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 .
Application Status
The preliminary amendments amendment filed May 7, 2026 is acknowledged. Claims 22-24, 26, 29-30, 35, 45-46, 50-54, 56-57, 59, 64, 74-75 are pending and under examination.
Drawings
The drawings are objected to for two reasons.
First, the drawings are objected to because they were submitted in color, but there is no granted petition to accept color drawings. It is noted that Applicant has submitted a petition to accept colored drawings, but it has not been granted yet.
Second, the lines, shadings, numbers and letters of FIG 2B, 3B, 5, 7-10, 12A, 14-16, 17B and 19A-E are not sufficient to provide satisfactory reproduction characteristics. 37 CFR 1.84(l) states that “all drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined.” In the instant case, the text the above FIGs is either light grey, too small, or otherwise not sufficiently dense or dark and dark to permit satisfactory reproduction characteristics.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Interpretation
The claims recite a DNA antisense oligomer complementary to an mRNA sequence having a premature termination codon (PTC), wherein “said antisense oligomer is complementary to said RNA sequence starting between a +4 and +8 nucleotide position downstream of the first nucleotide of said premature stop codon.” This phrase in the context of the rest of the claim is interpreted to mean:
The DNA oligomer is not limited in length as long as it is 2 or more DNA nucleotides
The DNA oligomer cannot be complementary to the PTC or any sequence upstream (i.e., toward the 5’ end of mRNA and/or toward the translational start site) of the PTC since the it is complementary “starting between +4…”
The DNA oligomer must have at least one nucleotide that is complementary to the five nucleotides following the PTC in the mRNA at its 3’ end.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 22, 24, 30 and 35 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claims are drawn to a composition comprising an mRNA and a DNA that is complementary to the mRNA, which are natural products. However, the claims do not include elements, when considered separately and in combination, that are sufficient to amount to significantly more than the judicial exceptions as outlined below.
Subject Matter Eligibility Test for Products and Processes – Claims 22 and 30
Step 1 - Is the Claim to a Process, Machine, Manufacture or Composition of Matter? YES
Claims 22 and 24 are directed to a composition comprising an mRNA and a DNA that is complementary to the mRNA, which are natural products. Thus, the claims are directed to a statutory category (e.g., a product).
Step 2A, Prong One - Does the Claim Recite an Abstract Idea, Law of Nature, or Natural Phenomenon? YES
Natural phenomena have been identified by the courts by way of example. The claims recite a single judicial exception – a composition comprising an mRNA and a DNA oligomer that is complementary to the mRNA. For natural products, products that are not “markedly different” than their naturally occurring counterpart are judicial exceptions. See MPEP 2016.04((b). It is noted that the courts have identified “isolated DNA” as one such natural product that may not be markedly different from their counterpart, DNA in cells. MPEP 2106.04(c) outlines the markedly different analysis. The claim recites a composition comprising an mRNA having a PTC and a DNA antisense oligomer that is complementary to the sequence immediately downstream of the PTC. For claim 24 the mRNA is from the CTFR or MeCBP2 gene. The closest naturally occurring counterpart to the claimed composition is a human cell that naturally comprises a nonsense mutation in the CFTR gene. Such a cell would transcribe the CFTR mRNA having the PTC. Such a cell would also comprise the DNA-encoding the mutant CFTR allele, which comprises a section of the antisense strand immediately downstream of the PTC. Both the mRNA and the section of the antisense strand coexist in a human cell of a CF patient harboring the naturally occurring nonsense allele and is encompassed by the claimed “composition”. As such, the claimed composition is not markedly different than its naturally occurring counterpart and constitutes a judicial exception.
Step 2A, Prong Two - Does the Claim Recite an Additional Elements that Integrate the Judicial Exception into a Practical Application? NO
The Supreme Court has long distinguished between principles themselves, which are not patent eligible, and the integration of those principles into practical applications, which are patent eligible. The phrase "integration into a practical application" requires an additional element or a combination of additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that it is more than a drafting effort designed to monopolize the exception. In this case, no other element is recited in the claims in addition to the composition. Therefore, the judicial exception is not integrated into a practical application.
