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 instant application is a 35 U.S.C. 371 national phase application, and claims
priority to, International Application No. PCT/ CN2021/105187, filing date 07/08/2021.
This PCT application claims priority to Chinese Application Nos. CN202010651373.0
(filed 07/08/2020) and CN202010650886.X (filed 07/08/2020). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Applicant is notified that to obtain the benefit of foreign priority under 35 U.S.C.
119(a)-(d) prior to declaration of an interference, certified English translations of the foreign applications CN202010651373.0 and CN202010650886.X must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e). Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
This correction is required to perfect priority (MPEP 216.01).
Status of Application/Claims
The preliminary amendment, filed 01/06/2023, in which original claims 1-31 were modified, is acknowledged. Claims 26-28 are canceled. Claim 32 is newly added. Claims 6,9, 12-13, 20-21, 25, 29, and 31 are amended. Claims 1-25 and 29-32 are currently pending and are examined on the merits herein.
Information Disclosure Statements
The information disclosure statements (IDSs) submitted on 01/06/2023, 10/15/2024, and 11/13/2024 have been fully considered by the examiner.
Specification
The use of the terms GenScript, Invivogen, Thermo Fisher Scientific, Corning, and VWR, which are a trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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.
Hyperlink is located on p.22, first paragraph of the disclosure.
Drawings
The drawings are objected to because of poor resolution in the following figures:
Numbers and Axes: Fig. 4C, Fig. 5C, Fig. 6C, Fig. 7C, Fig. 8C, and Fig. 9C.
Legends: Figs. 10-13
Labels and Axes: Figs. 16-17
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.
Claim Objections
Claim 3 is objected to because of the following informalities:
Claim 3 recites, “ …bundles of, from N-terminal to C-terminal, H2, H3, H4, and H1; H3, H4, H1 and H2; or H4, H1, H2 and H3.” This should be corrected to “…bundles selected from, from N-terminal to C-terminal, H2, H3, H4, and H1; H3, H4, H1 and H2; or H4, H1, H2 and H3.”
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.
Claims 1-23 and 25-32 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1-23:
Claim 1 recites the limitation "the accessibility" in line 4. There is insufficient antecedent basis for this limitation in the claim. Claims 2-17 and 25-32 are dependent on claim 1 and are, thus, also rejected as there is nothing in claims 2-17 and 25-32 that overcomes the rejection of claim 1.
Claim 4 recites the limitation "the amino acid" in lines 1 and 3; and the limitation “the uncircularly permutated cytokine” in lines 3-5. There is insufficient antecedent basis for these limitations in the claim.
Claim 17 recites the limitation "the insertion site" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 18 recites the limitation "the CD25 binding site" in line 8; and the limitation “the accessibility” in line 8. There is insufficient antecedent basis for these limitations in the claim. Claims 19-21 are dependent on claim 18 and are, thus, also rejected as there is nothing in claims 19-21 that overcomes the rejection of claim 18.
Claim 21 recites the limitation "the insertion site" in line2. There is insufficient antecedent basis for this limitation in the claim.
Claim 22 recites the limitation "the CD215 binding site" in lines 7-8; and the limitation “the accessibility” in line 8. There is insufficient antecedent basis for these limitations in the claim. Claim 23 is dependent on claim 22 and is, thus, also rejected as there is nothing in claim 23 that overcomes the rejection of claim 22.
Regarding claim 8:
Claim 8 is dependent on claim 7 and recites the limitation “…wherein the circularly permutated IL-2 comprises an amino acid sequence of SEQ ID NOs: 2, 3, 4, or 5.” While SEQ ID NOs” 2, 3, and 4 harbor amino acid fragments for IL-2, SEQ ID NO: 5 is the amino acid sequence that encodes for wild type IL-15. The known sequences for IL-2 and IL-15 are different. Further, SEQ ID NO: 5 is not a “circularly permutated” sequence of either IL-2 or IL-15. Thus, the limitation reads that SEQ ID NO: 5 as the “circularly permutated IL-2,” and the claim is rendered indefinite. Thus, it is unclear how the SEQ ID NOs recited in claim 8 relate to the helical orientations recited in claim 7.
