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 .
Claim Status
Claims 1-20 are examined on the merits.
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 pre-AIA 35 U.S.C. 112, except for the best mode requirement. 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 No. 63426882, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The application fails to provide support for the claims under examination, since there is no disclosure regarding SEQ ID NO 23. Therefore, the effective filling date of claim 8 is deemed to be November 21, 2023, the filling date of the application 18515479.
Claim Rejections - 35 USC § 112
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 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 requires a TEM1 mRNA that comprises a nucleotide sequence encoding a TEM1 protein or an immunogenic fragment for the induction of an immune response against TEM1 protein. The limitation “an immunogenic fragment” encompasses a large genus of fragments of the TEM1 protein, including fragments of different lengths, positions within the TEM1 protein, epitope content, provided that the fragment is capable of inducing an immune response. The claim does not limit the fragment to a particular amino acid sequence, length, epitope, domain.
Claim 8 requires a “TT mRNA that has a nucleotide sequence having at least 80% identity to SEQ ID NO: 23 or a portion of SEQ ID NO: 23”. The specification does not provide adequate support for the limitation “having at least 80% identity to SEQ ID NO: 23” “or a portion of SEQ ID NO: 23”. Under the broadest reasonable interpretation, the phrase “having at least 80% identity to SEQ ID NO: 23” “or a portion of SEQ ID NO: 23”” encompasses any nucleic acid sequence that includes the sequence of SEQ ID NO 23, including embodiments in which only a portion of SEQ ID NO 23 is present. For example, the claim language reads on sequences containing two or more consecutive nucleotides of SEQ ID NO 23. The specification does not provide adequate support for the limitation “having at least 80% identity to SEQ ID NO: 23”, this represent possession of a broader genus of nucleic acid sequences encompassed by the claimed 80% identity limitation. The specification does not disclose identify of which nucleotide substitutions, deletions or insertions are permissible while maintaining expression of a functional TT protein.
Claim 10 requires a “TEM1 mRNA operably linked to TT mRNA that has a nucleotide sequence having at least 80% identity to SEQ ID NO: 5”. The specification does not provide adequate support for the limitation “a nucleotide sequence having at least 80% identity to SEQ ID NO 5”, this represent possession of a broader genus of nucleic acid sequences encompassed by the claimed 80% identity limitation. The specification does not disclose identify of which nucleotide substitutions, deletions or insertions are permissible while maintaining expression of a functional TEM1-TT mRNA.
Claim 11 requires a “TEM1 mRNA that comprises a sequence that is at least 80% identity to SEQ ID NO: 2 or a portion of SEQ ID NO: 2. The specification does not provide adequate support for the limitation “comprises a nucleic acid sequence that is at least 80% identity to SEQ ID NO: 2 or a portion of SEQ ID NO: 2”. Under the broadest reasonable interpretation, the phrase “having at least 80% identity to SEQ ID NO: 2” “or a portion of SEQ ID NO: 2”” encompasses any nucleic acid sequence that includes the sequence of SEQ ID NO 2, including embodiments in which only a portion of SEQ ID NO 2 is present. For example, the claim language reads on sequences containing two or more consecutive nucleotides of SEQ ID NO 2. The specification does not provide adequate support for the limitation “comprises at least 80% identity to SEQ ID NO: 2”, this represent possession of a broader genus of nucleic acid sequences encompassed by the claimed 80% identity limitation. The specification does not disclose identify of which nucleotide substitutions, deletions or insertions are permissible while maintaining expression of a functional TEM1 protein.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof.
The specification envisions composition comprising a therapeutic component or a messenger ribonucleic acid (mRNA) and a delivery vehicle. The mRNA encodes: (1) a polypeptide comprising tumor endothelial marker-I or an immunogenic fragment thereof ("TEMI"); (ii) a polypeptide comprising tumor endothelial marker-I or an immunogenic fragment thereof that is operatively linked to N-terminal domain of fragment C of tetanus toxoid ("TT"); or (iii) a combination thereof. In some embodiments, the
mRNA comprises TEMI mRNA, TEMI mRNA that is linked to TT mRNA, or a combination thereof (e.g., paragraph 0009). The specification envisions a method for producing a composition comprising a delivery vehicle and an active therapeutic component or an mRNA disclosed herein. Typically, the mRNA encodes: (i) a polypeptide comprising tumor endothelial marker-I or an immunogenic fragment thereof ("TEM1"); (ii) a polypeptide comprising tumor endothelial marker-I or an immunogenic fragment thereof that is operatively linked to an N-terminal domain of fragment C of tetanus toxoid ("TEM1-TT"); or (iii) a combination thereof (e. g., paragraph 0014). The specification envisions the mRNA of the invention comprises at least about 80% identity, about 85% identity, 90% identity, 91 % identity, 92% identity, 93% identity, 94% identity, 95% identity, 96% identity, 97% identity, 98% identity, 99% identity, or I 00% identity to the mRNA sequence of SEQ ID NO: 2, 5, 8, or 11 (e.g., paragraph 0015). The specification envisions the produced mRNA encodes a protein having at least about 80%, at least about 85%, 80% identity, 85% identity, 90% identity, 91 % identity, 92% identity, 93% identity, 94% identity, 95% identity, 96% identity, 97% identity, 98% identity, 99% identity, or 100% identity to SEQ ID NO: 3, 6, 9, or 12 (e.g., paragraph 0017). The specification envisions that mRNA encoding TEMI comprises at least one nucleoside that is substituted with a modified nucleoside analog thereof. In some instances, said modified nucleoside analog comprises pseudouridine or N1-methylpseudouridine (e.g., paragraph 0018). The specification envisions cancer or tumor that is treated, inhibited, suppressed, decreased, or prevented from recurrence comprises lung cancer or tumor, melanoma, breast cancer or tumor, kidney cancer or tumor, cervical cancer or tumor, head and neck cancer or
tumor, breast cancer or tumor, an ano-genital cancer or tumor (e.g., paragraph 0024). The specification envisions producing mRNA for use as a vaccine. Construction of mRNA vaccines typically involves the insertion of the encoded oligonucleotide in a DNA template from where the mRNA is transcribed in vitro, isolated and used as an active vaccine component. The mRNA when administered to a subject, is incorporated into cells of the
