequence provided for SEQ ID NO:4 in the Sequence Listing is not an RNA sequence.
Required response - Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above submitted in accordance with either item 1. or 2.; together with
o A statement that identifies the location of all additions, deletions or replacements of sequence information relative to the replaced “Sequence Listing XML” as required by 37 CFR 1.835(b)(3);
o A statement that indicates support for the replacement “Sequence Listing XML” in the application, as filed, as required by 37 CFR 1.835(b)(4); and
o A statement that the replacement “Sequence Listing XML” includes no new matter as required by 37 CFR 1.835(b)(5).
AND
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125, inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
o A statement that the substitute specification contains no new matter.
Specification
The use of terms which are trade names or marks used in commerce (including Gibco and Life technologies among others), 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.
Claim Rejections - 35 USC § 112(b)
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 57, 59, and 65-81 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 57, 59, and 67-71 recite the limitation ”derived from the 3'-UTR”. The phrase “derived from” is unclear and renders the claim indefinite. For example, the phrase “derived from” can mean chemical modification, genetic modification or no modification. It is also unclear what extent of modification would be considered to satisfy “derived from”.
Claims 59 and 65-81 are similarly indefinite because they directly or indirectly depend from claim 57.
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 57, 59, 65-66, 68-71, and 73-75 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Trinklein et al. (WO2008112127, on IDS dated 01/24/2024) as evidenced by NM_014845.5 (GenBank Accession number NM_014845.5, Homo sapiens FIG4, first submitted 1993).
Regarding claim 57, Trinklein teaches libraries of expression constructs for determining the impact of regulatory sequences in the UTRs on translation of open reading frames (Abstract). Trinklein teaches producing a 3’ UTR expression construct (artificial nucleic acid molecule) comprising an open reading frame associated with a 3’ UTR sequence (Fig. 3). Trinklein teaches selecting the UTR from sequences that include SEQ ID NO: 14050 (para 6, claim 8). SEQ ID NO: 14050 has 100% homology to the FIG4 3’UTR (SEQ ID NO: 1 in the instant application) as shown below:
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Trinklein does not explicitly teach that the UTR sequence of SEQ ID NO: 14050 “is derived from the 3'-UTR of a Sac Domain-Containing Inositol Phosphatase 3 (FIG4) gene” as recited in claim 57.
However, SEQ ID NO: 14050 has 100% identity to residues 3000-3105 of NM_014845.5, Homo sapiens FIG4, as shown below:
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Trinklein further teaches using the constructs to determine the effect of the effect of a particular UTR sequence on mRNA stability, translation efficiency (para 14).
Regarding claim 59, Trinklein does not explicitly teach the 3’ UTR element is derived from the 3'-UTR of a vertebrate FIG4 gene.
However, SEQ ID NO: 14050 has 100% identity to residues 3000-3105 of NM_014845.5, Homo sapiens FIG4, as shown below:
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Regarding claim 65, Trinklein teaches the artificial nucleic acid molecule is an mRNA molecule (Fig. 3).
Regarding claim 66, Trinklein teaches 3’ UTR expression vectors (Fig. 1).
Regarding claims 68-71, Trinklein does not explicitly teach the 3’ UTR element is derived from the 3'-UTR of a mammalian FIG4 gene (claim 68), a primate FIG4 gene (claim 69), a human FIG4 gene (claim 70), or the human FIG4 gene according to GenBank Accession number NM_014845.5 (claim 71).
However, SEQ ID NO: 14050 has 100% identity to residues 3000-3105 of NM_014845.5, Homo sapiens FIG4, as shown below:
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Thus, Trinklein as evidenced by NM_014845.5 reads on the 3'-UTR of a mammalian FIG4 gene (claim 68), a primate FIG4 gene (claim 69), a human FIG4 gene (claim 70), and the human FIG4 gene according to GenBank Accession number NM_014845.5 (claim 71).
Regarding claim 73, Trinklein teaches an mRNA comprising a 5’cap (fig. 7).
Regarding claim 74, the claim recites the limitation “wherein the histone stem-loop comprises a sequence according to SEQ ID NO: 5”. However, claim 73, which claim 74 depends from, does not require a histone stem-loop, but, rather, requires one or more of the recited elements. Therefore, the limitations set forth in claim 74 are not in fact required.
