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
The application claims foreign priority to EP20198501.7, filed on 25 September 2020, and is a 317 of PCT/EP2021/076234, filed on 23 September 2021. As the applicant has provided a certified copy of EP20198501.7, the effective filing date is 25 September 2020.
Information Disclosure Statement
The information disclosure statements (IDS), filed on 10 March 2023, were considered by the examiner.
Status of Application, Amendments, and/or Claims
Claims are the original claim 1-18 are the original claims. In the amendments of 10 March 2023, claim 18 was cancelled, claims 1 and 3-17 were amended, and claims 19-21 were added. A requirement for restriction was issued on 10 December 2025, and as a result the applicant has elected Group 1, with traverse, regarding claims drawn to a polypeptide, which comprise claims 1-11 and 21. Claims 1-11 and 21 are the subject of this office action.
Claim Objections
Claims 4-6 are objected to because of the following informalities: the claims reference “aGPCR”, presumably adhesion-GPCR, however in the context of the claim set this abbreviation is never established. This could be remedied by simply adding “(aGPCR)” in claim 1, following the mention of “an adhesion GPCR” when describing the first sequence. Appropriate correction is required.
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 21 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. In the claim, the applicant refers to a polypeptide, wherein the first sequence differs from an amino acid sequence shown in any of SEQ ID Nos: 1-32 by less than 3-10 amino acids. It is unclear if the applicant requires that the sequence differs from SEQ ID Nos: 1-32 or if the limitation is establishing a range of tolerated variation. For the purpose of the office action, the examiner is interpreting the claim limitations to refer to a range of tolerated variation (i.e. the sequence cannot differ more than 3-10 amino acids from the sequences shown in SEQ ID Nos: 1-32).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 1-9 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/099689 A1 (herein Choe), cited in the IDS filed on 10 March 2023, in view of Vizurraga A, et al. (2020) Mechanisms of adhesion G protein-coupled receptor activation. J Biol Chem. 2020 Oct 9;295(41):14065-14083 (herein Vizurraga), also cited in the IDS filed on 10 March 2023.
In regard to claims 1 and 4, Choe et al relates to chimeric polypeptides, which modulate various cellular processes following cleavage of a force sensor cleavage domain, including non-Notch force sensor domains, induced by the binding of the chimera to its binding partner ([0005]). The chimeric polypeptides are taught to generally comprise: an extracellular domain comprising a first member of a binding pair; a force sensor cleavage domain comprising a proteolytic cleavage site; a cleavable transmembrane domain; and an intracellular domain ([0052]). It is taught that the force sensitive cleavage domain from adhesion-GPCRs may find use in the disclosed chimeric polypeptides (i.e. the first sequence of instant claim 1), and provides numerous exemplary proteins from which the domain may be derived, which include human CELSR1 and CELSR3, which comprise sequences corresponding to SEQ ID NOs: 6 and 8, respectively, of the current application, and are of direct relevance to instant claims 7 and 21 ([00108] and [00110]). Choe teaches that ectodomain shedding, which is defined as “the process whereby removal of one or more ectodomains is required for cleavage of a cleavable transmembrane domain”, may provide for subsequent cleavage at a transmembrane domain cleavage site in the disclosed chimeric polypeptides thereby releasing the intracellular domain (relevant to instant claim 2) ([00114] and [00130]). It is taught that the cleavable transmembrane domain may comprise a γ-secretase-sensitive transmembrane domain, such as that derived from a Notch protein (i.e. the second sequence of instant claim 1), with several non-limiting examples provided, which contain S3 and S4 sites (Relevant to instant claims 8 and 9) ([00116-00118], and [00129]). It is also taught that chimeric protein may comprise the S2 site of a Notch protein (relevant to instant claim 8) ([00129]). In certain embodiments, the intracellular domain is taught to comprise a transcriptional activator (i.e. transcription factor moiety), that may induce expression of a POI (relevant to the third sequence of instant claim 1) ([00208] and [00212]). A POI is defined as “essentially any polypeptide and may include but is not limited to polypeptides of research interest (e.g., reporter polypeptides, mutated polypeptides, novel synthetic polypeptides, etc.), polypeptides of therapeutic interest (e.g., naturally occurring therapeutic proteins, recombinant therapeutic polypeptides, etc.), polypeptides of industrial interest (e.g., polypeptides used in industrial applications such as e.g., manufacturing), and the like.”