subject and produces the desired antigen to stimulate the subject's immune response. Unlike DNA, mRNA only needs to reach the cytosol, where it can be transcribed into the antigen in vivo, using the cell machinery (e.g., paragraph 0025). The specification envisions a composition for inducing an immune response against a tumor endothelial marker-I (TEM1) protein, said composition comprising a delivery vehicle and a TEM1 mRNA that comprises a nucleotide sequence encoding a TEM1 protein or an immunogenic fragment thereof. In some embodiments, said delivery vehicle comprises a nanoparticle, a nanosome, a liposome, a biodegradable polymer complex, or a combination thereof. Still in other embodiments, said delivery vehicle comprises: a lipid nanoparticle (LNP); protamine; a positively charged oil-in-water cationic nanoemulsion; a
chemically modified dendrimer complexed with a lipid; a cationic polymer comprising a lipid component; a polysaccharide; or a cationic lipid, cholesterol, and optionally (i) a neutral lipid, (ii) a polyethylene-lipid, or (iii) a combination thereof (e.g., paragraph 0027). The specification envisions adjuvant comprises a TT mRNA that is operatively linked to said TEM1 mRNA, and wherein said TT mRNA comprises a nucleotide sequence that encodes a tetanus toxoid or an immunogenic fragment thereof. Still in other embodiments, said TT mRNA has a nucleotide sequence having at least 80% identity to SEQ ID NO: 23 or a portion of SEQ ID NO: 23 that produces an immunogenic fragment of tetanus toxoid (e.g., paragraph 0028). The specification envisions an mRNA of the disclosure encodes TEM1 protein or an immunogenic fragment thereof (i.e., an antigenic polypeptide thereof). As used herein, the term "an immunogenic fragment thereof' refers to a portion of the protein that elicits an immune response. Such fragments of TEM1 protein and tetanus toxoid are well known to one of ordinary skilled in the art or can be readily determined using standard technics and methods known to one skilled in the art. See, for example, Facciponte et al., J Clin Invest. 2014, 124(4), pp. 1497-1511. Briefly, a peptide of 15-mer, 20-mer, or 25-mer can be synthesized starting from amino acid residue 1, until the end, e.g., for 15-mer: 1-15, 2-16, 3-17, 4-18,…, 749-763, 750-764, and 751-765. These peptides can then be administered to, e.g., an animal model to determine CD8+ and
CD4+ T-cell response to determine immunogenic fragments (i.e., antigenic polypeptides). In some embodiments, the mRNA polynucleotide of the disclosure encodes TEM1 protein residues 516-530 (SEQ ID NO: 20), 511-525 (SEQ ID NO: 21), and/or 696-710 (SEQ ID NO: 22) (e.g., paragraph 0053). The specification envisions polynucleotides of the present disclosure, in some embodiments, are codon optimized. Codon optimization methods are known in the art and may be used as provided
herein. Codon optimization, in some embodiments, may be used to match codon frequencies in target and host organisms to ensure proper folding; bias GC content to increase mRNA stability or reduce secondary structures; minimize tandem repeat codons or base runs that may impair
gene construction or expression; customize transcriptional and translational control regions; insert or remove protein trafficking sequences; remove/add post translation modification sites in encoded protein (e.g. glycosylation sites); add, remove or shuffle protein domains; insert or delete restriction sites; modify ribosome binding sites and mRNA degradation sites; adjust
translational rates to allow the various domains of the protein to fold properly; or to reduce or eliminate problem secondary structures within the polynucleotide. Codon optimization tools, algorithms and services are known in the art. Exemplary services include, but are not limited to,
services from Gene Art (Life Technologies), DNA2.0 (Menlo Park CA) and/or proprietary methods. In some embodiments, the open reading frame (ORF) sequence is optimized using optimization algorithms (e.g., paragraph 0055). The specification envisions an mRNA of the disclosure encodes a polypeptide comprising TEM1 protein or an immunogenic fragment thereof that is operatively linked to N terminal domain of fragment C of tetanus toxoid ("TT") or an immunogenic fragment thereof. As used herein, the term "tetanus toxoid" or "TT" refers to N-terminal domain of fragment C of tetanus toxoid. In some embodiments, mRNA encodes a polypeptide comprising TEM1 protein or an immunogenic fragment thereof that is fused or linked to the first domain of the C fragment of the TT sequence (i.e., TT 865-1,120) at its carboxyl terminal (SEQ ID NO: 23) (e.g., paragraph 0054). The specification envisions an immunogenic fragment of TEM1 or TT protein is about 10 amino acids or longer, often about 15 amino acids or longer. Still in other embodiments, an
immunogenic fragment of TEM1 or TT protein is about 50 amino acids or less (e.g., paragraph 0059). The specification envisions A "polypeptide variant" is a molecule that differs in its amino acid sequence relative to a native sequence or a reference sequence. Amino acid sequence variants may possess substitutions, deletions, insertions, or a combination of any two or three of the foregoing, at certain positions within the amino acid sequence, as compared to a native sequence or a reference sequence. Ordinarily, variants possess at least 50% identity to a native sequence or a
reference sequence. In some embodiments, variants share at least 80% identity, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at
least about 99% identity with a native sequence or a reference sequence (e.g., paragraph 0060). The specification envisions a nucleotide sequence that is substantially homologous to a nucleotide sequence encoding TEM1 mRNA or TEM1 mRNA - TT mRNA can typically be isolated from a producer organism based on the information contained in the nucleotide sequence by means of introducing conservative or non-conservative substitutions, for example. Other examples of possible modifications include the insertion of one or more nucleotides in the sequence, the addition of one or more nucleotides in any of the ends of the sequence, or the deletion of one or more nucleotides in any end or inside the sequence (e.g., paragraph 0099).
The working examples disclose processes for producing a TEM1 mRNA vaccine (Full length TEM1): Design TEMI mRNA constructs, design and develop plasmid DNA with TEM1 mRNA constructs, Tern I-TT mRNA (Tumor Endothelial Marker I fused with Tetanus Toxoid), In-vitro transcription and purification of TEMI mRNA (e.g., paragraph 0172).
The working examples described in the specification only provides data for the in vitro synthesis of TEM1-TT mRNA (full length TEM1) and it is not representative of a very large variations allowed by the claims.
