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 amendment filed February 2, 2024 is acknowledged. Claims 1, 107-114, 117-118, 120, 125-131 and 135 are pending and under examination.
Priority
Applicant' s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of 35 U.S.C. 112 (pre-AlA). See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application Nos. 63/163,484 fail(s) to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) for one or more claims of this application. The applications fail to provide support for the claims under examination, since there is no disclosure therein of SEQ ID NOs 61 or 62, or nucleotide sequences for DNAH5, which the Specification of this examined application discloses as SEQ ID NOs 61-62 as encoding. The first evidence of support DNAH5 coding sequence or specifically SEQ ID NOs 61-62 is the PCT application PCT/US2022/021032 (filed March 18, 2022). As such, the effective filing date for all claims is March 18, 2022.
Drawings
The drawings are objected to because text in FIG. 3A and 3B is 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, some of the text in FIGs 3A and 3B is very light grey and not sufficiently dense 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.
Specification
The use of the term MessengerMax®, which is a trade name or a mark used in commerce, 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.
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.
1) 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 - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located in Table 1 (DNAH5 – altered Nucleotide Usage 1). Although the sequences are labeled “SEQ ID NO 61” and “SEQ ID NO: 62” the sequence listing only goes up to SEQ ID NO 55. There do not appear to be any sequences that match the sequences in Table 1 labeled DNAH5 in the sequence listing.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also 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;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Claim Objections
Claim 118 is objected to because of the following informalities:
“DNAF2 in line 3” should be “DNAAF2” as per Table 1 in the Specification (page 27). Appropriate correction is required.
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 1, 107-114, 117-118, 120, 125-131 and 135 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 1, 125 and 135 recite “wherein said synthetic polynucleotide comprises a nucleic acid sequence having at least about 70% sequence identity to a sequence selected from…”. The phrase “at least about” renders the claim indefinite because it is not clear what minimum percent identity to the recited SEQ ID NOs is required. For instance, 69% identity is “about 70%” but not “at least 70%”; whereas 85% identity is “at least 70%” but not “about 70%”. It is not clear if 69% is included or 85% identity is included.
Claims 107-114, 117-118, 120 and 126-131 are rejected for depending from claims 1 and 125 and not remedying the indefiniteness because they do not recite a definite range needed for identity.
Claim 117 recites “wherein said synthetic polynucleotide is an mRNA of a gene set for in Table 1.” Reference to tables in claims renders the claim indefinite when there is no practical way to define the invention in words. See MPEP 2173.05(s). Here, the tables contain exclusively text, and the appropriate text could simply be imported into the claim. Merely pasting the gene names into the claim, however, would not overcome this rejection because the sequence in table 1 have ORFs, ORFs with 5’ UTRs and 3’ tails, ORFs with HA tags and the 5’ and 3’ sequences. It is not clear what is included in “a gene set form in table 1”. To overcome this rejection, applicants must amend claim 117 such that it clearly sets forth a closed list of alternatives for the gene that the mRNA encodes.
Claim 118 depends from claim 117, but is not included in this rejection because it clearly lists the genes for which the mRNA must encode.
Claim 128 recites “wherein said pharmaceutical composition comprises a polymer-conjugated lipid (e.g., poly(ethylene glycol) (PEG)-conjugated lipid).” The use of “e.g.” meaning “for example" 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).
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 1, 107-109, 112-113, 117-118, 125, 127 and 129 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 polynucleotides, 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 – Claim 1
Step 1 - Is the Claim to a Process, Machine, Manufacture or Composition of Matter? YES
Claim 1 is directed to a polynucleotide. Thus, the claims are directed to a statutory category (e.g., a product).