Step 2B - Does the Claim Recite Additional Elements that Amount to Significantly More than the Judicial Exception? NO
The Supreme Court has identified a number of considerations for determining whether a claim with additional elements amounts to "significantly more" than the judicial exception(s) itself. The claim as a whole is evaluated as to whether it amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim (MPEP 2106.05). However, the additional elements, individually and in combination, do not amount to "significantly more" because no other element is recited in the claims in addition to the composition. Therefore, the claims do not amount to something significantly more than the judicial exceptions.
Dependent claims
Claim 30 recites specific stop codons in the target mRNA. The Specification discloses that the CFTR gene has a UGA premature stop codon and the recited 4-nucleotide sequences, UGAC, UGAG, UGAA and UGAT represent all possible 4th nucleotide after the UGA codon (page 21, FIG 6). Thus, the recited PTCs cover all naturally occurring CTFR mutant sequences and the claimed composition is not markedly different than a human cell comprising a known CFTR SNP.
Claim 35 recites specific sequences for the oligomer. The Specification discloses that each of the sequences are 100% identical to the sequence of the antisense strand downstream of the premature stop codon (FIG 6). Thus, the recited sequences are still identical to the CFTR antisense DNA downstream of the naturally occurring PTC and the claimed composition is not markedly different than a human cell comprising a known CFTR SNP.
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.
Claim 29 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.
Claim 29 recites “the composition of claim 22, where said aminoglycoside is selected…” Claim 22 does not recite an aminoglycoside. The term lacks proper antecedent basis.
To remedy the indefiniteness, it is suggested to have claim 29 depend from claim 26.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 22-24, 26, 29, 30, 45-46, 50-54, 56-57, 59, 64, 74-75 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for using compositions comprising oligonucleotides at least 16 nucleotides in length in combination with aminoglycosides for examining readthrough mechanisms in CTFR and MeCP2 nonsense alleles, does not reasonably provide enablement for antisense oligonucleotides having less than 16 nucleotides or more than 30 nucleotides or methods using the any antisense oligonucleotide in the absence of aminoglycosides or in methods of treating disease. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use and/or practice the invention commensurate in scope with these claims.
Exemplary factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 U.S.P.Q.2d 1400, 1404 (Fed. Cir. 1988) (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP 2164.01(a). All of these factors were considered, along with others, and a sufficient number are addressed below so as to create a prima facie case.
Nature of the Invention and Breadth of Claims
Claims 22 and 50 are drawn a composition comprising an antisense DNA oligonucleotide (ASO) that hybridizes just downstream or an mRNA having a PTC, and methods of treatment using the antisense oligonucleotide. Claim 50 does not limit diseases to those that are caused by the PTC. Thus, any disease whether the PTC is causal or not is included in the genus of diseases. Additionally, other than requiring at least 2 nucleotides that hybridize to the nonsense allele mRNA, the rest of the structure of DNA oligomer is undefined. Thus, the genus of antisense oligomers includes oligonucleotides as short as two nucleotides, as long as an entire coding sequence downstream of the PTC, and encompasses non-coding RNAs that could trigger RNase H-mediated RNAi silencing pathways.
Accordingly, enablement of the method requires one skilled in the art to use any length ASO that hybridizes downstream of a PTC, and for the purpose of treating (i.e., reducing symptoms) of nearly any disease where there may be a PTC somewhere in a genome in at least one cell or the patient. For the reasons described below, Applicant’s evidence in combination with the prior art does not support enablement for the use of the composition of the ASO and PTC-containing mRNA or a method of treatment for the full scope of the claims.