The specification discloses the full length TEM1 protein and three TEM1 peptides, residues 516-530 (SEQ ID NO: 20), 511-525 (SEQ ID NO: 21), and/or 696-710 (SEQ ID NO: 22). However, the disclosure of these particular peptides does not reasonably convey possession of the full claimed genus of immunogenic TEM1 fragments. The specification does not disclose representative fragments spanning the length of the TEM1 protein, fragments having different sizes, fragments containing different antigenic domains. Further, the specification does not provide common structural characteristics that would permit one of ordinary skills in the art distinguish immunogenic TEM1 fragments from non-immunogenic fragments throughout the claimed scope. For example, the specification does not identify conserved epitopes, define peptide length criteria, describe MHC-binding motifs. The number of possible TEM1 fragments encompassed by the claim is large and immunogenicity depends upon factors including peptide sequence, epitope accessibility, antigen processing and the relevant immune response.
Furthermore, the examples described in the specification does not meet the limitation of the rejected claims “having at least 80% identity to SEQ ID NO: 23” “or a portion of SEQ ID NO: 23”. “A nucleotide sequence having at least 80% identity to SEQ ID NO 5”. “Having a nucleic acid sequence of SEQ ID NO: 3” “or a sequence at least 80% identical to SEQ ID NO: 3”.
The state of the art with respect to using TEM1 for treatment of cancer disease is under developed and unpredictable. Facciponte et al. (J Clin Invest. 2014) teaches development of a DNA vaccine that expresses the full length mouse Tem1 gene fused to the first domain of the C fragment of the TT adjuvant (TT 865–1,120) (e.g., paragraph 1st, left column, page 1498). Facciponte teaches that Tem1-TT DNA vaccine suppresses tumor growth and induces CD3+ T cell tumor infiltration compare with single Tem 1 and TT constructs in all 3 tumor models (e.g., paragraph 1st, column left, page 1501; Fig. 3A). Facciponte teaches that to characterize the TEM1 sequences recognized by CD4+ and CD8+ T cells generated by the Tem1-TT vaccine, TEM1516–530 (ITSATHPARSPPYQP), induced a stronger CD8+ T cell response compared with minipools f and 5, corresponding to TEM1511–525 (GHKPGITSATHPARS) (e.g., paragraph 2nd, right column, page 1498; Fig. 2C). Facciponte teaches that full-length antigen rather than peptide, thus bypassing a major limitation of peptide-based cancer vaccines, namely MHC restriction (e.g., paragraph 2nd, left column, page 1507). Synthetic long peptides or RNA vaccines encoding long neoepitope peptides have shown immune responses directed against mutated epitopes delivered. Interestingly, the vast majority of these responses driven by RNA or SLPs have been MHC class II–restricted, CD4+ T cells, both in early clinical studies and in preclinical mouse studies. This induction of CD4+ T-cell responses occurs despite the fact that the epitopes were selected in silico for high MHCI binding affinity, as shown by Ott et al. (Nature, 2017) that discloses overlapping 15- to 16-mer assay peptides (ASP) spanning the entirety of each IMP and 9- to 10-mer peptides corresponding to each predicted class I epitope (EPT) were prepared and pooled to match the corresponding IMP pool (e.g., paragraph 4th, right column page 217; Fig. 2a). Ott teaches that vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively (e.g., abstract). Similarly, Sahin et al. (Nature, 20a7) teaches ten selected mutations per patient (five for patient P09) were engineered into two synthetic RNAs, each encoding five linker-connected 27 mer peptides with the mutation in position 14 (pentatope RNAs) (e.g., paragraph 1st, right column, page 222; Fig. 1b). Sahin teaches that the majority of neo-epitopes mounted exclusively CD4+ responses. A smaller fraction was recognized by CD8+ cytotoxic lymphocytes (CTLs) only. One-quarter showed concomitant CD4+ and CD8+ responses, recognizing different regions of the mutated 27mer sequence (e.g., paragraph 2nd, right column, page 222; Fig. 1e, Extended Data Fig. 2b,c, d). Kreiter et al. (Nature, 2015) teaches T-cell responses against the neo-epitopes, starting with those with a high likelihood of MHC I binding. Mice were vaccinated with synthetic 27 mer peptides, the responses against nearly all mutated epitopes (16/17, 95%) were CD4+ (e.g., paragraph 2nd, left column, page 1; Fig. 1b). Kreiter teaches that to exclude bias associated with the peptide format, this experiment was repeated using in vitro transcribed (IVT) mRNA encoding the neo-epitopes. Also, in this setting the majority of mutation-specific immune responses (10/12, ,80%) were conferred by CD4+ T cells
( e.g., paragraph 2nd, right column, page 1; Extended Data Fig. 1, Extended Data Table 1).
Thus, the prior art does not overcome the deficiency of the specification with regard to the description of a genus of TEM1 variants. The teachings are consistent with the prior art demonstrating the underdeveloped and unpredictability of the nature of the invention.
The claims encompasses significantly more than what is disclosed in the specification and does not satisfy the written description requirement under 35 U.S.C 112(a).
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1-20.
Claims 17-20 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 a method of inhibiting the growth of, decreasing the incidence, and/or recurrence of a tumor or a cancer cell in a subject, the method comprising administering to said subject a composition comprising a delivery vehicle and a TEM1 mRNA that encodes a TEM1 protein or an immunogenic fragment thereof, wherein the immunogenic fragment is selected from the group consisting of SEQ ID NO: 20, 21 and 22, does not reasonably provide enablement for treating cancer with other immunogenic fragments of TEM1. 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 the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404: Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex part Forman. 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 instant claim 17 is drawn to a method of inhibiting the growth of a tumor or cancer comprising administering the composition of claim 1 a TEM1 mRNA encoding a TEM1 protein or an immunogenic fragment to the subject. The nature of the claim is complicated, because the claim requires the outcome of treating cancer, yet the claim is drawn to administering TEM1 immunogenic fragment to the subject. The limitation “an immunogenic fragment” encompasses a large genus of fragments of the TEM1 protein, including fragments of different lengths, positions within the TEM1 protein, epitope content, provided that the fragment is capable of inducing an immune response. The claim does not limit the fragment to a particular amino acid sequence, length, epitope, domain.
The instant claim 18 is drawn to a method of treating a tumor or cancer comprising administering the composition of claim 1 a TEM1 mRNA encoding a TEM1 protein or an immunogenic fragment to the subject. The nature of the claim is complicated, because the claim requires the outcome of treating cancer, yet the claim is drawn to administering TEM1 immunogenic fragment to the subject. The limitation “an immunogenic fragment” encompasses a large genus of fragments of the TEM1 protein, including fragments of different lengths, positions within the TEM1 protein, epitope content, provided that the fragment is capable of inducing an immune response. The claim does not limit the fragment to a particular amino acid sequence, length, epitope, domain.
