DETAILED ACTION
Claims 2-3, 5-9, 11-12, 15-18 and 22-28 are currently pending. Claims 1, 4, 10, 13-14, 19-21 are cancelled.
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 I (claims 2-3, 5-9, 11 and 22-25) in the reply filed 2/11/2026 is acknowledged.
Claims 12, 15-18 and 26-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 2/11/2026.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 1/10/2023 and 5/22/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
35 USC § 101
The Examiner notes that claim 2 is directed to an isolated polynucleotide encoding a polypeptide, wherein the polynucleotide requires a second nucleic acid comprising a plurality of thymine nucleotides of at least 130 consecutive thymine nucleotides (poly(T) sequence), and would correlate to a poly(A) tail found at the 3’ end of messenger RNA (mRNA).
As set forth in WO 2019/036513 (“WO ‘513”) (see PTO-892), it is noted in nature, as mRNA is produced from DNA, a terminal transferase adds adenine nucleotides to the 3' end of mRNA ([0002]). WO ‘513 teaches mRNA is now being used as a therapeutic molecule, for example, for the treatment of various diseases and disorders. The mRNA is prepared via transcription from a DNA template, often contained in a plasmid, and the poly-A tail is encoded on the plasmid itself and thus encoded from corresponding poly(T) sequence and not from a naturally occurring terminal transferase ([0004]). The poly-A tail is encoded by a complementary DNA sequence within the plasmid using a sequence of repeating thymine (T) nucleotides in a DNA sequence, e.g. a homopolymer T sequence ([0006]).
Thus, Applicant’s claimed isolated polynucleotide comprising a second nucleic acid comprising a plurality of thymine nucleotides of at least 130 consecutive thymine nucleotides has a markedly different characteristic from what occurs in nature and is therefore eligible subject matter.
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.
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) 2-3, 6-8, 11, and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Sahin et al., (US 2010/0129877; IDS 1/10/2023) (“Sahin”).
Sahin is directed to a strategy for optimizing RNA-transfected DC vaccines by using RNA which has been modified to provide RNA with increased stability and translation efficiency. The modified RNA is achieved by genetically modifying expression vectors which serve as a template for in vitro RNA transcription (i.e., an isolated polynucleotide), particularly RNA having an open-ended poly(A) sequence was found to be translated more efficiently than RNA having a poly(A) sequence with a masked terminus. It was found that a long poly(A) sequence, in particular of about 120 bp, results in optimal RNA transcript stability and translation efficiency (Abstract and [0011]-[0014]).
Regarding claim 2, Sahin teaches an open-ended poly(A) sequence in the RNA can be achieved by introducing a type IIS restriction cleavage site (i.e., endonuclease cleavage site) into an expression vector which allows RNA to be transcribed under the control of a 5' RNA polymerase promoter and which contains a polyadenyl cassette (poly(A) sequence), wherein the recognition sequence (i.e., endonuclease recognition site) is located 3' of the poly(A) sequence, while the cleavage site is located upstream and thus within the poly(A) sequence. Restriction cleavage at the type IIS restriction cleavage site enables a plasmid to be linearized within the poly(A) sequence (i.e., linear vector as recited in claim 11). Sahin teaches the linearized plasmid can then be used as template for in vitro transcription, the resulting transcript ending in an unmasked poly(A) sequence ([0015] and FIG. 2).
Thus, it is understood that Sahin’s plasmid template that is transcribed and results in the long poly(A) sequence would comprise the corresponding plurality of thymine nucleotides (poly (T) sequence).
Sahin’s FIG. 2 is illustrated here for convenience:
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As illustrated above, Sahin’s polynucleotide comprises a nucleic acid comprising a plurality of consecutive thymine nucleotides wherein the endonuclease cleavage site is located within the plurality of thymine nucleotides (i.e., a second nucleic acid), as recited in claim 2, and Sahin’s polynucleotide comprises a nucleic acid comprising an endonuclease recognition site (RES) that is within 5 nucleotides of the exemplified SapI endonuclease cleavage site and covalently linked to the 5’ terminal thymine nucleotide (i.e., a third nucleic acid, wherein the second nucleic acid is covalently linked to the third nucleic acid at one end of the third nucleic acid), as recited in claim 2.
Further regarding claim 2 and the limitation the second nucleic acid comprises at least 130 consecutive thymine nucleotides, it is noted that Sahin teaches nucleic acid sequence (d), when transcribed under control of the disclosed promoter, codes for nucleotide sequence comprising up to 150-500 consecutive A (adenine) nucleotides ([0023]). Thus, it is understood that Sahin’s plasmid template that is transcribed and results in the long poly(A) sequence comprising up to 150-500 consecutive A (adenine) nucleotides would comprise the corresponding plurality of 150-500 consecutive thymine nucleotides (poly (T) sequence).
