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 .
DETAILED ACTION
Status of the Claims
Claims 29-42 are pending and the subject of this NON-FINAL Office Action. This is the first action on the merits.
Note on Claims
The claims seem to be directed to the application of mRNA display to cyclotides, which is not allowable, as explained below. In contrast, the specification describes “proteinaceous coagulation factor XIIa (FXIIa) inhibitors and their use for treating or inhibiting the development of a condition in which inhibiting FXIIa stimulates or effects treatment or inhibition of the development of the condition” (Abstract). This seems to be the invention, rather than the conventional mRNA display technique applied to cyclotides to discover new cyclotide iterations with drug/treatment potential.
Claim Rejections - 35 USC § 112- Indefiniteness
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.
Claims 29-42 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The metes and bounds of the claims are so unclear and confusing that the Office cannot determine if the instant claims are patentable because it would require the Office to speculate as to the metes and bounds of the instant claims. See MPEP § 2173.06 (“Second, where there is a great deal of confusion and uncertainty as to the proper interpretation of the limitations of a claim, it would not be proper to reject such a claim on the basis of prior art. As stated in In re Steele, 305 F.2d 859, 134 USPQ 292 (CCPA 1962), a rejection under 35 U.S.C. 103 should not be based on considerable speculation about the meaning of terms employed in a claim or assumptions that must be made as to the scope of the claims.”). Specifically, the metes and bounds of the following potentially critical limitation are unclear: “preparing an mRNA library based on a disulfide rich peptide scaffold.” First, it is unclear how an mRNA library is “based on” a peptide scaffold. An mRNA is a ribonucleic acid; whereas a peptide is a string of amino acids; yet the relationship between them (“based on”) is not clear from this clause. The relationship could be mRNA encoding the peptide; or mRNA with attached peptide. Applicants are encouraged to amend the claim to recite the structure of the library (e.g. mRNA encoding peptide).
Second, and most important, the metes and bounds of “disulfide rich peptide scaffold” are unclear. Based on a reading of Applicants’ specification, they believe this limitation is novel and non-obvious (this is debatable). Yet, neither the specification nor the claims clearly define “disulfide rich,” much less in the context of the mRNA sequence. For example, neither the specification nor the claims provide a minimum number of disulfide bonds in a peptide, or number versus amino acid length, that meet the minimum threshold of “disulfide rich.” Applicants must provide a specific minimum number, or range, of disulfide bonds per peptide, or per amino acid.
Finally, Applicants’ invention seems to be the “discovery of proteinaceous molecules derived from the cyclotide, Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II) that inhibit FXIIa activity” (Spec., para. 0008). Thus, Applicants are strongly encouraged to amend the claims to recite this invention. As an example, claim 1 could be amended to recite: “preparing an mRNA library comprising sequences that encode cyclotidesee Baggio et al, Identification of epitope-like consensus motifs using mRNA display, J. Mol. Recognit., 15: 126-134. https://doi.org/10.1002/jmr.567, 05/10/2002; Yamaguchi et al, cDNA display: a novel screening method for functional disulfide-rich peptides by solid-phase synthesis and stabilization of mRNA–protein fusions, Nucleic Acids Research, Volume 37, Issue 16, 1 September 2009, Page e108, https://doi.org/10.1093/nar/gkp514; Hipolito et al, A Macrocyclic Peptide that Serves as a Cocrystallization Ligand and Inhibits the Function of a MATE Family Transporter, Molecules 2013, 18(9), 10514-10530, https://doi.org/10.3390/molecules180910514; Goto & Suga, The RaPID Platform for the Discovery of Pseudo-Natural Macrocyclic Peptides, Accounts of Chemical Research (2021) 54(18) 3604-3617).
Claim Rejection - 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.
Claims 29-41 are rejected under 35 U.S.C. § 103 as being unpatentable over Goto & Suma, The RaPID Platform for the Discovery of Pseudo-Natural Macrocyclic Peptides, Accounts of Chemical Research (2021) 54(18) 3604-3617, in view of KOLMAR (US 20090130692 A1) as evidenced by Baggio et al, Identification of epitope-like consensus motifs using mRNA display, J. Mol. Recognit. 15 (2002) 126-134, and WO 2013039857 A1.
This rejection is presented in the interest of compact prosecution to the extent the claims attempt to recite mRNA display applied to cyclotides.
It would have been prima facie obvious to a person of ordinary skill in the mRNA display art to apply familiar cyclotides to the familiar mRNA display techniques of the prior art as explicitly suggested by the prior art to screen for peptides that treat disease with a reasonable expectation of success.