Breadth of the claim: The claims encompass a method for treating cancer comprising administering to the subject a delivery vehicle and a TEM1 mRNA that comprises a nucleotide sequence encoding a TEM1 protein or an immunogenic fragment thereof. The claims are broad with respect to the treatment of cancer with any TEM1 immunogenic fragment. Furthermore, the claims broadly encompass the administration of any immunogenic fragment. 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 envisions composition comprising a therapeutic component or a messenger ribonucleic acid (mRNA) and a delivery vehicle. The mRNA encodes: (1) a polypeptide comprising tumor endothelial marker-I or an immunogenic fragment thereof ("TEMI"); (ii) a polypeptide comprising tumor endothelial marker-I or an immunogenic fragment thereof that is operatively linked to N-terminal domain of fragment C of tetanus toxoid ("TT"); or (iii) a combination thereof. In some embodiments, the mRNA comprises TEMI mRNA, TEMI mRNA that is linked to TT mRNA, or a combination thereof (e.g., paragraph 0009). The specification envisions a method for producing a composition comprising a delivery vehicle and an active therapeutic component or an mRNA disclosed herein. Typically, the mRNA encodes: (i) a polypeptide comprising tumor endothelial marker-I or an immunogenic fragment thereof ("TEM1"); (ii) a polypeptide comprising tumor endothelial marker-I or an immunogenic fragment thereof that is operatively linked to an N-terminal domain of fragment C of tetanus toxoid ("TEM1-TT"); or (iii) a combination thereof (e. g., paragraph 0014). The specification envisions the mRNA of the invention comprises at least about 80% identity, about 85% identity, 90% identity, 91 % identity, 92% identity, 93% identity, 94% identity, 95% identity, 96% identity, 97% identity, 98% identity, 99% identity, or I 00% identity to the mRNA sequence of SEQ ID NO: 2, 5, 8, or 11 (e.g., paragraph 0015). The specification envisions the produced mRNA encodes a protein having at least about 80%, at least about 85%, 80% identity, 85% identity, 90% identity, 91 % identity, 92% identity, 93% identity, 94% identity, 95% identity, 96% identity, 97% identity, 98% identity, 99% identity, or 100% identity to SEQ ID NO: 3, 6, 9, or 12 (e.g., paragraph 0017). The specification envisions that mRNA encoding TEMI comprises at least one nucleoside that is substituted with a modified nucleoside analog thereof. In some instances, said modified nucleoside analog comprises pseudouridine or N1-methylpseudouridine (e.g., paragraph 0018). The specification envisions cancer or tumor that is treated, inhibited, suppressed, decreased, or prevented from recurrence comprises lung cancer or tumor, melanoma, breast cancer or tumor, kidney cancer or tumor, cervical cancer or tumor, head and neck cancer or tumor, breast cancer or tumor, an ano-genital cancer or tumor (e.g., paragraph 0024). The specification envisions producing mRNA for use as a vaccine. Construction of mRNA vaccines typically involves the insertion of the encoded oligonucleotide in a DNA template from where the mRNA is transcribed in vitro, isolated and used as an active vaccine component. The mRNA when administered to a subject, is incorporated into cells of the
subject and produces the desired antigen to stimulate the subject's immune response. Unlike DNA, mRNA only needs to reach the cytosol, where it can be transcribed into the antigen in vivo, using the cell machinery (e.g., paragraph 0025). The specification envisions a composition for inducing an immune response against a tumor endothelial marker-I (TEM1) protein, said composition comprising a delivery vehicle and a TEM1 mRNA that comprises a nucleotide sequence encoding a TEM1 protein or an immunogenic fragment thereof. In some embodiments, said delivery vehicle comprises a nanoparticle, a nanosome, a liposome, a biodegradable polymer complex, or a combination thereof. Still in other embodiments, said delivery vehicle comprises: a lipid nanoparticle (LNP); protamine; a positively charged oil-in-water cationic nanoemulsion; a
chemically modified dendrimer complexed with a lipid; a cationic polymer comprising a lipid component; a polysaccharide; or a cationic lipid, cholesterol, and optionally (i) a neutral lipid, (ii) a polyethylene-lipid, or (iii) a combination thereof (e.g., paragraph 0027). The specification envisions adjuvant comprises a TT mRNA that is operatively linked to said TEM1 mRNA, and wherein said TT mRNA comprises a nucleotide sequence that encodes a tetanus toxoid or an immunogenic fragment thereof. Still in other embodiments, said TT mRNA has a nucleotide sequence having at least 80% identity to SEQ ID NO: 23 or a portion of SEQ ID NO: 23 that produces an immunogenic fragment of tetanus toxoid (e.g., paragraph 0028). The specification envisions an mRNA of the disclosure encodes TEM1 protein or an immunogenic fragment thereof (i.e., an antigenic polypeptide thereof). As used herein, the term "an immunogenic fragment thereof' refers to a portion of the protein that elicits an immune response. Such fragments of TEM1 protein and tetanus toxoid are well known to one of ordinary skilled in the art or can be readily determined using standard technics and methods known to one skilled in the art. See, for example, Facciponte et al., J Clin Invest. 2014, 124(4), pp. 1497-1511. Briefly, a peptide of 15-mer, 20-mer, or 25-mer can be synthesized starting from amino acid residue 1, until the end, e.g., for 15-mer: 1-15, 2-16, 3-17, 4-18,…, 749-763, 750-764, and 751-765. These peptides can then be administered to, e.g., an animal model to determine CD8+ and CD4+ T-cell response to determine immunogenic fragments (i.e., antigenic polypeptides). In some embodiments, the mRNA polynucleotide of the disclosure encodes TEM1 protein residues 516-530 (SEQ ID NO: 20), 511-525 (SEQ ID NO: 21), and/or 696-710 (SEQ ID NO: 22) (e.g., paragraph 0053). The specification envisions polynucleotides of the present disclosure, in some embodiments, are codon optimized. Codon optimization methods are known in the art and may be used as provided
herein. Codon optimization, in some embodiments, may be used to match codon frequencies in target and host organisms to ensure proper folding; bias GC content to increase mRNA stability or reduce secondary structures; minimize tandem repeat codons or base runs that may impair
gene construction or expression; customize transcriptional and translational control regions; insert or remove protein trafficking sequences; remove/add post translation modification sites in encoded protein (e.g. glycosylation sites); add, remove or shuffle protein domains; insert or delete restriction sites; modify ribosome binding sites and mRNA degradation sites; adjust
translational rates to allow the various domains of the protein to fold properly; or to reduce or eliminate problem secondary structures within the polynucleotide. Codon optimization tools, algorithms and services are known in the art. Exemplary services include, but are not limited to,