Regarding claim 75, the claim recites the limitation “wherein the 5'-UTR is a 5' terminal oligopyrimidine tract UTR”. However, claim 73, which claim 75 depends from, does not require a histone stem-loop, but, rather, requires one or more of the recited elements. Therefore, the limitations set forth in claim 75 are not in fact 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.
Claims 67, 72, and 76-81 are rejected under 35 U.S.C. 103 as being unpatentable over Trinklein et al. (WO2008112127, on IDS dated 01/24/2024) as evidenced by NM_014845.5 (GenBank Accession number NM_014845.5, Homo sapiens FIG4, first submitted 1993) in view of Von Der Mulbe et al. (US20050032730, on IDS dated 01/24/2024).
The teachings of Trinklein and NM_014845.5 as they relate to claim 57 are stated in the 102 rejection above in this office action.
Von Der Mulbe teaches sequence modifications that promote stabilization and translational efficiency of modified mRNA of the invention, including combining an RNA coding for a protein with a non-endogenous stabilizing 3’UTR (para 95).
Regarding claim 67, Trinklein teaches transgenic expression constructs for gene therapy with enhanced therapeutic efficacy can be aided by identification and characterization of regulatory elements such as the 3’UTR regulatory element of the Trinklein expression constructs (para 50). However, Trinklein teaches the ORF encodes a reporter gene (Fig. 3).
Von Der Mulbe teaches use of a modified mRNA encoding an antigen, such as surface antigen of a pathogenic organism or a tumor antigen (paras 53 and 54).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Trinklein and Von Der Mulbe to arrive at the instantly claimed invention. The modification would have entailed selecting the antigens or therapeutic proteins of Von Der Mulbe as the ORF in the expression construct of Trinklein. One would have been motivated by the ability to use the 3’UTR regulatory elements of Trinklein to improve expression constructs useful for gene therapy by using the antigen and therapeutic encoding mRNAs taught by Von Der Mulbe. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 72, Trinklein teaches a polyA signal positioned 3’ of the 3’ UTR (para 24, Figs. 1 and 7). Trinklein is silent regarding the length of the poly(A) sequence.
Von Der Mulbe teaches modifying mRNA to stabilize the sequence and optimize translation (abstract). Von Der Mulbe teaches a modification comprises a poly-A tail of at least 50 nucleotides, preferably at least 70 nucleotides, and more preferably at least 100 nucleotides (para 43).
Von Der Mulbe states that the length of the poly-A tail is a modification that can stabilize an mRNA against decomposition by RNases (para 15).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Trinklein and Von Der Mulbe to arrive at the instantly claimed invention. The modification would have entailed using the polyA lengths as taught by Von Der Mulbe in the expression constructs of Trinklein. Determining an appropriate poly(A) sequence length is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. Von Der Mulbe provides guidance regarding optimal lengths of the polyA tail for stabilization of mRNA sequences, a stated goal of Trinklein. The selection of the polyA lengths of Von Der Mulbe would have been prima facie obvious to the ordinary artisan at the time of the invention in the absence of an unexpected result. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claims 76 and 77, Trinklein does not teach the G/C content of the open reading frame is increased compared to the wild type open reading frame (claim 76) or the open reading frame comprises a codon-optimized region (claim 77).
Regarding claim 76, Von Der Mulbe teaches a stabilizing modification comprises increasing the G/C content of the region of the modified mRNA coding for the peptide or polypeptide (open reading frame) relative to that of the G/C content of the coding region (open reading frame) of the wild type mRNA coding for the peptide or polypeptide (para 21).
Regarding claim 77, Von Der Mulbe teaches optimizing expression levels by codon optimization of the coding sequence (paras 32-34).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Trinklein and Von Der Mulbe to arrive at the instantly claimed invention. The modification would have entailed adding the stabilizing modifications of increased G/C content and optimized codons as taught by Von Der Mulbe to the expression constructs of Trinklein. One would have been motivated by the benefit of a stabilized RNA and increased protein production as taught by Von Der Mulbe and desired by Trinklein.
There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claims 78-80, Trinklein teaches the design of transgenic expression constructs for gene therapy with enhanced therapeutic efficacy can be aided by identification and characterization of regulatory elements such as the 3’UTR regulatory element (para 50).