Thus, Sahin does render obvious a second nucleic acid comprising a plurality of thymine nucleotides of at least 130 consecutive thymine nucleotides, that is, Sahin teaches the limitations required by the current claims and as all limitations are found in one reference it is held that a polynucleotide comprising a second nucleic acid plurality of thymine nucleotides of at least 130 consecutive thymine nucleotides is within the scope of the teachings of Sahin, and thus renders the invention of claim 2 prima facie obvious. The rationale to support this conclusion of obviousness is that the single reference provides the teachings and suggestion to include a second nucleic acid comprising a plurality of thymine nucleotides ranging from 150-500 thymine nucleotides (i.e., at least 130 consecutive thymine nucleotides). Furthermore, there is no evidence on the record that shows that the claimed limitation has any greater or unexpected results than that exemplified by Sahin.
Further regarding claims 2 and 3 and the limitation the polynucleotide includes a first nucleic acid encoding the polypeptide, it is noted that Sahin teaches the expression vector includes sequence coding for a peptide or protein (open reading frame) ([0016] and [0040]), wherein the peptide is an antigen, specifically a tumor antigen (i.e., an antigen for cancer vaccine) ([0067] and [0115]).
Thus, Sahin does render obvious a first nucleic acid encoding a polypeptide, that is, Sahin teaches the limitations required by claims 2 and 3 and as all limitations are found in one reference it is held that a polynucleotide comprising a first nucleic acid encoding a polypeptide is within the scope of the teachings of Sahin, and thus renders the invention of claims 2 and 3 prima facie obvious. The rationale to support this conclusion of obviousness is that the single reference provides the teachings and suggestion to include a first nucleic acid encoding a polypeptide, e.g., a tumor antigen. Furthermore, there is no evidence on the record that shows that the claimed limitation has any greater or unexpected results than that exemplified by Sahin.
Regarding claim 6, Sahin teaches the nucleic acid molecule comprises a promoter (a) operably linked to the transcribable nucleic acid sequence (b) ([0017] and [0022]), thus meeting the limitation of claim 6.
Regarding claim 7, Sahin teaches the endonuclease recognition site is a Type II restriction endonuclease recognition site ([0015], [0028] and FIG. 2), thus meeting the limitation of claim 7.
Regarding claim 8, although Sahin’s FIG. 2 exemplifies the endonuclease recognition site is a SpaI recognition site, and does not further comment on the endonuclease recognition site is a BsaI recognition site, it is noted that Sahin at paragraph [0122], further teaches the restriction endonuclease recognition site is selected from numerous restriction endonucleases, including BsaI.
Thus, Sahin does render obvious the endonuclease recognition site is a BsaI recognition site, that is, Sahin teaches the limitation required by claim 8 and as said limitation is found in one reference it is held that use of a BsaI endonuclease recognition site is within the scope of the teachings of Sahin, and thus renders the invention of claim 8 prima facie obvious. The rationale to support this conclusion of obviousness is that the single reference provides the teachings and suggestion to use a variety of Type II restriction endonucleases, including BsaI. Furthermore, there is no evidence on the record that shows that the claimed limitation has any greater or unexpected results than that exemplified by Sahin.
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute a BsaI endonuclease recognition site for the SpaI endonuclease recognition site since both endonuclease recognition sites are Type II restriction endonuclease sites. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of Type II restriction endonuclease site for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
Regarding claim 11, as set forth above regarding claim 2, Sahin teaches a linear vector comprising the isolated polynucleotide of claim 2 ([0015]), thus meeting the limitation of claim 11.
Regarding claim 22-23, as set forth above regarding claim 2, Sahin renders obvious the nucleotide of claim 2 and transcribing an RNA polynucleotide from the linear vector comprising corresponding consecutive adenine nucleotides (at least 130 covalently linked consecutive adenine nucleotides), as discussed at paragraph [0015] of Sahin and further illustrated at Sahin’s FIG. 2.
As to a polymerase in contact with the isolated polynucleotide, it is noted that Sahin teaches transcription under the control of a 5' RNA polymerase promoter and the nucleic acid sequences are transcribed by RNA polymerase ([0084], [0096]). Thus, Sahin’s teaching renders obvious instant claims 22-23.
Regarding claim 24, as set forth above regarding claim 3, Sahin teaches the expression vector includes sequence coding for a peptide or protein (open reading frame) ([0016] and [0040]), wherein the peptide is an antigen, specifically a tumor antigen (i.e., an antigen for cancer vaccine) ([0067] and [0115]), thus meeting the limitation of claim 24.
Claims 5 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Sahin, as applied to claims 2-3, 6-8, 11, and 22-24 above, and further in view of Sahin et al., (NATURE REVIEWS, Vol 13, October 2014, pages 759-780, published online 19 September 2014; see PTO-892) (“Sahin 2014”).
The teaching of Sahin is set forth above.
Regarding claim 5 and the limitation the first nucleic acid is codon optimized for expression in a human cell, it is noted that Sahin teaches the invention provides for nucleic acids, in particular RNA, to be administered to a patient ([0117]) and teaches transfection of the modified RNA in human dendritic cells (DCs), which are the most important modulators of the immune system, thus the RNA-transfected DCs are considered for vaccination ([0128]). However, Sahin does not further teach codon optimization for expression in a human cell.