services from Gene Art (Life Technologies), DNA2.0 (Menlo Park CA) and/or proprietary methods. In some embodiments, the open reading frame (ORF) sequence is optimized using optimization algorithms (e.g., paragraph 0055). The specification envisions an mRNA of the disclosure encodes a polypeptide comprising TEM1 protein or an immunogenic fragment thereof that is operatively linked to N terminal domain of fragment C of tetanus toxoid ("TT") or an immunogenic fragment thereof. As used herein, the term "tetanus toxoid" or "TT" refers to N-terminal domain of fragment C of tetanus toxoid. In some embodiments, mRNA encodes a polypeptide comprising TEM1 protein or an immunogenic fragment thereof that is fused or linked to the first domain of the C fragment of the TT sequence (i.e., TT 865-1,120) at its carboxyl terminal (SEQ ID NO: 23) (e.g., paragraph 0054). The specification envisions an immunogenic fragment of TEM1 or TT protein is about 10 amino acids or longer, often about 15 amino acids or longer. Still in other embodiments, an immunogenic fragment of TEM1 or TT protein is about 50 amino acids or less (e.g., paragraph 0059). The specification envisions A "polypeptide variant" is a molecule that differs in its amino acid sequence relative to a native sequence or a reference sequence. Amino acid sequence variants may possess substitutions, deletions, insertions, or a combination of any two or three of the foregoing, at certain positions within the amino acid sequence, as compared to a native sequence or a reference sequence. Ordinarily, variants possess at least 50% identity to a native sequence or a
reference sequence. In some embodiments, variants share at least 80% identity, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at
least about 99% identity with a native sequence or a reference sequence (e.g., paragraph 0060). The specification envisions a nucleotide sequence that is substantially homologous to a nucleotide sequence encoding TEM1 mRNA or TEM1 mRNA - TT mRNA can typically be isolated from a producer organism based on the information contained in the nucleotide sequence by means of introducing conservative or non-conservative substitutions, for example. Other examples of possible modifications include the insertion of one or more nucleotides in the sequence, the addition of one or more nucleotides in any of the ends of the sequence, or the deletion of one or more nucleotides in any end or inside the sequence (e.g., paragraph 0099).
The working examples disclose processes for producing a TEM1 mRNA vaccine (Full length TEM1): Design TEMI mRNA constructs, design and develop plasmid DNA with TEM1 mRNA constructs, Tern I-TT mRNA (Tumor Endothelial Marker I fused with Tetanus Toxoid), In-vitro transcription and purification of TEMI mRNA (e.g., paragraph 0172).
The specification discloses the full length TEM1 protein and three TEM1 peptides, residues 516-530 (SEQ ID NO: 20), 511-525 (SEQ ID NO: 21), and/or 696-710 (SEQ ID NO: 22). However, the disclosure of these particular peptides does not reasonably convey possession of the full claimed genus of immunogenic TEM1 fragments. The specification does not disclose representative fragments spanning the length of the TEM1 protein, fragments having different sizes, fragments containing different antigenic domains. Further, the specification does not provide common structural characteristics that would permit one of ordinary skills in the art distinguish immunogenic TEM1 fragments from non-immunogenic fragments throughout the claimed scope. For example, the specification does not identify conserved epitopes, define peptide length criteria, describe MHC-binding motifs. The number of possible TEM1 fragments encompassed by the claim is large and immunogenicity depends upon factors including peptide sequence, epitope accessibility, antigen processing and the relevant immune response.
Predictability and state of the art: The state of the art with respect to using TEM1 immunogenic fragments for treatment of cancer disease is under developed and unpredictable. Facciponte et al. (J Clin Invest. 2014) teaches development of a DNA vaccine that expresses the full length mouse Tem1 gene fused to the first domain of the C fragment of the TT adjuvant (TT 865–1,120) (e.g., paragraph 1st, left column, page 1498). Facciponte teaches that Tem1-TT DNA vaccine suppresses tumor growth and induces CD3+ T cell tumor infiltration compare with single Tem 1 and TT constructs in all 3 tumor models (e.g., paragraph 1st, column left, page 1501; Fig. 3A). Facciponte teaches that to characterize the TEM1 sequences recognized by CD4+ and CD8+ T cells generated by the Tem1-TT vaccine, TEM1516–530 (ITSATHPARSPPYQP), induced a stronger CD8+ T cell response compared with minipools f and 5, corresponding to TEM1511–525 (GHKPGITSATHPARS) (e.g., paragraph 2nd, right column, page 1498; Fig. 2C). Facciponte teaches that full-length antigen rather than peptide, thus bypassing a major limitation of peptide-based cancer vaccines, namely MHC restriction (e.g., paragraph 2nd, left column, page 1507). Buonaguro et al. (Frontiers in Immunology, 2023) teaches that the sequence length of peptide vaccines is important to promote a strong immunogenic response. Typically, peptides can be either short (8– 11 amino acids) or long (11– 30 amino acids) for presentation in MHC class I or II molecules, respectively (e.g., paragraph 2nd, right column, page 3). Buonaguro teaches that an important condition for success of a cancer vaccine is the induction of a robust and sustained of both specific CD8+ and CD4+ T cells response as well as the increase in the CD4+:Treg ratio, to counteract the immunosuppressive TME (e.g., paragraph 7th, right column, page 3). Synthetic long peptides or RNA vaccines encoding long neoepitope peptides have shown immune responses directed against mutated epitopes delivered. Interestingly, the vast majority of these responses driven by RNA or SLPs have been MHC class II–restricted, CD4+ T cells, both in early clinical studies and in preclinical mouse studies. This induction of CD4+ T-cell responses occurs despite the fact that the epitopes were selected in silico for high MHCI binding affinity, as shown by Ott et al. (Nature, 2017) that discloses overlapping 15- to 16-mer assay peptides (ASP) spanning the entirety of each IMP and 9- to 10-mer peptides corresponding to each predicted class I epitope (EPT) were prepared and pooled to match the corresponding IMP pool (e.g., paragraph 4th, right column page 217; Fig. 2a). Ott teaches that vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively (e.g., abstract). Similarly, Sahin et al. (Nature, 20a7) teaches ten selected mutations per patient (five for patient P09) were engineered into two synthetic RNAs, each encoding five linker-connected 27 mer peptides with the mutation in position 14 (pentatope RNAs) (e.g., paragraph 1st, right column, page 222; Fig. 1b). Sahin teaches that the majority of neo-epitopes mounted exclusively CD4+ responses. A smaller fraction was recognized by CD8+ cytotoxic lymphocytes (CTLs) only. One-quarter showed concomitant CD4+ and CD8+ responses, recognizing different regions of the mutated 27mer sequence (e.g., paragraph 2nd, right column, page 222; Fig. 1e, Extended Data Fig. 2b,c, d). Kreiter et al. (Nature, 2015) teaches T-cell responses against the neo-epitopes, starting with those with a high likelihood of MHC I binding. Mice were vaccinated with synthetic 27 mer peptides, the responses against nearly all mutated epitopes (16/17, 95%) were CD4+ (e.g., paragraph 2nd, left column, page 1; Fig. 1b). Kreiter teaches that to exclude bias associated with the peptide format, this experiment was repeated using in vitro transcribed (IVT) mRNA encoding the neo-epitopes. Also, in this setting the majority of mutation-specific
immune responses (10/12, ,80%) were conferred by CD4+ T cells
( e.g., paragraph 2nd, right column, page 1; Extended Data Fig. 1, Extended Data Table 1).