As to the claimed mRNA display technique, this is well-known in the art. For example, as to claim 1, Goto & Suma teaches a) preparing an mRNA library based on a peptide scaffold; b) ligating mRNA in the library to puromycin to form mRNA-puromycin conjugates; c) translating the mRNA-puromycin conjugates using a prokaryotic translation system to produce mRNA-puromycin-peptide conjugates; d) reverse transcribing the conjugates to form mRNA:cDNA-puromycin-peptide conjugates; e) performing affinity selection against the target substance to select for mRNA:cDNA-puromycin-peptide conjugates that bind to the target substance; f) performing nucleic acid amplification on the cDNA of the selected mRNA:cDNA-puromycin-peptide conjugates to generate an enriched cDNA library; and g) sequencing the enriched cDNA library to identify a disulfide rich peptide which binds to the target substance (Fig. 2).
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As to claim 40, the steps of claim are repeated (Fig. 2).
As to claims 35-39, Goto & Suga teaches RaPID mRNA display system with the same components (Abstract). This system was conventional in the art at the time of effective filing and known to allow integration with other complex peptides such as cyclotides (Abstract).
Goto & Suga does not explicitly teach cyclotides (“disulfide rich peptides”) with knots; or the RaPID mRNA display components of claims 35-39.
As to the application of mRNA display techniques to cyclotides, this was routinely taught in the prior art. For example, KOLMAR teaches
Peptides of the inhibitor cystine knot family share a common architecture that is defined by a combination of three intramolecular disulfide bonds. These interesting molecules show diverse biological activities including for example neurotoxins (Narasimhan, 1994) and enzyme inhibitors (Hamato, 1995; Chakraborty, 2001). Because of their enormous intrinsic stability and the possibility to apply methods of molecular evolution for the isolation of variants with predefined binding capabilities (Wentzel, 1999; Baggio, 2002), cystine knot proteins are considered to be ideal scaffolds for drug design (Craik, 2001)
(para. 0266). Baggio is entitled “Identification of epitope-like consensus motifs using mRNA display”. See Baggio et al, J. Mol. Recognit. 15 (2002) 126-134. It teaches the same mRNA display technique as claimed (Abstract; Fig. 1; Experimental). WO 2013039857 A1 applied this very suggestion to cyclotides (Example 7; cyclotides of SEQ ID NOS: 602-604) which are known ultrastable polypeptide scaffolds for drug discovery. In other words, the prior art routinely applies, or suggests to apply, familiar cyclotide scaffolds, which are familiar drug discovery targets, to familiar mRNA display techniques to discover new drugs.
In sum, a skilled artisan would have been motivated to apply familiar mRNA display techniques to familiar cyclotides to discover new drugs and achieve familiar results.
Claim 42 is rejected under 35 U.S.C. § 103 as being unpatentable over Goto & Suma, The RaPID Platform for the Discovery of Pseudo-Natural Macrocyclic Peptides, Accounts of Chemical Research (2021) 54(18) 3604-3617, in view of KOLMAR (US 20090130692 A1) as evidenced by Baggio et al, Identification of epitope-like consensus motifs using mRNA display, J. Mol. Recognit. 15 (2002) 126-134, and WO 2013039857 A1, in view of WO 2014057284 A2.
The prior art of the rejections above do not recite SEQ ID NO: 44. However, this cyclotide was already a familiar drug target. For example, WO 2014057284 A2 teaches
In a further embodiment, cyclotides of the invention are derived from linear or cyclic form of cyclotides of the Momordicae, Rubiaceae and Violaceae, plant species. In a preferred aspect, cyclotides of the invention are derived from linear or cyclic form of cyclotides of the Momordicae species including the squash serine protease inhibitor family (Otlewski & Korowarsch Acta Biochim Pol. 1996;43(3):431 - 44), and in a more preferred aspect from Momordica cochinchinensis trypsin inhibitors MCoTI-l [SEQ ID NO: 001 ] and -II [SEQ ID NO: 002] (naturally cyclic) and MCoTI-lll (naturally linear) [SEQ ID NO: 3] below.
Mcoti-I GGVCPKILQRCRRDSDCPGACICRGNGYCGSGSD [SEQ ID NO: 001]
Mcoti-II GGVCPKILKKCRRDSDCPGACICRGNGYCGSGSD [SEQ ID NO: 002]
Mcoti-III ERACPRILKKCRRDSDCPGACICRGNGYCG [SEQ ID NO: 003]
(pg. 4; emphasis added). This cyclotide was subjected to vector display technique to evolve the cyclotide to find iterations that have “enhanced blood-brain barrier translocation characteristics” (id.) A skilled artisan of ordinary creativity reading this would have been well-aware of the option of using mRNA display to do the same. Thus, the application of mRNA display to the same cyclotide of SEQ ID NO: 44 is obvious.
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/YUNG-SHENG M TSUI/ Primary Examiner, Art Unit 1684
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