Regarding claim 11:
Claim 11 is dependent on claims 1, 6, and 10; and, recites the limitation “…wherein the circularly permutated IL-15 comprises an amino acid sequence of SEQ ID NO: 7.” Given its broadest reasonable interpretation, the circularly permutated sequence is interpreted to comprise sequence fragments for IL-15 that are four α-helical bundles of H3, H4, H1, and H2. However, SEQ ID NO: 7 is comprised of sequence fragments for albumin (i.e., a carrier) and IL-2. Further, the SLIC sequence label for SEQ ID NO: 7 is noted as “C361-IL2-1.” Thus, claim 11 is rendered indefinite as it is not comprised of sequences encoding IL-15.
For further examination, claim 11 is interpreted as meant to reference SEQ ID NO: 6, which comprises permutated sequence fragments for IL-15.
Regarding claim 15-17:
Claim 15 is dependent on claims 1, 13, and 14; and, recites the limitation “…wherein the loop is selected from… the positions are numbered by reference to SEQ ID NO: 16.” The claim 15 limitation is referencing a loop of carrier protein human serum albumin (HSA). SEQ ID NO: 16 is only comprised of the 4 amino acids “GGGG,” which is the sequence for a linker, not HSA. Thus, claim 15 is rendered indefinite as it is not comprised of sequences encoding any part of the HSA protein. Claims 16-17 are dependent on claim 15 and, thus, are also rejected as there is nothing in claims 16 or 17 that overcomes the rejection of claim 15.
For further examination, claim 15 is interpreted as meant to reference SEQ ID NO: 15, which encodes for wild type human serum albumin.
Regarding claims 15-17:
Claim 15 recites the limitation “the loop” in line 1.
Claim 16 recites the limitation “the loop” in line 2.
Claims 15 and 16 are dependent on claim 1 which recites the limitation “loops,” indicating that there is more than one loop in the carrier protein. Thus, it is unclear which loop is being referred to in each of claims 15 and 16. Thus, claims 15 and 16 are rendered indefinite. Claim 17 is dependent on claim 15 and, thus, is also rejected as there is nothing in claim 17 that overcomes the rejection of claim 15.
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 1-5 and 13 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 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.
Claims 1-4 are drawn to a fusion polypeptide product comprising a carrier, a polypeptide of interest (PPI), and a linker.
Claim 1
Claim 1 recites functional limitations for the carrier, wherein the carrier shields a site of interest on the PPI and blocks the accessibility of the site. The only structural requirement for the carrier is that it “has a plurality of helical domains linked with loops.”
Claim 1 recites the PPI, which is only limited by the functional limitation of being inserted into a loop of the carrier protein.
Claim 2
Claim 2 recites the additional limitation that the PPI “is derived from a cytokine of the four α-helical bundle cytokine family, the cytokine comprises four α-helix bundles of, from N-terminal to C-terminal, helical bundle 1 (H1), helical bundle 2 (H2), helical bundle 3 (H3), and helical bundle 4 (H4).”
Claim 3
Claim 3 recites the additional limitation that the PPI is a circularly permutated cytokine that can be any of the following arrangements, from N- to C-termini: H2, H3, H4 and H1; H3, H4, H1, and H2; or, H4, H1, H2, and H3.
Claim 4
Claim 4 recites a linker that is used to join the N-terminal and C-terminal ends of the circularly permutated cytokine.
Claim 5
Claim 5 recites that the linker is a GS linker or a polyglycine linker having a length of 1-10 amino acids.
Claim 13
Claim 13 recites that the carrier protein is an albumin.
The claims are drawn to a genus of fusion polypeptides comprising carriers and PPIs (and, thus, also a linker) that are only limited by the recited functional limitations and insufficient structural limitations, which would produce a fusion polypeptide that encompasses a vast number of protein-protein fusion combinations that the instant disclosure does not support in sufficient detail so that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See MPEP 2163.