Thus, the teachings of the post-filing art are consistent with the prior art demonstrating the underdeveloped and unpredictable nature of the invention.
Amount of experimentation necessary: Cancer is highly complex with different etiologies and mRNA vaccines based therapy are still in developmental stages. It would require large amount of experimentation to make use of TEM1 immunogenic fragments for treatment of cancer. For a specific mRNA encoding a TEM1 immunogenic fragment vaccine to be efficacious it would require to address: (1) the half-life of the mRNA should be carefully adjusted to prevent chronic antigen stimulation of T and B cells, (2) the type of lipid nanoparticle to avoid an inflammatory response or to avoid off-target accumulation in the liver (3) the type of MHC response induced by the TEM1 immunogenic fragments.
In view 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 17-20 are not considered to be fully enabled by the instant disclosure.
In view of the breadth of the claims, the lack of guidance provided by the specification, the lack of the predictability of the art to which the invention pertains, undue amount of experimentation would be required to make and use the claimed invention to treat cancer in a subject, with a reasonable expectation of success. Because the specification does not contain a detailed description of how to make and use the method based on administration of lipid nanoparticles comprising the claimed mRNA encoding the TEM1 immunogenic fragment peptides, according to the invention, and absent working examples that provide evidence that is reasonably predictive of the ability of treating cancer disease in subjects, the claims are not enabled commensurate in scope with the claimed invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-7, 9, 11-20 are rejected under 35 U.S.C. 103 as being unpatentable over Coukos et al. (“Coukos”, US 9,290,556 B2) in view of De Smedt et al. (“De Smedt”, WO 2020/058239 A1).
Regarding claims 1, 12, Coukos teaches vaccine comprising a nucleic acid construct comprising a nucleic acid sequence encoding a tumor vasculature marker (TVM), wherein said vaccine can abrogate growth of a tumor whose vasculature expresses said TVM (e.g., line 57, column 5). Coukos teaches the TVM is tumor endothelial marker (TEM)-1 (e.g., line 46, column 6).
Regarding claims 6-7, 9, Coukos teaches the vaccine further comprises an adjuvant. The nucleic acid construct further comprises a nucleic acid sequence encoding an adjuvant. The adjuvant is the N-terminal domain of fragment C of tetanus toxoid (e.g., line 63, column 94). Coukos teaches that the nucleic acid construct comprises a nucleic acid sequence encoding a tumor endothelial marker (TEM)-1 protein or variant thereof fused in frame to a nucleic acid sequence encoding the N-terminal domain of fragment C of tetanus toxoid (e.g., line 1, column 95).
Coukos teaches SEQ ID NO 38 which has 73.9% identity to SEQ ID NO 5 of the instant claims.
Regarding claim 11, Coukos teaches SEQ ID NO 38 which has 100% identity to SEQ ID NO 2 of the instant claims.
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Regarding claim 13, Coukos teaches SEQ ID NO 39 which has a 100% identity with SEQ ID NO 3 of the instant claims.
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Regarding claim 17, Coukos teaches methods of immunizing a subject against a tumor, inhibiting tumor growth, inhibiting tumor recurrence, treating, suppressing the growth of, or decreasing the incidence of a tumor, overcoming tolerance to a tumor vasculature marker (TVM) in a subject comprising the step of administering a vaccine comprising a TVM or a nucleic acid encoding a TVM and related vaccines (e.g., abstract). Coukos teaches the TVM is tumor endothelial marker (TEM)-1 (e.g., line 46, column 6).
Regarding claim 18, Coukos teaches "treating" refers to either therapeutic treatment or prophylactic or preventative measures, wherein the object is to prevent or lessen the targeted pathologic condition or disorder as described herein above (e.g., line 22, column 122). Coukos teaches therapeutic administration of TEM1-Dom DNA vaccine results in a significant Lewis lung carcinoma tumor growth impairment (e.g., line 42, column 5; Fig. 18).
Regarding claims 19-20, Coukos teaches the cancer treated by a method is, a cervical cancer tumor, breast cancer tumor, ano-genital cancer, melanoma, ovarian cancer (e.g., line 18, column 82).
Coukos does not teach the administration of TEM1 mRNA, as required by the instant claims. Coukos does not teach the delivery vehicle as a lipid nanoparticle as required by the instant claims. Coukos does not teach the modified nucleotide N1- methylpseudouridine (m1Ψ). However, this is cured by De Smedt.