Step 2A, Prong One - Does the Claim Recite a Judicial Exception (Abstract Idea, Law of Nature, or Natural Phenomenon)? YES
Judicial exceptions have been identified by the courts by way of example, including natural phenomena and natural products. The claim recites 1 judicial exception: a synthetic polynucleotide comprising a nucleic acid sequence having at least [] 70% sequence identity to SEQ ID NOs 1-32, 61 or 62”. For natural products, products that are not “markedly different” than their naturally occurring counterpart are judicial exceptions. See MPEP 2016.04((b). Although the claims recite “synthetic” before “polynucleotide”, this qualifier is interpreted as the means to which the polynucleotide is produced. Synthetically-made and naturally-made polynucleotides can have the same structure. Thus “synthetic” cannot distinguish the claimed polynucleotides from naturally occurring ones. Additionally, 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 the polynucleotide encodes a primary ciliary dyskinesia (PCD)-associated protein and comprises a nucleic acid sequence that is at least [] 70% sequence identity to SEQ ID NOs 1-32, 61 and 62. Each of the recited SEQ IDs are listed and briefly described in Table 1. SEQ ID NO 1 is described as DNAI2 (ORF), and appears to be a codon-optimized version of the cDNA. Although cDNAs are typically not considered judicial exceptions because they differ from the chromosomal sequence comprising intronic sequences, claim 1 is broader and encompasses a generic “polynucleotide”, which incudes RNA. The Specification even defines polynucleotide as a ribonucleotide (RNA) or deoxyribonucleotide (DNA) ([0024]). Furthermore, although SEQ ID NOs 1-32 are noted in the sequence listing as “DNA”, “identity” as measured by means known in the art, includes uracil nucleotides (U) as equivalent to thymine nucleotides (T). Dependent claims even limit the “polynucleotide having at least 70% identity to SEQ ID NOs 1-32” as comprising mRNA (see claims 117-118). Thus, the closest naturally occurring counterpart to the claimed polynucleotide is a mRNA having at least 70% identity to one of the recited SEQ ID NOs. The human dynein axonemal intermediate chain 2 (DNAI2), transcript variant 1 mRNA (Genbank NM_023036; https://www.ncbi.nlm.nih.gov/nucleotide/NM_023036.6, retrieved February 18, 2026]) comprises a nucleic sequence that has 83% identity to SEQ ID NO 1 (see OA Appendix, pages 1-5). The claimed synthetic polynucleotide comprising a nucleic acid sequence with at least 70% identity to SEQ ID NO 1 acid is not markedly different than its naturally occurring counterpart, the naturally occurring DNAI2 mRNA transcript variant 1, 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, there are no additional limitations in the claim that integrate the judicial exception 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, there are no additional elements recited in the claim. Therefore, the claim does not amount to something significantly more than the judicial exception.
Subject Matter Eligibility Test for Products and Processes – Dependent claims
The dependent claims do not recite additional elements other than the polynucleotide or the polynucleotide in a composition, which must be compared to the naturally occurring counterpart as a composition. Therefore, the analysis below focuses on Step 2A, Prong 1 as the answers to Step 2A, Prong 2 and Step 2B are both “no”.
Claim 107 recites “the polynucleotide comprising a 3’ or 5’ noncoding region. DNAI2 mRNA transcript variant one comprises 123 noncoding nucleotides before the start of the coding sequence that is SEQ ID NO 1 (see alignment and Genbank entry, page 3). Therefore, the claimed polynucleotide is not markedly different than its naturally occurring counterpart, the naturally occurring DNAI2 mRNA transcript variant 1, and constitutes a judicial exception.
Claim 108 recites the non-coding region enhances expression of the PCD-associated polypeptide. It is well known in the art that 5’UTR sequences enhance expression by providing a ribosome binding site (see e.g., Leppek et al., Nature Reviews (2018), 19: 158-174). Thus, the claimed polynucleotide is not markedly different than its naturally occurring counterpart, the naturally occurring DNAI2 mRNA transcript variant 1, and constitutes a judicial exception.
Claim 109 recites the polynucleotide further comprises a 5’ cap structure. It is well known in the art that eukaryotic mRNAs require 5’ cap structures for stability and translation initiation (see e.g., Leppek et al., Nature Reviews (2018), 19: 158-174). Thus, the claimed polynucleotide is not markedly different than its naturally occurring counterpart, the naturally occurring DNAI2 mRNA transcript variant 1, and constitutes a judicial exception.