However, Trinklein does not teach the open reading frame encodes a human therapeutic protein (claim 78), a pathogen antigen (claim 79), or a tumor antigen (claim 80).
Regarding claim 78, Von Der Mulbe teaches a modified mRNA encoding a biologically active peptide that restores the expression and/or activity of the biologically active peptide or polypeptide in the patient (para, 51), which reads on human therapeutic protein.
Regarding claim 79, Von Der Mulbe teaches a modified mRNA encoding an antigen, such as surface antigen of a pathogenic organism (paras 53 and 54).
Regarding claim 80, Von Der Mulbe teaches a modified mRNA encoding an antigen, such as tumor antigen (paras 53 and 54).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Trinklein and Von Der Mulbe to arrive at the instantly claimed invention. The modification would have entailed selecting the antigens or therapeutic proteins of Von Der Mulbe as the ORF in the expression construct of Trinklein. One would have been motivated by the ability to use the 3’UTR regulatory elements of Trinklein to improve expression constructs useful for gene therapy by using the antigen and therapeutic encoding mRNAs taught by Von Der Mulbe. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 81, Trinklein teaches libraries of expression constructs for determining the impact of regulatory sequences in the UTRs on translation of open reading frames (Abstract). Trinklein teaches producing a 3’ UTR expression construct (artificial nucleic acid molecule) comprising an open reading frame associated with a 3’ UTR sequence (Fig. 3). Trinklein teaches selecting the UTR from sequences that include SEQ ID NO: 14050 (para 6, claim 8). SEQ ID NO: 14050 has 100% homology to the FIG4 3’UTR (SEQ ID NO: 1 in the instant application) as shown below:
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Trinklein does not explicitly teach that the UTR sequence of SEQ ID NO: 14050 is derived from the 3'-UTR of a Sac Domain-Containing Inositol Phosphatase 3 (FIG4) gene.
However, SEQ ID NO: 14050 has 100% identity to residues 3000-3105 of NM_014845.5, Homo sapiens FIG4, as shown below:
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Trinklein further teaches using the constructs to determine the effect of the effect of a particular UTR sequence on mRNA stability, translation efficiency (para 14).
Trinklein does not teach at least one open reading frame (ORF) encoding a pathogen antigen, tumor antigen or a human therapeutic protein or a poly(A) sequence having a length of 40 to 200 adenine nucleotides.
Von Der Mulbe teaches sequence modifications that promote stabilization and translational efficiency of modified mRNA of the invention, including combining an RNA coding for a protein (an ORF) with a non-endogenous stabilizing 3’UTR (para 95), i.e. . wherein the ORF is heterologous to the 3'-UTR element.
Von Der Mulbe teaches a modified mRNA encoding an antigen, such as surface antigen of a pathogenic organism or a tumor antigen (paras 53 and 54).
Von Der Mulbe also teaches modifying mRNA to stabilize the sequence with a modification comprising a poly-A tail of at least 50 nucleotides, preferably at least 70 nucleotides, and more preferably at least 100 nucleotides (para 43).
Von Der Mulbe states that the length of the poly-A tail is a modification that can stabilize an mRNA against decomposition by RNases (para 15).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Trinklein and Von Der Mulbe to arrive at the instantly claimed invention. The modification would have entailed selecting the antigens or therapeutic proteins of Von Der Mulbe as the ORF in the expression construct of Trinklein. One would have been motivated by the ability to use the 3’UTR regulatory elements of Trinklein to improve expression constructs useful for gene therapy by using the antigen and therapeutic encoding mRNAs taught by Von Der Mulbe. The modification would further have entailed using the polyA lengths as taught by Von Der Mulbe in the expression constructs of Trinklein. Determining an appropriate poly(A) sequence length is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. Von Der Mulbe provides guidance regarding optimal lengths of the polyA tail for stabilization of mRNA sequences, a stated goal of Trinklein. The selection of the polyA lengths of Von Der Mulbe would have been prima facie obvious to the ordinary artisan at the time of the invention in the absence of an unexpected result. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JESSICA GRAY whose telephone number is (571)272-0116. The examiner can normally be reached Monday-Friday 8-5 with second Fridays off.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, WINSTON SHEN can be reached at (571)272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JESSICA GRAY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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