De Smedt teaches a method and composition for optimized intracellular delivery of nucleic acids, in particular mRNA (e.g., abstract). De Smedt teaches the mRNA as provided herein encodes an antigen or polypeptide of interest, in particular a tumor specific antigen (e.g., line 28, page 3). De Smedt teaches a method of delivering an mRNA to a cell (e.g., a mammalian cell) involving administering to a subject (e.g., a mammal) a nanoparticle composition including (i) a lipid component, (ii) a mRNA and (iii) an iNKT cell agonist, in which administering involves contacting the cell with the nanoparticle composition, whereby the mRNA
and glycolipid antigen are delivered to the cell. (e.g., line 33, page 4). De Smedt teaches lipid nanoparticles composed with ionizable cationic lipids, and other "helper" lipids, such as a phospholipid, cholesterol and a poly(ethylene glycol) (PEG) lipid, are considered to be the most
clinically advanced technology for RNA therapeutics (e.g., line 16, page 39). De Smedt teaches the incorporation of modified nucleotides N1- methylpseudouridine (m1Ψ) that improves the mRNA stability and translation, resulting in higher and more sustainable levels of mRNA expression. This enhanced mRNA expression is advantageous in the development of vaccines, since the resulting increased antigen presentation is shown to be beneficial for the induction of long-lived antibody and helper T cell responses, including the formation of follicular T cells (e.g., line 1, page 2). De Smedt teaches that by using nucleoside-modified mRNA, the intracellular mRNA recognition by TLR3, TLR7, and TLR8 can be reduced, which makes the mRNA 'immunosilent' and avoids the release of type I IFNs. Furthermore, nucleotide modifications can render the RNA more resistant to enzymatic degradation (e.g., line 2, page 16).
Based on these teachings, it would have been prima facie obvious to
one of ordinary skill in the art, before the effective filing date of the claimed
invention, to substitute the DNA vaccine encoding TEM1 or TEM1-TT taught by Coukos with the mRNA format encoding TEM1-TT, lipid nanoparticle and nucleotide modification N1- methylpseudouridine (m1Ψ) that improves the mRNA stability and translation taught by De Smedt; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a method comprising a lipid nanoparticle carrying a nucleotide-modified TEM1-TT mRNA to treat cancer.
One of ordinary skill in the art before the effective filing date of the
invention would have been motivated to develop a method for treatment of cancer comprising a lipid nanoparticle carrying a nucleotide-modified (N1- methylpseudouridine (m1Ψ)) TEM1-TT mRNA yielding more stable mRNA with improved translation capacity and to make the mRNA TEM1-TT immunosilent avoiding the release of type I IFNs.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Coukos et al. (“Coukos”, US 9,290,556 B2) and De Smedt et al. (“De Smedt”, WO 2020/058239 A1) as applied to claim 1-7, 9, 11-16 above, and further in view of La Monica et al. (“La Monica”, US 8,188,244 B2).
Coukos and De Smedt do not teach SEQ ID NO 23, as required by the instant claim 8. However, this is cured by La Monica.
La Monica teaches polynucleotides encoding fusion proteins wherein the fusion proteins comprise at least a portion of the tumor associated polypeptide carcinoembryonic antigen, fused to a substantial portion of an immunoenhancing element, such as a bacterial toxin (tetanus toxin fragment) (e.g., line 48, column 2) teaches SEQ ID NO 47 which has 100% identity with SEQ ID NO 23 of the instant claims.
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Based on these teachings, it would have been prima facie obvious to
one of ordinary skill in the art, before the effective filing date of the claimed invention, to substitute the tetanus toxoid (TT) in the mRNA TEM1-TT vaccine encoding TEM1-TT taught by Coukos and De Smedt with the SEQ ID NO 47 encoding the immunoenhancing element tetanus toxoid taught by La Monica; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a method comprising a lipid nanoparticle carrying a nucleotide-modified TEM1-tetanus toxoid mRNA to treat cancer.
One of ordinary skill in the art before the effective filing date of the
invention would have been motivated to develop a method for treatment of cancer comprising a lipid nanoparticle carrying a nucleotide-modified TEM1-tetanus toxoid mRNA to enhance the immune response against TEM1.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-9, 11-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5 of U.S. Patent No. 9290556 in view of De Smedt et al. (“De Smedt”, WO 2020/058239 A1), La Monica et al. (“La Monica”, US 8,188,244 B2) and Coukos et al. (“Coukos”, US 10,874,728 B2).
Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to vaccine comprising a nucleic acid encoding a tumor endothelial marker (TEM1).
Claim 1 of the ‘556 patent is drawn to the product of “A vaccine comprising a nucleic acid construct comprising a nucleic acid sequence encoding a tumor endothelial marker (TEM)-1 protein or immunogenic fragment thereof fused in frame to a nucleic acid sequence encoding the N-terminal domain of fragment C of tetanus toxoid (DOM)”. Claim 1 of the ‘556 does not require mRNA to produce TEM1-TT protein and does not require a lipid nanoparticle as delivery system. However, De Smedt teaches a method and composition for optimized intracellular delivery of nucleic acids, in particular mRNA (e.g., abstract). De Smedt teaches the mRNA encodes an antigen or polypeptide of interest, in particular a tumor specific antigen (e.g., line 28, page 3). De Smedt teaches a method of delivering an mRNA to a cell (e.g., a mammalian cell) involving administering to a subject (e.g., a mammal) a nanoparticle composition including (i) a lipid component, (ii) a mRNA (e.g., line 33, page 4). De Smedt teaches the incorporation of modified nucleotides N1- methylpseudouridine (m1Ψ) that improves the mRNA stability and translation, resulting in higher and more sustainable levels of mRNA expression (e.g., line 1, page 2). It would have been obvious to one of ordinary skills in the art to substitute the DNA encoding TEM1-TT by a mRNA encoding TEM1-TT to achieve the outcome of a vaccine comprising a mRNA encoding TEM1-TT in the “556 patent. Accordingly, instant claims 1-7, 9, 12, 14-16 are not patentably distinct from claim 1 of the “556 patent.
Claim 4 of the ‘556 patent depends from claim 1 and limits method of immunizing a subject against a tumor, comprising administering to said subject the vaccine. Accordingly, the instant claims 17-18 are not patentably distinct from claim 4 of the ‘556 patent.
Claim 5 of the ‘556 patent depends of claim 4 and limits the tumor is selected from the group consisting of an ovarian tumor, a renal tumor 15
and a breast tumor. Accordingly, claim 5 of the ‘556 anticipates instant claims 19-20.
‘556 does not teach SEQ ID NO 23 as required by the instant claim 8. ‘556 does not teach SEQ ID NO 2, as required by the instant claim 11. ‘556 does not teach SEQ ID NO 3, as required by instant claim 13. However, this is cured by La Monica and Coukos.