Claims 112-113 recites the 3’ non-coding region comprises a poly-adenosine tail, at most 200 adenosines. The canonical order for mRNA processing in cells is 1) 5’ capping, 2) splicing and removal of intronic sequences, and 3) addition of a polyA tail (see e.g., Shenasa and Bentley, Trends Genet. (2023), 39: 672-685). As such the DNAI2 pre-mRNA would first be capped at the 5’ end, then have introns removed co-transcriptionally, and finally have the addition of adenosines by the polyA polymerase. As such, at some point during DNAI2 mRNA processing, there exists in a cell a capped mature RNA with less than 200 adenosines on the 3’ end. Thus, the claimed polynucleotide is not markedly different than its naturally occurring counterpart, the naturally occurring DNAI2 mRNA transcript variant 1, and constitutes a judicial exception.
Claims 117-118 recite the polypeptide is an mRNA of a gene including DNAI2, which does not distinguish the claimed polypeptide from the naturally occurring counterpart, the DNAI2 mRNA transcript variant 1 for the reasons described above for claim 1.
Claim 125 recites a pharmaceutical composition comprising [the polynucleotide of claim 1] and a lipid composition. The Specification defines "pharmaceutically acceptable" as referring to those “compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and/or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.” ([0032]). Cells are part of organ transplants and tissue grafts and therefore are considered encompassed by “a pharmaceutical composition”. The naturally occurring counterpart to the claimed compositions is a human cell that expresses the DNAI2 mRNA, which is any ciliated cell (see Genbank reference above and references therein). Human cells have lipid-based membranes. The claimed composition is not markedly different than a ciliated human cell.
Claims 127 and 129 requires the lipid composition to comprise a phospholipid or a steroid. Human cells normally comprise a phospholipid-based cell membrane with embedded cholesterol (i.e., a sterol) for fluidity. Thus, the claimed compositions are not markedly different than their naturally occurring counterpart, a ciliated cell expressing DNAI2.
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.
(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 1, 107-110, 112-114, 117-118, 120, 125-131 and 135 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Rudolph (US 20220211807 A1, priority to at least February 13, 2020). Claims 107-108 are evidenced by Elfakess (Elfakess et al., Nucleic Acids Research (2011), 39: 7598–7609). Claim 111 is evidenced by BenchChem (BenchChem Technical Support Team, An In-depth Technical Guide to Anti-Reverse Cap Analogs (ARCAs), December 2025). Claim 114 is evidenced by 4basebio (Blog post: Why polyA tail stability matters for mRNA therapeutic development? Current challenges in the plasmid DNA manufacturing process, Jan 27, 2025; https://www.4basebio.com/blog/why-polya-stability-matters-for-mrna-therapeutic-development, [retrieved February 18, 2026]). Claims 126-127 are evidenced by Wikipedia (Lipofectamine, https://en.wikipedia.org/wiki/Lipofectamine [retrieved February 18, 2026]).
Regarding claims 1, 107-114 and 117-118, the Specification does not define “synthetic”, which is interpreted as a product-by-process limitation here. A “synthesized” polynucleotide will be examined according to the structure of the polynucleotide that is synthesized. None of the claims recite any specific means for synthesis; so, any polynucleotide, whether naturally occurring, in vitro polymerized, or produced recombinantly in a cell, that has at least 70% sequence identity to the claimed SEQ ID NOs reads on the claimed “synthetic” polynucleotide.
Regarding claim 1, Rudolph teaches “the present invention relates to a pharmaceutical composition comprising a polyribonucleotide (i.e., a polynucleotide) for use in treating ciliopathy ([0001], including primary ciliary dyskinesia (PCD) ([0005]). Rudolph teaches the polynucleotide is an mRNA that encodes CCDC40 ([0013], Table 14). Rudolph teaches the mRNA sequence is set forth in SEQ ID NO 6 ([0154], pages 38-40). Rudolph teaches the sequence of SEQ ID NO 6 (pages 38-40) comprises a sequence that is 92% identical to SEQ ID NO 29 of the examined application (See OA Appendix, pages 6-8).