Guidance in the Specification
The specification teaches that antisense DNA oligomers (ASOs) that range in length from 16-30 nucleotides, and having a melting temperature between 28-66 oC are capable of mediating readthrough translation such that the ribosome produces the full-length protein (Figures 5 and 7). However, the highest readthrough efficiencies used oligomers with 34-47 oC (Fig 7). It also appears that the DNA antisense oligomers had little or no effect of readthrough of some PCTs like UGAG without the co-administration of an aminoglycoside (Fig 9). Applicant does not test out oligonucleotides that are shorter than 16 nucleotides or longer than 30 nucleotides. As such, it is not clear what effect longer ASOs would have on the stability of the mRNA as a whole or specifically on PTC readthrough. It appears that all of the luciferase assays were in vitro rabbit reticulocyte mRNA translation assays. It is not clear from the Brief description of drawings or the working examples of whether Applicant ever measured readthrough success in cells. Applicant does not provide any data of delivering the antisense DNA oligomers to any patient or disease animal model. As such, in view of the Specification it is highly unpredictable whether the results seen in vitro with an engineered reporter protein can be recapitulated in a patient, or even in culture cells. Accordingly, in light of the specification, it is highly unpredictable how one would use ASOs that are shorter than 16 nucleotides or longer than 30 nucleotides that specifically hybridize immediately downstream of a PTC. It is also entirely unpredictable whether the readthrough effects demonstrated in cell culture could be recapitulated in vivo such that they could mediate high levels of readthrough without the aid of tested aminoglycosides.
State of the Prior Art
The idea of promoting readthrough of PTCs using an ASO is a relatively new one. Besides the inventor’s disclosure, only one other prior art discloses using ASOs to promote ribosome readthrough – Kar et al., Biochemistry (2020), 59: 80-84. Kar designs ASOs that hybridize to positions +4 and +12 targeted to a PTC in the HBB gene (Fig 1A). Whereas the inventors found that readthrough efficiency at positions at +9, +11 and +14 in the CFTR mRNA did not result in any readthrough (Fig 7), Kar found that the +12 position produced robust readthrough in the HBB mRNA (Fig 1). Thus, the design parameters for readthrough-mediating ASOs have not been established such that a skilled artisan could use the evidence from one PTC-containing gene like HBB and apply it other PTC-containing mRNAs. Kar did not attempt to recapitulate the ASO treatment on any other mRNA other than a reporter. Kar did not alter the length of the ASOs independent of hybridization starting position relative to the PTC or attempt to administer the ASOs to any patient-derived cells or disease models. Kar did not combine the HBB-targeted ASOs with aminoglycosides.
The claimed ASOs are similar in structure to ASOs used to down-regulate the expression of the target mRNA through RNaseH mediated degradation (See e.g., Dhuri et al., J. Clin. Med. (2020), 9: 2004, pages 1-24). ASOs are generally 15-20 nucleotides in length and are generally 100% identical to the target mRNA (Section 3), which is a similar design as many of the ASOs used in the working examples of the present invention. ASOs mediate mRNA silencing through RNaseH cleavage or steric hindrance (Fig 2). The PTC-targeted ASOs tested by the Inventors were shown to be capable of increasing readthrough of PTCs, but only in a rabbit reticulocyte translation system (FIG 11), which have very low levels of RNaseH. Kar assayed readthrough in HEK293 culture cells using an HBB-GFP reporter (Figure 2). Kar measured mRNA levels in cells with increased protein expression (Fig 4); however, it is hard to evaluate the RT-PCR image to compare mRNA levels between samples. In fact, it is possible that the reason Kar’s +1 oligo (equivalent to the claimed +4 oligo) did not result in high levels of protein is because there was less mRNA for translation due to the +1 oligo ASO triggering RNAseH-mediated decay.
Finally, a thorough search of the prior art found no evidence that an ASO targeting a PTC-containing mRNA that is not causative of a disease has any treatment potential of that disease. Since the nonsense allele is not the root cause of a disease, promoting its readthrough would likely have no effect on disease symptoms.
Accordingly, in light of the prior art, it is highly unpredictable how one would use ASOs that are shorter than 16 nucleotides or longer than 30 nucleotides that target a PTC in an mRNA. It is also highly unpredictable that ASOs that also trigger RNaseH-mediated decay could mediate PTC readthrough since RNaseH-mediated decay would function upstream of translation. Thus, it appears that readthrough-promoting ASOs would need to be tested in cells that have functional RNaseH-mediated decay to see if the ASOs also trigger RNAi, thereby reducing mRNA the amount of functional protein that would be needed to treat the disease. It is also entirely unpredictable whether the readthrough effects demonstrated in cell culture could be recapitulated in vivo such that they could mediate high levels of readthrough without the aid of tested aminoglycosides. Even in diseases where aminoglycosides are already a proven therapy, adding an ASO could potentially mediate RNaseH-mediated degradation before the readthrough-mediating aminoglycosides could function, rendering the aminoglycoside useless.