Regarding claim 8, La Monica teaches polynucleotides encoding fusion proteins wherein the fusion proteins comprise at least a portion of the tumor associated polypeptide carcinoembryonic antigen, fused to a substantial portion of an immunoenhancing element, such as a bacterial toxin (tetanus toxin fragment) (e.g., line 48, column 2) teaches SEQ ID NO 47 which has 100% identity with SEQ ID NO 23 of the instant claims.
Regarding claim 11, Coukos teaches SEQ ID NO 38 which has 100% identity to SEQ ID NO 2 of the instant claims.
Regarding claim 13, Coukos teaches SEQ ID NO 39 which has a 100% identity with SEQ ID NO 3 of the instant claims.
Based on these teachings, it would have been prima facie obvious to
one of ordinary skill in the art, before the effective filing date of the claimed
invention, to combine the teachings of “556 patent – an mRNA encoding TEM1-TT with modified uridine, with the teachings of Coukos a TEM1 mRNA of SEQ ID NO 38, a TIM1 protein of SEQ ID NO 39, with the teachings of La Monica -TT mRNA of SEQ ID NO 47; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a lipid nanoparticle carrying a nucleotide-modified TEM1-TT mRNA to treat cancer.
One of ordinary skill in the art before the effective filing date of the
invention would have been motivated to develop an mRNA vaccine comprising a lipid nanoparticle carrying a nucleotide-modified (N1- methylpseudouridine (m1Ψ)) TEM1-tetanus toxoid mRNA to improves the mRNA stability, translation and to enhance the immune response to TEM1 protein for treatment of cancer.
Claims 1-9, 11-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10874728 in view of La Monica et al. (“La Monica”, US 8,188,244 B2), Coukos et al. (“Coukos”, US 9,290,556 B2)
Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to a method of inhibiting the growth of, suppressing the incidence and/or recurrence of a tumor in a subject with the administration of a nucleic acid encoding a tumor endothelial marker (TEM1) fused to a N-terminal domain of fragment C of tetanus toxoid.
Claim 1 of the ‘728 patent is drawn to the steps of “(d) contacting said subject with a polypeptide comprising said TEM-1 protein or an immunogenic fragment thereof comprising an extracellular domain of TEM-1, said TEM-1 protein or said immunogenic fragment thereof fused to the N-terminal domain of fragment C of tetanus toxoid (DOM), or with a nucleic acid construct encoding said TEM-1 protein or said immunogenic
fragment thereof, said nucleic acid fused in frame to a nucleic acid sequence encoding the N-terminal domain of fragment C of tetanus toxoid (DOM), to induce an immune response against said TEM-1”. Claim 1 of the ‘728 does not require mRNA to produce TEM1-TT protein and does not require a lipid nanoparticle as delivery system. However, De Smedt teaches a method and composition for optimized intracellular delivery of nucleic acids, in particular mRNA (e.g., abstract). De Smedt teaches the mRNA encodes an antigen or polypeptide of interest, in particular a tumor specific antigen (e.g., line 28, page 3). De Smedt teaches a method of delivering an mRNA to a cell (e.g., a mammalian cell) involving administering to a subject (e.g., a mammal) a nanoparticle composition including (i) a lipid component, (ii) a mRNA (e.g., line 33, page 4). De Smedt teaches the incorporation of modified nucleotides N1- methylpseudouridine (m1Ψ) that improves the mRNA stability and translation, resulting in higher and more sustainable levels of mRNA expression (e.g., line 1, page 2). It would have been obvious to one of ordinary skills in the art to substitute the DNA encoding TEM1-TT by a mRNA encoding TEM1-TT to achieve the outcome of a method of inhibiting the growth of, decreasing the incidence and/or recurrence of a tumor in a subject in the “728 patent. Accordingly, instant claims 1-7, 14-18. are not patentably distinct from claim 1 of the “728 patent.
‘728 does not teach SEQ ID NO 23 as required by the instant claim 8. ‘728 does not teach SEQ ID NO 2, as required by the instant claim 11. ‘728 does not teach SEQ ID NO 3, as required by instant claim 13. ‘728 does not teach cancer or tumor comprises lung cancer or tumor, melanoma, breast cancer or tumor, kidney cancer or tumor, cervical cancer or tumor, head and neck cancer or tumor, breast cancer or tumor, an ano-genital cancer or tumor, as required by claims 19-20. However, this is cured by La Monica and Coukos.
Regarding claim 8, La Monica teaches polynucleotides encoding fusion proteins wherein the fusion proteins comprise at least a portion of the tumor associated polypeptide carcinoembryonic antigen, fused to a substantial portion of an immunoenhancing element, such as a bacterial toxin (tetanus toxin fragment) (e.g., line 48, column 2) teaches SEQ ID NO 47 which has 100% identity with SEQ ID NO 23 of the instant claims.
Regarding claim 11, Coukos teaches SEQ ID NO 38 which has 100% identity to SEQ ID NO 2 of the instant claims.
Regarding claim 13, Coukos teaches SEQ ID NO 39 which has a 100% identity with SEQ ID NO 3 of the instant claims.
Regarding claims 19-20, Coukos teaches the cancer treated by a method is, a cervical cancer tumor, breast cancer tumor, ano-genital cancer, melanoma, ovarian cancer (e.g., line 18, column 82).
Based on these teachings, it would have been prima facie obvious to
one of ordinary skill in the art, before the effective filing date of the claimed
invention, to combine the teachings “728 patent – a method of inhibiting the growth of a tumor in a subject with an mRNA encoding TEM1-TT with modified uridine, with the teachings of Coukos a TEM1 mRNA of SEQ ID NO 38, a TIM1 protein of SEQ ID NO 39, with the teachings of La Monica -TT mRNA of SEQ ID NO 47; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of a method of inhibiting the growth of a tumor in a subject with a lipid nanoparticle carrying a nucleotide-modified TEM1-TT mRNA.
One of ordinary skill in the art before the effective filing date of the
invention would have been motivated to develop a method of inhibiting the growth of tumor comprising a lipid nanoparticle carrying a nucleotide-modified (N1- methylpseudouridine (m1Ψ)) TEM1-tetanus toxoid mRNA to improve the mRNA stability, translation and to enhance the immune response against TEM1 protein.
Conclusion
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/JULIO WASHINGTON GOMEZ RODRIGUEZ/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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