Regarding claims 107-108, Rudolph teaches the SEQ ID NO 6 also comprises a TISU element 5’ of the coding CCDC40 coding sequence (i.e., a 5’ non-coding region). Rudolph is silent regarding the function of the TISU element. Elfakess teaches TISU stands for Translation Initiator of Short 5’ UTR (Abstract) and promotes translation of the mRNA (i.e.., enhances expression of the PCD-associated protein) (Figure 1). Therefore, Rudolph’s SEQ ID NO 6 inherently comprised a 5’ noncoding region that enhances expression of the CCDC40 polypeptide within cells.
Regarding claim 109, Rudolph teaches the procedure for producing the CCDC40 mRNA included capping by addition of an ARCA cap analogue (i.e., the CCDC40-encoding polynucleotide further comprised a 5’ cap structure) ([0224]).
Regarding claim 110, Rudolph teaches the 5’ cap analogue was purchased from Jena Biosciences (Table 4). Rudolph is silent regarding the effect of the ARCA cap on the pharmacokinetics of the polynucleotide. BenchChem teaches ARCA caps are “Anti-Reverse Cap Analogs” (page 1). BenchChem teaches ARCA caps have a 3-OMe group that prevents the RNA polymerase from initiating transcription form the 7-methylated guanosine in a naturally occurring 5’ cap (page 2). BenchChem teaches that 5’ caps are critical for protecting mRNAs from endonuclease degradation (i.e., improves a pharmacokinetic characteristic of the polynucleotide) (page 2). Therefore, Rudolph’s mRNA comprising SEQ ID NO 6 that was capped with an ARCA cap inherently comprised a 5’ cap that improved a pharmacokinetic characteristic.
Regarding claims 112, Rudolph teaches the CCDC40 mRNA was polyadenylated at the 3’ end ([0226]) including SEQ ID NO 6 (pages 38-40).
Regarding claim 113, Rudolph teaches the poly(A) tail length was determined to be between 100-250 nucleotides (i.e., at least one mRNA polynucleotide had 200 or less adenosines) ([0226]).
Regarding claim 114, Rudolph is silent on the function of a polyadenosine tail that is 100-250 adenosines. 4basebio teaches that polyA tails of between 70-200 adenosines provide stability to enhance transcript stability and therapeutic performance (i.e., improves a pharmacokinetic characteristic of the polynucleotide in a subject) (page 1). Therefore, Rudolph’s mRNA comprising SEQ ID NO 6 that was capped and polyadenylated with between 100-250 adenosines inherently comprised a polyA tail that improved a pharmacokinetic characteristic in a subject.
Regarding claims 117-118, Rudolph teaches SEQ ID NO 6 encodes CCDC40 as recited above for claim 1 (pages 38-40).
Regarding claim 120, Rudolph teaches the mRNA was produced with chemically modified ribonucleotides including 5-Iodocytidine and 5-Iodouridine (i.e., nucleoside analogues) ([0224]).
Regarding claims 125-127, the teachings of Rudolph regarding the CCDC40-encoding mRNA with 92% identity to SEQ ID NO 29 is recited above for claim 1. Rudolph teaches transfecting the CCDC40 mRNA into cells by mixing it with a lipoplex mix comprising Lipofectoamine 2000. Rudolph is silent regarding the composition of lipofectamine. Wikipedia teaches that Lipofectamine 2000 consists of a mixture of DOSPA, which is a cationic lipid, and DOPE, which is a phospholipid (i.e., a lipid composition comprising a cationic lipid and a phospholipid) (page 1). Therefore, Rudolph’s composition comprising mRNA having SEQ ID NO 6 and Lipofectamine inherently was a composition that included a cationic lipid and a phospholipid.
Regarding claims 128-129, Rudolph teaches the CCDC40-encoding mRNA formulated with a “LF111 formulation” and delivered to human respiratory epithelial cells ([0265]). Rudolph teaches the LF111 formation comprises DMG-PEG2000, which is a PEGylated lipid, and cholesterol (i.e., a steroid) ([0136]).
