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 and Election
The preliminary amendment filed February 20, 2024 is acknowledged. Claims 16-35 are pending.
Applicant's election with traverse of Group I, directed to claims 16-29, in the reply filed on August 31, 2026 is acknowledged. The traversal is on the ground(s) that that there is no undue burden to search for Group 1 and 2. This is not found persuasive because the application is a 371 application and the restriction was based on a lack of unity. Restriction in a 371 application does not require a search burden. The requirement is still deemed proper and is therefore made FINAL. Claims 30-35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected group, there being no allowable generic or linking claim.
In the reply filed August 31, 2026, Applicant also elected without traverse, the species of IL-4 cytokine and the species CRM197 as the T cell epitope. Applicant did not indicate a SEQ ID NO for the IL-4 species selection as suggested. The IL-4 cytokine species is thus interpreted as full length IL-4. During the course of examination, compositions with a generic IL-13 sequence were identified. Therefore, the cytokine species under examination includes fill length IL-4 and generic IL-13. Claims 19 and 21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 16-18, 20 and 22-29 are under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). At least one amino acid sequence of 4 or more amino acids appears on pages 4, 45, 90, 91 and 92. Each recitation of an amino acid with 4 or more residues requires a SEQ ID NO.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, 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.
Drawings
The drawings are objected to because the lines, shadings, numbers and letters of FIGs 1, 2, 3, 4, and 7 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 in FIG 7 is light grey, very small and/or otherwise not sufficiently dense and dark to permit satisfactory reproduction characteristics. The letters over shading especially in FIGs 1-4 are not sufficiently dark for reproduction; for instance, the white “TpD” and “p2” are barely legible above the light shading.
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.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. It is noted that the Specification/Drawings of this Application differs from the Specification/Drawings the certified copy of the EP 21306131.0 and the US provisional application 63/235351. Neither the EP application nor the US provisional application contains Example 2 (i.e., disclosures of administering mRNA to mice) or Table 8 and FIGs 5-9 (i.e., results from mRNA administration to mice). However, the claims under examination appear to be fully supported by the disclosure in the EP application and US provisional application. The effective filing date of the examined claims is August 20, 2021.
Claim Objections
Claim 24 is objected to because of the following informalities:
Claim 24 requires a SEQ ID NO to identify each of the amino acid sequences that is 4 or more residues in length. 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 23 and 24 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.
Claim 23 recites wherein the at least on T cell epitope is… CRM197, TpD, TT, universal CD4 polyepitopes, variants and fragments thereof. Use of “variants” renders the claim indefinite because it is not clear how much a protein or peptide can be varied and still be considered a “variant” of the original. The Speficiation does not define “variant” or provide a description to rely to determine the level of variance that the term “variant” encompasses. For instance, CRM197 is 535 amino acids in length (SEQ IDNO 48). It is not clear if 5%, 20%, 50% or all 535 amino acids can be changed, and the resultant protein still be considered a “variant” of CRM197.
To overcome this rejection, it is suggested that “variant” be removed from the claims or alternatively for the claim to recite a series of SEQ ID NOs for each of the encompassed T cell epitopes.
Claim 24 recites “wherein the at least one spacer is selected from the group consisting of… amino acids doublets…” It is not clear what is meant by “amino acids doublets”. The Specification does not define the term or give any examples for an amino acids doublet. It is not clear if it encompasses any two amino acids but can also include additional amino acids. Additionally, “doublet” could imply that the two amino acids are to be identical such that AA and WW would be included, but AW and AP would not be. Finally, the pluralization of “acids” before the plural version of “doublets” is also confusing. It is not clear if the doublet must be of two different amino acids, like AAWW, but excludes a single amino acid doublet like AA. Because the metes and bounds of “amino acids doublets” is undefined, the claim as a whole is indefinite.
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 16 and 25-29 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Ashman (US 20060147417 A1; of record).
Regarding claim 16, Ashman teaches an IL-13 element (i.e., at least one cytokine or epitope thereof) in a fusion protein with a T-cell helper epitope (i.e., at least one T cell epitope) wherein the two are recombinantly manufactured together (i.e., a single nucleic acid encoding the fusion protein) ([0050]). Ashman teaches the polypeptides may be encoded by polynucleotides, and is typically RNA (0106]).
Regarding claims 25-26, Ashman teaches the polynucleotides of the invention encapsulated by liposomes ([0138]).
Regarding claims 27-28, Ashman teaches the present invention provides methods of generating an anti-self IL-13 antibody response by administration of vaccines (i.e., the RNA encoding IL-13 and a T-cell epitope is a vaccine and a pharmaceutical composition) ([0135]). Ashman teaches providing the vaccine formulated with an adjuvant (i.e., a pharmaceutically acceptable excipient) ([0136]).
Regarding claim 29, Ashman teaches the present invention provides for treating or preventing IL-13 mediated diseases (i.e., a medicament) ([0134]).
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.
Claims 17-18, 20 and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Ashman (US 20060147417 A1; of record) in view of Grouard-Vogel (WO 2019228674 A1, published December 5, 2019) Sahin (US 20210113606 A1, published April 22, 2021).
The teachings of Ashman are recited above as for claims 16 and 25-29 and are incorporated here. Ashman also teaches that techniques have been designed with the aim of breaking tolerance to a self-antigen, including linking it to a highly immunogenic carrier protein, including creating a fusion protein comprising both the carrier protein and the self-protein ([0014]-[0015]). Ashman provides that creating fusion proteins is routine in the art and only requires the skilled artisan to know the amino acid sequence of the components and the genetic code to determine a polynucleotide sequence encoding the components and the knowledge of PCR to create the nucleic acid encoding the fusion protein ([0105]).
Ashman does not teach wherein the cytokine is an IL-4 or an IL-13 protein. Ashman does not teach wherein the carrier protein is a CRM197 protein.
Grouard-Vogel teaches IL-4 is a pleiotropic cytokine that has been observed in serum of asthmatic patients and likely acts in the early phase of allergy development (page 2, ¶3). Grouard-Vogel teaches IL-13 is involved in late phages of allergic reactions and is sufficient to induce airways hyperresponsiveness, mucus production and airway smooth muscle alterations (page 2, ¶5). Grouard-Vogel teaches that recombinant antibodies directed to IL-4 and IL-13 or their receptors have recently been developed to treat allergies, but has a high cost (page 3, ¶2). Grouard-Vogel teaches an alternative approach is to administer an immunogenic product comprising IL-4 and Il-13 conjugated to CRM197 (i.e., a T-cell epitope, a carrier protein) (page 3, ¶3-9). Grouard-Vogel illustrates a conjugation method to produce two fused proteins (FIG. 1), which requires purification of two different proteins followed by functionalization and conjugation in vitro (pages 53-54). Grouard-Vogel teaches the IL-4-CRM197 and IL-13-CRM197 conjugated proteins could elicit an immunological response towards IL-4 and IL-13, respectively (FIGs 4, 8) and was therapeutic for a mouse model of dust mite-induced allergy/asthma (FIG 10). Grouard-Vogel provides the amino acid sequence for CRM197 (page 9), full length IL-4 and epitopes thereof (page 12-13) and full length IL-13 and epitopes thereof (pages 21-22).
Sahin teaches administering a mRNA-based vaccine encoding the cytokine IL-2 or IL-7 fused to a “pharmacokinetic-extending” (PK) peptide like albumin or immunoglobulin fragment ([0009]-[0013]). Sahin teaches basic molecular biology cloning techniques for producing polynucleotide encoding the fusion proteins ([0348]). Sahin teaches a linker (i.e., spacer) cloned between the cytokine and PK peptide ([0348]). Sahin teaches the linker was 30 nucleotides long (i.e., 10 amino acids) encoding glycine (G) and serine (S) residues ([0348]). Sahin teaches administration of the RNA encoding the cytokine-PK fusion protein was sufficient for eliciting an immune response ([0351]).
Regarding claims 17-18, 20 and 23, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have produced Grouard-Vogel’s IL-4 or IL-13 conjugation to CRM197 using Ashman’s and Sahin’s method of creating a genetically encoded fusion protein comprising the cytokine and immunogenic carrier protein. It would have amounted to substituting one known cytokine coding sequence for another and substituting one known immunogenic protein coding sequence for another by known means to yield predictable results. The skilled artisan would have predicted that an IL-4-CRM197 or an IL-13-CRM197 protein could be produced as a genetically encoded protein encoded by an RNA, because each element is amino acid-based and creating fusion proteins is routine in the art as noted by Ashman and Sahin. The skilled artisan would have been motivated to produce the IL-4-CRM197 or IL-13-CRM197 fusion proteins using an RNA encoding it instead of conjugation because it eliminates three steps – 1) functionalization of the cytokine and CRM197, 2) conjugation of the functionalized proteins, and 3) purification of the conjugated proteins from unconjugated products and the crosslinking element.
Regarding claim 22, Grouard-Vogel also provides an example of administering both an IL-4-CRM197 fusion protein and an IL-13-CRM197 fusion protein (page 66, combo). Grouard-Vogel teaches the combination therapy had higher therapeutic effect than either of the IL-4 or IL-13 therapies alone (page 68, ¶3; Figure 10).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have included both IL-4-CRM197 and IL-13-CRM197 coding sequences rendered obvious above on the same RNA molecule. It would have amounted to the simple combination of known or obvious elements by known means to yield predictable results. The skilled artisan would have predicted that both fusion proteins could be encoded on the same RNA molecule because it would only require standard methods of molecular biology. Additionally, means to express two fusion proteins from the same transcript are known, such as including internal ribosomal entry sites (IRES) and self-cleaving peptides like P2A sequences. The skilled artisan would have been motivated to have included both because Grouard-Vogel teaches the combination therapy is more effective than the single IL-4 or IL-13 therapy. Additionally, providing the fusion proteins via a single RNA allows the combination therapy in a single administration step.
Regarding claim 24, Sahin teaches the linkers (i.e., spacers) between the cytokine and additional peptide in the fusion protein comprised 10 glycine and serine residues (i.e., amino acids doublets) ([0348]).
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.
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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.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