Regarding the carrier, the disclosure provides that the carrier protein is preferably able to bind to a newborn Fc receptor (FcRn) (such as albumin) or is able to bind a protein which can bind to FcRn (such as albumin binding protein) (p.17, para.6). Additionally, Fig.4 and p.17, para.4 support that the only carrier capable of shielding the binding site is human serum albumin (HAS). Further, regarding “insertion” into a loop of the carrier, the disclosure only provides support for specific structural amino acid residues for insertion of the PPI into an HSA carrier so as to provide the claimed function (p.3, para.6-7; p.4, para.2). The disclosure’s functional term “shielding” is in reference to the carrier protein shielding a site of interest wherein the carrier protein sterically hinders the binding of the site of interest to its receptor (p.13, para.4). The disclosure provides for fusion proteins comprising cpIL-2 and cpIL-15 peptides: “…the HSA shields the CD25 binding site of the circularly permutated IL-2…” (p.19, para.1) and “…the HSA shields the CD215 binding site of the circularly permutated IL-15…” (p.20, para.1). The disclosure’s description of “accessibility of a site” in reference to the carrier protein refers to the ability of a site (on the PPI) to contact and bind to its binding partner (p.13, para.4). The only examples of receptors for PPIs supported in the disclosure are receptors for IL-2 and IL-15.
Regarding the PPI, the disclosure recites that the PPI is a cytokine of the four α-helical bundle cytokine family which includes IL-2, IL-4, IL-6, IL-7, IL-9, IL-15, IL-21, G-CSF and GM-CSF (p.11, para.4; p.17, para.1). Examples of PPIs of the instant disclosure are limited to circularly permutated IL-2 (i.e., cpIL-2) and circularly permutated IL-15 (i.e., IL-15) (Figs.4-7; p.3, paras.6-7; p.4, para.2). Circular permutation of cytokines in the four α-helical bundle cytokine family is, thus, limited to cytokines in which a “shift” in the N- to C-terminal orientation has occurred and are limited to the following possible circularly permutated (cp) cytokine orientations: H2, H3, H4, and H1 (i.e., H2/H3/H4/H1); H3, H4, H1, and H2 (i.e., H3/H4/H1/H2); and, H4, H1, H2, and H3 (H4/H1/H2/H3) (p.11, para.5). Further, for cpIL-2, the instant disclosure provides support for the H3/H4/H1/H2 and H4/H1/H2/H3 helical orientations; and for cpIL-15, the instant disclosure provides support for the helical H3/H4/H1/H2 orientation (p.3, para.7; p.4, para.2).
Regarding the linker recited in claim 4, the disclosure provides that the amino acids constituting the linker can be selected based on certain properties of the linker or the resulting molecule, such as flexibility, hydrophilicity, net charge or whether it is proteolytically sensitive, and non-immunogenic (p.12, para.1) and claim 5 stipulates that the linker can be any GS linker of 1-10 amino acids; and, the length of the linker is related to the distance between N-terminal and C-terminal in the original protein (p.16, para.2). Thus, the choice of the linker structure is dependent on the structure and resultant function of the fusion polypeptide protein components. The disclosure provides linker locations, lengths, and amino acid identities for linkers used for PPIs that are cpIL-2 and cpIL-15 (p.15, para.5-7 – p.16, para.1-3).
While the disclosure provides specific examples for producing fusion polypeptide structures via circular permutation of IL-2 and IL-15 using appropriate linkers and structural information regarding insertion of PPIs cpIL-2 and cpIL-15 into specific loop sites of an HSA carrier protein in order to block IL-2Rα/CD25 and IL-15Rα/CD215 binding accessibility, respectively, there is no evidence that applicant was in possession of any fusion polypeptides other than HSA-cpIL-2 and HSA-cpIL-15.
Overall, the disclosure and drawings provide only two examples of fusion polypeptides that includes sufficient structural information to produce a fusion polypeptide structure that would result in the claimed functions: HSA-cpIL-2, HSA-cpIL-15. