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 .
Priority
Acknowledgment is made of applicant’s claim for priority based on a foreign application filed as PCT/EP 2020/087469 on 12/21/2020.
All claims are given the priority date of 12/21/2020.
Application Status
Receipt is acknowledged of amendment, filed 12/19/2024. Claims 1-6, 8-10, 12, 13, 21-24, 28-31 and 37 are currently pending.
Information Disclosure Statement
Receipt of acknowledgment of the information disclosure statements filed on 06/16/2023 and 08/08/2025 have been received and all references have been considered.
Drawings
The drawings are objected to for the following reasons:
37 CFR 1.84 (u)(1) states “View numbers must be preceded by the abbreviation "FIG."”
In the current case, the view numbers for Figures 1-24 are preceded by the word "Figure" instead of the abbreviation "FIG.".
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 disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Rejections - 35 USC § 112
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 12 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.
The term “preferably” in claim 12 is a relative term which renders the claim indefinite. The term “preferably” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear whether the limitations that are listed after the term “preferably” are required by the instant invention or not.
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 1-6, 8-10, 12, 13, 21-24, 28-31 and 37 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 “wherein the at least one RNA encodes: (i) an amino acid sequence comprising human IL7 (hIL7) and/or (ii) an amino acid sequence comprising human IL2 (hIL2)”, does not reasonably provide enablement for “wherein the at least one RNA encodes: (i) an amino acid sequence comprising human IL7 (hIL7), a functional variant thereof, or a functional fragment of the hIL7 or the functional variant thereof; and/or (ii) an amino acid sequence comprising human IL2 (hIL2), a functional variant thereof, or a functional fragment of the hIL2 or the functional variant thereof”. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: The claims are drawn to a composition or medical preparation comprising at least one RNA wherein the at least one RNA encodes: (i) an amino acid sequence comprising human IL7 (hIL7) and/or (ii) an amino acid sequence comprising human IL2 (hIL2). The claims require a specific structure of the composition or medical preparation. The nature of the invention is complex in that the function of the RNA sequence is described by the structure of an amino acid sequence comprising human IL7 (hIL7) and/or (ii) an amino acid sequence comprising human IL2 (hIL2) is not specified. The independent claim also allows that functional variants or fragments of these amino acid sequence could be use, however, the function that these sequences must provide is not defined.
Breadth of the claims: The claims broadly encompass the RNA sequence encodes: (i) an amino acid sequence comprising human IL7 (hIL7), a functional variant thereof, or a functional fragment of the hIL7 or the functional variant thereof; and/or (ii) an amino acid sequence comprising human IL2 (hIL2), a functional variant thereof, or a functional fragment of the hIL2 or the functional variant thereof. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples: The specification defines the term “variant” as an amino acid sequence that differs from a parent amino acid sequence by virtue of at least one amino acid modification and the term “fragment” as an amino acid sequence (peptide or protein), relates to a part of an amino acid sequence, i.e. a sequence which represents the amino acid sequence shortened at the N-terminus and/or C-terminus (Page 40, Paragraphs 3-4). The specification describes the term "variant" includes all mutants, splice variants, posttranslationally modified variants, conformations, isoforms, allelic variants, species variants, and species homologs, in particular those which are naturally occurring. The term "variant" includes, in particular, fragments of an amino acid sequence (Page 41, Paragraph 2). The specification also describes the term "functional fragment" or "functional variant" of an amino acid sequence relates to any fragment or variant exhibiting one or more functional properties identical or similar to those of the amino acid sequence from which it is derived, i.e., it is functionally equivalent (Page 44, Paragraph 3). The specification continues to describe that the term "functional fragment" or "functional variant", as used herein, in particular refers to a variant molecule or sequence that comprises an amino acid sequence that is altered by one or more amino acids compared to the amino acid sequence of the parent molecule or sequence and that is still capable of fulfilling one or more of the functions of the parent molecule or sequence, e.g., stimulating or inducing an immune response (Page 44, Paragraph 3). No description is provided of any specific fragments or variants of these sequences that retain the desired functional activity for the instant invention.
Predictability and state of the art: The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of fragments or variant capable of the retained function of the IL-7 and/or IL-2. Specifically, Mazzucchelli et al (Semin Immunol. 2012 June; 24(3): 225–230) teaches polymorphisms in IL-7R have been shown be a risk factor for a number of diseases that are autoimmune or involve excess immune and inflammatory responses including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, primary biliary cirrhosis, inflammatory bowel disease, atopic dermatitis, inhalation allergy, sarcoidosis and graft versus host disease (Page 225, Abstract). Therefore, it would be unknown which fragments or variants of the human IL-7 would cause increased risks for these diseases and which ones would not.
In addition, Ju et al (Journal of Biological Chemistry, Volume 262, Issue 12, 25 April 1987, Pages 5723-5731) teaches that most amino acid substitutions resulted in a rIL-2 analog which retained 100% bioactivity, specifically in region I (the NH2 terminus), deletion of the first 10 amino acids reduced activity slightly, to 50-70% of the wild type rlL-2 (A 50% variation in bioactivity is within the error of the CTLL assay.); however, when this deletion was extended to include the next 10 amino acids, the bioactivity dropped significantly, to less than 1 % of the control (Page 5725, Column 2). Therefore, the specific amino acid sequence is essential for the function and not any fragment or variant would be capable of the same function of the wild-type.
Amount of experimentation necessary: In order to practice the claimed invention, an immense amount of experimentation would be required. As disclosed above, the specification itself provides the amino acid sequences that encode the human IL-7 and/or human IL-3 and only provides the suggestion that “functional fragments” or “functional variants” could be used if they retained the functional activity of the amino acid sequences that encode the human IL-7 and/or IL-2. The specification does not teach any fragments or variants of these sequences that retain the functional activity. Therefore, experiment could be conducted, but in view of the specification there does not appear to be any amount of experimentation that would be sufficient to reliably produce the exact product of the invention. Such experimentation would not be possible due to not having the functions required of the variants or fragments of the original sequence. Therefore, it would require immense amount of unpredictable experimentation to practice the claimed invention with such variants in the possible result.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 1-6, 8-10, 12, 13, 21-24, 28-31 and 37 are not considered to be fully enabled by the instant disclosure.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-6, 8-10, 13, 21, 23, 24, 28-31 and 37 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Sahin et al (WO 2019/154985 A1).
Regarding claim 1, Sahin teaches RNA encoding peptides or proteins used for vaccination and RNA encoding IL-2 attached to a pharmacokinetic modifying group and RNA encoding IL-7 attached to a pharmacokinetic modifying group (Page 1, Abstract).
Regarding claim 2, Sahin teaches the human IL2 (hll2) was fused to the N- (hlL2-hAlb) or C-terminus (hAlb-hlL2) of human Albumin (hAlb) (Page 82, Line 33 bridging Page 83, Line 4).
Regarding claims 3 and 4, Sahin teaches the human IL7 (hlL7) was fused to the N- (hlL7-hAlb) of human Albumin (hAlb) (Page 83, Lines 20-32).
Regarding claims 5 and 6, Sahin teaches the human IL2 (hlL2) was fused to the N- (hlL2-hAlb) or C-terminus (hAlb-hlL2) of human Albumin (hAlb) (Page 82, Line 33 bridging Page 83, Line 4).
Regarding claim 8, Sahin teaches RNA encoding peptides or proteins used for vaccination and RNA encoding IL-2 attached to a pharmacokinetic modifying group and RNA encoding IL-7 attached to a pharmacokinetic modifying group (Page 1, Abstract).
Regarding claim 9, the phrase “an amino acid” is interpreted as any two or more consecutive amino acids with 100% identity not over the entire sequence.
Sahin teaches IL-7 comprises the amino acid sequence of SEQ ID NO: 2 which is 100% identical to two or more consecutive amino acids of instant SEQ ID NO: 4 (Page 31, Lines 20-25; See Appendix I).
Regarding clam 10, the phrase “an amino acid” is interpreted as any two or more consecutive amino acids with 100% identity not over the entire sequence.
Sahin teaches IL-2 comprises the amino acid sequence of SEQ ID NO: 1 which is 100% identical to two or more consecutive amino acids of instant SEQ ID NO: 6 (Page 30, Lines 17-22; See Appendix II).
Regarding claim 13, Sahin teaches a 3’ poly(A) tail wherein the poly(A) tail comprises at least about 20, at least about 40, at least about 80, or at least about 100, and up to about 500 nucleotides in length (Page 28, Lines 1-5).