In summary, Choe teaches a chimeric polypeptide, comprising structural elements matching that of the current application, in which sequences corresponding to the second and third sequences of instant claim 1 are explicitly disclosed. Additionally, Choe teaches an extracellular domain and a force sensor cleavage domain, corresponding to sequence one of instant claim 1, which may comprise an extracellular domain of an adhesion-GPCRs ([00108] and [00110]). As noted in the current specification, page 2 paragraph 5, Choe does not explicitly mention a GAIN domain. Choe also does not teach a chimeric polypeptide, in which the extracellular region comprises the N-terminal part of said adhesion-GPCR. The teachings of Vizurraga render the inclusion of a GAIN domain and an aGPCR extracellular region obvious.
Vizurraga reviews the state of the art regarding the mechanism of adhesion-GPCR activation, near the effective filing date of the current application (Abstract). Vizurraga teaches that adhesion-GPCRs have large extracellular regions, ranging from hundreds to thousands of residues in length, that are autoproteolytically cleaved within the GPCR seven-transmembrane-spanning bundle-proximal extracellular GAIN domain, which results in a two-fragment holoreceptor (Abstract). The two fragments of the holoreceptor include the extracellular N-terminal fragment and a membrane-intercalated C-terminal fragment, which are associated via a dense network of hydrogen bonds (Section: The unique structural topology of adhesion GPCRs). Vizurraga teaches that several lines of evidence, support two fundamental modes of adhesion-GPCR activation: orthosteric agonism (i.e. tethered-peptide agonism) and allosteric regulation (Page 14068 Section: Adhesion GPCR activation mechanisms). The orthosteric agonism model most closely aligns with the mechanism referenced in the current application and Choe. In this model, force-mediated dissociation of the N-terminal and C-terminal fragments, exposes a tethered peptide agonist, which rapidly binds to its orthosteric binding pocket within the seven-transmembrane-spanning bundle and ultimately triggers G protein signaling (Sections: Orthosteric agonism (tethered-peptide agonism). It is taught that adhesion-GPCR self-proteolysis requires proper folding of the GAIN domain (Section: The self-proteolytic reaction of adhesion GPCRs). Additionally, it is taught that, outside of small number of examples, adhesion-GPCRs remain relatively untapped as therapeutic targets, due to a poor understanding of endogenous ligands (i.e. mechanism of activation and identity of endogenous ligands) (Section: Conclusions).
In view of the teachings of Vizurraga, the inclusion of a GAIN domain in the extracellular domain of the chimeric polypeptide disclosed by Choe would have been obvious. Vizurraga teaches that the inclusion of a properly folded GAIN domain is required for self-proteolysis of the force sensor cleavage domain of the aGPCR, thus is required for the force sensing function disclosed in the chimeric polypeptides, taught by Choe (relevant to instant claim 6) (Section: The self-proteolytic reaction of adhesion GPCRs). Vizurraga also provides motivation for the use of sequences comprising the extracellular region of aGPCRs, in that aGPCRs have been relatively untapped in terms of therapeutics (Section: Conclusions). By including the sequence of extracellular regions from GPCRs into the chimeric polypeptide, disclosed by Choe, comprising a Notch transmembrane domain and a transcriptional activator, which may induce expression of a reporter gene ([00212]), one would effectively have a chimeric receptor capable of reporting the release of the N-terminal fragment and/or proteolytic cleavage within the GAIN domain (relevant to instant claim 11). This receptor could be used as a tool for the screening/identification of aGPCR binding partners, which Vizurraga teaches is lacking in the art (Section: Conclusions).
In regard to claims 5, as discussed above for the 35 U.S.C. 103 rejection of claim 1, Choe and Vizurraga teach chimeric polypeptides that comprise: an extracellular domain comprising a first member of a binding pair; a force sensor cleavage domain comprising a proteolytic cleavage site (comprising a GAIN domain derived from aGPCRs); a cleavable transmembrane domain (derived from Notch proteins); and an intracellular domain (that may possess the capacity to act as a transcriptional activator). Vizurraga teaches that GAIN domains are located in the extracellular region of aGPCRs (referred to as the N-terminal fragment), and end 7-18 residues prior to the start of the first seven-transmembrane-spanning bundle, in the context of a natural aGPCR (Section: The unique structural topology of adhesion GPCRs). In this context, the N-terminal fragment of the GAIN domain, when still associated with the C-terminal fragment, inhibits proteolysis of the transmembrane domain, according to the orthosteric agonism model, taught by Vizurraga (Section: Orthosteric agonism). In the context of the chimeric polypeptide, taught by Choe and Vizurraga, in which the chimera comprises a Notch transmembrane domain, the GAIN domain serves a similar function, and as such would also end before the transmembrane domain.
Allowable Subject Matter
Claim 10 is objected to as being dependent upon a rejected base claim (claim 1), but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. gook
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW CURRAN METCALF whose telephone number is (571)272-5520. The examiner can normally be reached 7:30AM-5:00PM.
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/MATTHEW CURRAN METCALF/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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