Regarding claim 130, the Specification describes a “nanoparticle” as including lipid nanoparticles including PEGYlated lipids to encapsulate the polynucleotides ([00148]-[00149]). Rudolph teaches the CCDC40-encoding mRNA formulated LF111 formulation ([0265]), which forms a liposome (i.e., a lipid nanoparticle) ([0136]).
Regarding claim 131, Rudolph teaches the LF111 formulation for delivery of the CCDC40-encoding mRNA can be administered to a patient using a spray, droplets and/or by inhalation (i.e., formulated for local administration) ([0146]).
Regarding claim 135, the teachings of Rudolph regarding the CCDC40-encoding mRNA with 92% identity to SEQ ID NO 29 is recited above for claim 1. Rudolph teaches using the CCDC40-encoding mRNA formulated LF111 formulation (i.e., in a lipid composition) in a method of treating a ciliopathy in which the mRNA encodes a functional version of a protein whose deficiency is associated with the ciliopathy ([0147]). Rudolph teaches a functional CDCC40 protein is missing in PCD ([0011], Table 1).
Claim Rejections - 35 USC § 103
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.
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 111 is rejected under 35 U.S.C. 103 as being unpatentable over Rudolph (US 20220211807 A1, priority to at least February 13, 2020) as applied to claims 1, 107-110, 112-114, 117-118, 120, 125-131 and 135 above, and further in view of Henderson (Henderson et al., Current Protocols (2021); 1, e39, pages 1-17; first published February 1, 2021).
The teachings of Rudolph are recited above and applied as for claims 1, 107-110, 112-114, 117-118, 120, 125-131 and 135. Briefly, Rudolph teaches a CCDC40-encoding mRNA with over 90% identity to SEQ ID NO 29, wherein the mRNA is capped with an ARCA cap (see rejection of claims 1 and 109 above).
Rudolph does not teach a 5’ cap that is a Cap-1 structure.
Henderson teaches synthetic mRNA-based technologies are popular approaches to gene therapies (Abstract). Henderson teaches that mature mRNA requires a 5’-cap for gene expression and mRNA stability (Abstract). Henderson teaches that first-generation cap analogs, such as ARCA incorporate cap-0 structures at lower efficiency and rection yields (Abstract). Henderson teaches CleanCap® technologies co-transcriptionally adds a cap-1 structure to mRNA during in vitro transcription (IVT) (Abstract). Henderson teaches CleanCap® provides higher mature capped mRNA.
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used CleanCap® to add a 5’ cap-1 structure to Rudolph’s CCD40-encoding mRNA. It would have amounted to the simple substitution of one 5’ cap for another by known means to yield predictable results. The skilled artisan would have had a reasonable expectation that Rudolph’s mRNA could be capped using CleanCap® to place a Cap-1 structure because Henderson teaches that CleanCap® is used for IVT-produced mRNAs, which is the process by which Rudolph produces the therapeutic mRNAs. The skilled artisan would have been motivated to make the substitution because Henderson teaches CleanCap® produces higher yields of the desired mature RNA.
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.
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Claims 1, 107-114, 117-118, 120, 125-131 and 135 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11786610 in view of Rudolph (US 20220211807 A1, priority to at least February 13, 2020). Claim 111 is rejected further in view of Henderson (Henderson et al., Current Protocols (2021); 1, e39, pages 1-17; first published February 1, 2021).
Patented claim 1 recites A composition comprising a nucleic acid construct encoding a polypeptide at least 95% identical to a coiled-coil domain containing 39 (CCDC39) polypeptide (i.e., a PCD-associated protein), wherein said composition is formulated for administration to lung cells of a subject, wherein said composition comprises a cationic lipid; a fusogenic lipid; a cholesterol (i.e., a sterol) and a polyethylene glycol (PEG) lipid; and wherein said nucleic acid construct comprises 1-methylpseudouridine (i.e., a nucleoside analog). Patented claims 6-7 recite the nucleic acid construct is an mRNA. Patented claim 10 recites the composition is formulated in a nanoparticle. Patented claims 11-15 recite the nucleic acid constructs further comprise 3’ and 5’ noncoding regions, 5’ cap structure, poly(A) tail that is at most 200 adenosines, and that enhance expression of the nucleic acid construct in cells (i.e., improve pharmacokinetics).