Regarding claim 21, Sahin teaches a 3’ poly(A) tail wherein the poly(A) tail comprises at least about 20, at least about 40, at least about 80, or at least about 100, and up to about 500 nucleotides in length (Page 28, Lines 1-5).
Regarding claims 23 and 24, Sahin teaches 20 μg gp70 RNA-LPX intravenously, and either 3 μg hAlb-hlL2, hlL7-hAlb, or the combination of the two, formulated as lipid nanoparticles (LNP) and injected intravenously (Page 83, Lines 24-25).
Regarding claims 28 and 29, Sahin teaches 20 μg gp70 RNA-LPX intravenously, and either 3 μg hAlb-hlL2, hlL7-hAlb, or the combination of the two, formulated as lipid nanoparticles (LNP) and injected intravenously (Page 83, Lines 24-25).
Regarding claims 30 and 31, Sahin teaches the medical preparation comprises: the RNA encoding extended-PK IL2; the RNA encoding extended-PK IL7; the RNA encoding a peptide or protein comprising an epitope for inducing an immune response against an antigen in a subject; and the immune checkpoint inhibitor as a kit wherein the medical preparation
comprises each RNA in a separate container (Page 6, Lines 18-30).
Regarding claim 37, Sahin teaches co-administering to the subject RNA encoding peptides or proteins used for vaccination and RNA encoding IL-2 attached to a pharmacokinetic
modifying group and/or RNA encoding IL-7 attached to a pharmacokinetic modifying group (Page 1, Abstract).
Claims 1, 10, 12, 13, 21, 22, 30, 31 and 37 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Gieseke et al (WO 2018/160540 A1).
Regarding claim 1, Gieseke teaches an IL-2 RNA composition comprising or consisting of the nucleotides of SEQ ID NOs: 12 or 13 (amino acid sequence of SEQ ID NO: 9), wherein the RNA comprises a 5' cap, a 5' UTR, a nucleic acid encoding IL-2, a 3' UTR, and a poly-A tail, in that order (Page 91, [0090-0097]).
Regarding claim 10, the phrase “an amino acid” is interpreted as any two or more consecutive amino acids with 100% identity not over the entire sequence.
Gieseke teaches IL-2 comprises the amino acid sequence of SEQ ID NO: 9 which is 100% identical to two or more consecutive amino acids of instant SEQ ID NO: 6 (Page 55, Table 1; See Appendix III).
Regarding claim 12, Gieseke teaches the codon-optimized sequences of the IL-2 sequence used as SEQ ID NO: 13 (Page 55, Table 1 and Page 90-91, [0088]).
Regarding claim 13, Gieseke teaches an IL-2 RNA composition comprising or consisting of the nucleotides of SEQ ID NOs: 12 or 13 (amino acid sequence of SEQ ID NO: 9), wherein the RNA comprises a 5' cap, a 5' UTR, a nucleic acid encoding IL-2, a 3' UTR, and a poly-A tail, in that order (Page 91, [0090-0097]).
Regarding claims 21 and 22, Gieseke teaches the poly(A) tail is at least 100 nucleotides in length wherein Gieseke teaches the poly(A) tail sequence as SEQ ID NO: 78 which is 100% identical to instant SEQ ID NO: 15 (Page 82, Table 1; See Appendix IV and Page 91, [0096]).
Regarding claims 30 and 31, Gieseke teaches the medical preparation comprises a kit, wherein the included RNAs may be in the same or separate vials and the medical preparation further comprising instructions for use of the composition for treating or preventing a solid tumor (Page 116, [00196]).
Regarding claim 37, Gieseke teaches a method for treating or preventing cancer, reducing the size of a tumor, preventing the reoccurrence of cancer in remission, or preventing cancer
metastasis in a subject comprising administering an IL-2 RNA composition comprising or consisting of the nucleotides of SEQ ID NOs: 12 or 13 (amino acid sequence of SEQ ID NO: 9), wherein the RNA comprises a 5' cap, a 5' UTR, a nucleic acid encoding IL-2, a 3' UTR, and a poly-A tail, in that order (Page 23 and Page 91, [0090-0097])
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA ROSE LIPPOLIS whose telephone number is (703)756-5450. The examiner can normally be reached Monday-Friday, 8:00am to 5:00pm EST.
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/ALEXANDRA ROSE LIPPOLIS/Examiner, Art Unit 1637
/CELINE X QIAN/Primary Examiner, Art Unit 1637