Experimentation Required
In order to practice the invention, one skilled in the art would need to test a variety of lengths of PTC-targeted ASO for each gene and disease. The ASOs would need to be tested in cell culture to see if they could function in the context of an active RNaseH mRNA degradation pathway, and tested in animal studies for efficacy and safety. Furthermore, each ASO would need to be assayed to determine whether it could also mediate disease treatment of all diseases that are not even caused by a PTC, which would certainly be undue since there is no precedent for targeting a gene that is not causative of or contributory to a disease.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant, and the lack of working examples of treating a disease or otherwise testing the ASOs in cell culture, it is the conclusion that an undue experimentation would be required to make and use the invention across its entire claimed scope.
Dependent claims
Claims 23-24, 30, 45 and 46 are directed to the composition of the mRNA and the PTC-adjacent targeting ASO. However, they do not limit the sequence targeted or the length of the ASO. It is not predictable how the skilled artisan would use the composition since any readthrough promotion in a readthrough assay required the presence of an aminoglycoside.
Claims 26 and 29, while requiring the presence of an aminoglycoside which has many known uses, does not limit the sequence targeted or the length of the ASO. It is unclear how an ASO that is very short, like 2-nt, or the entire length of the mRNA after the PTC, would function in combination with the aminoglycoside, and what the skilled artisan would use such a combination for.
Claims 51-54, 56-57, 59, 64, 74 and 75 are directed to methods of treating a disease using the PTC-adjacent targeting ASO. However, each of the claims still encompass one or more of: treatment without an aminoglycoside and an undefined ASO sequence that could trigger RNaseH-mediated decay thereby interfering with any potential effect of a known therapeutic aminoglycoside.
Claim Rejections - 35 USC § 102
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.
Claims 22-23 and 45-46 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kar (Kar et al., Biochemistry (2020), 59: 80-84).
Regarding claim 22, Kar teaches a DNA antisense oligo (ASO) designed to bind immediately downstream of the premature stop codon at the +1 position, which is equivalent to the claimed +4 position, in the HBB mRNA that comprises a premature stop codon (page 80, ¶3; Fig 1). Kar teaches delivering the antisense oligo to cells such that it is in a composition with the PTC-containing PTC (Fig 1).
Regarding claim 23, Kar teaches the ASO hybridizes to the target mRNA (page 80, ¶3; Fig 1).
Regarding claim 45-46, Kar teaches providing the ASOs with a 2’-O-methyl group or at least one phosphorothioate linkage (page 82, ¶2).
Allowable Subject Matter
Combining the limitations of claims 22, 26 and 35 into a single claim would be allowable. Such a combination would overcome all the rejections of record. Applicant demonstrates a use for 16-30-mer ASOs targeted to the +4-+8 region of the CFTR and MeCP2 mRNA in combination with an aminoglycoside to promote readthrough translation. Additionally, the inclusion of the aminoglycoside would make the DNA-mRNA composition markedly different than the contents of a human cell with a nonsense CFTR allele.
The closest prior art is Kar (Biochemistry (2020), 59: 80-84), whose teachings are recited above in paragraphs 26 and 37-39. Briefly, Kar teaches readthrough ASOs targeting the HBB mRNA. However, in contrast to Applicant’s data, ASOs targeting the +4 position were not very effective at promoting readthrough in cells (Fig 4). Kar only tested the +4 and +12 positions, so it was unknown what other hybridization positions would have been effective at promoting readthrough. Also, Kar’s +4 and +12 oligonucleotides were different lengths (29-mer and 18-mer, respectively), so it is unknown if the difference between readthrough-promoting activities was due to starting position, melting temperature of the ASO, or the ASO promoting RNaseH-mediated target mRNA degradation. The state of the art of using ASOs to promote PTC readthrough was not mature around the effective filing date of the claimed invention, and as such, predicting the activity of one ASO targeted to an mRNA using the data of a different ASO/mRNA target was not feasible.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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, Ram Shukla can be reached at (571)272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
Prosecution Insights