The patented claims do not recite the sequence of the CCDC39-encoding sequence. The patented claims do not recite a cap-1 structure or a method of using the patented composition for treating PCD.
Rudolph teaches an mRNA-encoding CCDC39 formulated for delivery to cells (FIG 9; [0205]). Rudolph teaches a codon-optimized sequence of CCDC39 is comprised within SEQ ID NO 2 (page 33). Rudolph’s CCDC39-encoding sequence is 96% identical to SEQ ID NO 25 of the examined application (see OA Appendix, pages 9-11). Rudolph teaches transfecting the CCDC39-encoding mRNA into cells using Lipofectamine, which can then express the CCDC39 protein (FIG 9; [0205]). Rudolph teaches using the CCDC39-encoding mRNA in a lipid composition in a method of treating a ciliopathy in which the mRNA encodes a functional version of a protein whose deficiency is associated with the ciliopathy ([0147]). Rudolph teaches a functional CDCC39 protein is missing in PCD ([0011], Table 1).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used Rudolph’s CCDC39-encoding nucleic acid sequence in the patented claims and then use the composition in a method for treating PCD. It would have amounted to using a known sequence that is optimized for delivery to humans for the known purpose of treating a ciliopathy. The skilled artisan would have predicted that Rudolph’s sequence can be used because they teach that it is functional for expressing the CCDC39 protein in cells and teachings using the mRNA in therapeutic methods to replace a gene whose deficiency causes PCD.
Regarding claim 111, the teachings of Henderson are recited above in paragraph 59. It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have further used CleanCap® to add a 5’ cap-1 structure to the patented CCD39-encoding mRNA with Rudolph’s SEQ ID NO 2. It would have amounted to using a known 5’ cap structure for the generically patented one by known means to yield predictable results. The skilled artisan would have had a reasonable expectation that the patented mRNA could be capped using CleanCap® to place a Cap-1 structure because Henderson teaches that CleanCap® is used for IVT-produced mRNAs, which is a common process for producing therapeutic mRNAs, as shown in Rudolph. The skilled artisan would have been motivated to use the Cap-1 structure because Henderson teaches CleanCap® produces higher yields of the desired mature RNA.
Claims 1, 107-114, 117-118, 120, 125-131 and 135 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 6-13, 15, 17-23 and 25-27 of copending Application No. 18420141 in view of Rudolph (US 20220211807 A1, priority to at least February 13, 2020). Claim 111 is rejected further in view of Henderson (Henderson et al., Current Protocols (2021); 1, e39, pages 1-17; first published February 1, 2021).
Copending claim 1 recites A method for treating a subject having or suspected of having a lung disorder resulting from aberrant expression or activity of a gene or a polypeptide, the method comprising: administering… aerosol droplets comprising a lipid composition and a heterologous polynucleotide assembled with the lipid composition comprising DODAP, a phospholipid, a sterol, a PEG-lipid… wherein the heterologous polynucleotide is mRNA. Copending claim 10 recites wherein the mRNA comprises nucleoside analogues. Copending claim 12 recites wherein the disorder is PCD. Copending claims 25 recites wherein the mRNA encodes CCDC39. Copending claims 26 recites wherein the lipid composition is a liposome or lipid nanoparticle.
The copending claims do not recite the sequence of the CCDC39-encoding sequence. The patented claims do not recite 5’ and 3’ noncoding regions, a cap-1 structure, or polyA tail.