Sahin 2014 discusses mRNA-based therapeutics for delivering genetic information for mRNA-based cancer immunotherapies, specifically using in vitro transcribed (IVT) mRNA (Abstract) and Sahin 2014 teaches that, IVT mRNA has undergone extensive preclinical investigation for therapeutic cancer vaccination (page 759, right col, second paragraph).
Sahin 2014 acknowledges that codon composition is known to effect translation efficiency and reuse of the same tRNA accelerates translation and replacing rare codons with synonymous frequent codons improves translation yield. Sahin 2014 teaches that codon-optimized IVT mRNAs have been successfully used in vaccine studies against viral infections.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize codons for expression in human cells.
The person of ordinary skill in the art would have been motivated to modify the IVT-mRNA polynucleotide of Sahin to include a codon-optimized polynucleotide encoding a polypeptide, as taught by Sahin 2014, for the predictable result of successfully optimizing translation, e.g., accelerating translation and improving translation yield, thus meeting the limitation of claim 5.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Sahin and Sahin 2014 because each of these teachings are directed at therapeutic uses of in vitro transcribed mRNA (IVT RNA).
Regarding claim 25, it is noted that, although Sahin teaches the polynucleotide comprises Type II restriction endonucleases (restriction enzymes that cleave dsDNA), Sahin does not further teach the polypeptide encodes a nuclease, specifically the restriction enzyme transcription activator-like effector nuclease (TALENS), as recited in claim 25. However, Sahin 2014 discusses mRNA-based therapeutics for delivering genetic information for mRNA-based cancer immunotherapies, specifically using in vitro transcribed (IVT) mRNA (Abstract).
Sahin 2014 teaches that, IVT mRNA has undergone extensive preclinical investigation for therapeutic cancer vaccination (page 759, right col, second paragraph). Sahin teaches cancer immunotherapy is the field in which mRNA-based technologies have the longest history of systematic exploration in integrated preclinical and clinical programs. Sahin teaches that it has been demonstrated that DCs (dendritic cells) exposed to mRNA coding for specific antigens induced T cell immune responses and inhibited the growth of established tumors (page 766, right col at Cancer immunotherapy). Sahin further teaches that IVT mRNA drugs provide an approach in which the robust and tunable production of a therapeutic protein is possible and utilizing IVT mRNA will help address challenges in targeted genome engineering, generation and reprograming of stem cells as well as production of on-demand personalized vaccines (page 772 at Clinical translation of IVT mRNA). Sahin teaches the use of IVT mRNAs encoding TALENS have been applied successfully to edit genomes since their transient expression minimizes off-target effects (page 772, left col at Genome editing with IVT mRNA-encoded engineered nucleases).
Therefore, given the intention of Sahin is to provide a stabilized in-vitro transcribed RNA (IVT-RNA) for transfection of dendritic cells and subsequent use in cancer immunotherapy, e.g., vaccination ([0006]) and Sahin 2014 likewise teaches the use of in vitro transcribed mRNA (IVT mRNA) for genome engineering and production of on-demand vaccines, wherein use of use of IVT mRNAs encoding TALENS have been applied successfully to edit genomes since their transient expression minimizes off-target effects, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to provide a polynucleotide encoding a TALENS polypeptide.
The person of ordinary skill in the art would have been motivated to modify the IVT-mRNA polynucleotide of Sahin to include a polynucleotide encoding a TALENS polypeptide, as taught by Sahin 2014, for the predictable result of successfully engineering on-demand cancer vaccines with reduced off-target effects, thus meeting the limitation of claim 25.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Sahin and Sahin 2014 because each of these teachings are directed at therapeutic uses of in vitro transcribed mRNA (IVT RNA).
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Sahin, as applied to claims 2-3, 6-8, 11, and 22-24 above, and further in view of Godiska et al. (US 2009/0263873; see IDS 1/10/2023) (“Godiska”).
The teaching of Sahin is set forth above.
Regarding claim 9, Sahin does not further teach the polynucleotide comprises a telomere.
Godiska teaches the invention relates to improving linear cloning vectors, wherein the invention permits cloning of large or “difficult” polynucleotide sequences which may otherwise not be cloned using conventional circular plasmid vectors ([0011]). Godiska teaches the linear vector comprises a telomere (paragraph [0012]).
Godiska, at paragraph [0032], teaches telomeres are polynucleotides or polypeptide structures located on the end (or ends) of a linear DNA molecule that protects the termini of the DNA from recombination and/or exonucleolytic degradation. Suitable telomeres include covalently closed ends, sequences capable of binding terminal proteins (e.g., as in PRD1), and tracts of polynucleotide repeats (e.g., poly A, C, G, T or U tracts).
Therefore, it would have been obvious to a person of ordinary skill in the art at the time of filing to have the vector described by Sahin and include a telomere. A person of ordinary skill in the art would be motivated to do so in order to protect the linear vector sequence from exonucleolytic degradation. Given the teachings of the prior art and the level of the ordinary skilled artisan at the time of filing, it must be considered, absent evidence to the contrary, that said skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
Accordingly, Sahin, further in view of Godiska, render obvious claim 9.
Conclusion
No claim is allowed. No claim is free of prior art.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633