Rudolph teaches an mRNA-encoding CCDC39 formulated for delivery to cells (FIG 9; [0205]). Rudolph teaches a codon-optimized sequence of CCDC39 is comprised within SEQ ID NO 2 and having a 5’ non-coding region with a translational start site and a polyA tail (page 33). Rudolph’s CCDC39-encoding sequence comprises a sequence that is 96% identical to SEQ ID NO 25 of the examined application. Rudolph teaches transfecting the CCDC39-encoding mRNA into cells using Lipofectamine, which can then express the CCDC39 protein (FIG 9; [0205]). Rudolph teaches using the CCDC39-encoding mRNA in a lipid composition in a method of treating a ciliopathy in which the mRNA encodes a functional version of a protein whose deficiency is associated with the ciliopathy ([0147]). Rudolph teaches a functional CDCC39 protein is missing in PCD ([0011], Table 1).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used Rudolph’s CCDC39-encoding nucleic acid sequence in the copending method for treating PCD. It would have amounted to using a known sequence that is optimized for delivery to humans for the known purpose of treating a ciliopathy. The skilled artisan would have predicted that Rudolph’s sequence can be used because they teach that it is functional for expressing the CCDC39 protein in cells and teachings using the mRNA in therapeutic methods to replace a gene whose deficiency causes PCD.
Regarding claim 111, the teachings of Henderson are recited above in paragraph 59. The obviousness of using a Cap-1 structure on the mRNA in the copending method is recited above in paragraph 67.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 107-114, 117-118, 120, 125-131 and 135 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 6-13, 15, 17-23 and 25-27 of copending Application No. 19400701 in view of Rudolph (US 20220211807 A1, priority to at least February 13, 2020). Claim 111 is rejected further in view of Henderson (Henderson et al., Current Protocols (2021); 1, e39, pages 1-17; first published February 1, 2021).
Copending claim 1 recites A method for selectively delivering an mRNA to the lungs of a subject, wherein the method comprises nebulizing a liquid pharmaceutical composition which comprises lipid nanoparticles (LNPs) comprising said mRNA to generate an aerosolized pharmaceutical composition, and administering the aerosolized pharmaceutical composition to the subject, wherein the LNPs comprise an ionizable lipid, a phospholipid, a PEG-lipid, and a sterol, wherein the LNPs have an mRNA integrity of between 75% and 99%, … wherein administering the aerosolized pharmaceutical composition to the subject results in minimal amounts of mRNA in the blood, liver, and spleen of the subject. Copending claim 10 recites wherein the mRNA comprises nucleoside analogues. Copending claim 12 recites wherein the disorder is PCD. Copending claims 25 recites wherein the mRNA encodes CCDC39. Copending claims 26 recites wherein the lipid composition is a liposome or lipid nanoparticle. Copending claim 29 recites wherein the mRNA encodes a CCDC39 protein.
The copending claims do not recite the sequence of the CCDC39-encoding sequence or a method of treatment for PCD. The patented claims do not recite 5’ and 3’ noncoding regions, a cap-1 structure, or polyA tail.
Rudolph teaches an mRNA-encoding CCDC39 formulated for delivery to cells (FIG 9; [0205]). Rudolph teaches a codon-optimized sequence of CCDC39 is comprised within SEQ ID NO 2 and having a 5’ non-coding region with a translational start site and a polyA tail (page 33). Rudolph’s CCDC39-encoding sequence comprises a sequence that is 96% identical to SEQ ID NO 25 of the examined application. Rudolph teaches transfecting the CCDC39-encoding mRNA into cells using Lipofectamine, which can then express the CCDC39 protein (FIG 9; [0205]). Rudolph teaches using the CCDC39-encoding mRNA in a lipid composition in a method of treating a ciliopathy in which the mRNA encodes a functional version of a protein whose deficiency is associated with the ciliopathy ([0147]). Rudolph teaches a functional CDCC39 protein is missing in PCD ([0011], Table 1).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used Rudolph’s CCDC39-encoding nucleic acid sequence in the copending method and the method to be used for treating PCD. It would have amounted to using a known sequence that is optimized for delivery to humans for the known purpose of treating a ciliopathy. The skilled artisan would have predicted that Rudolph’s sequence can be used because they teach that it is functional for expressing the CCDC39 protein in cells and teachings using the mRNA in therapeutic methods to replace a gene whose deficiency causes PCD.
Regarding claim 111, the teachings of Henderson are recited above in paragraph 59. The obviousness of using a Cap-1 structure on the mRNA in the copending method is recited above in paragraph 67.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowable.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635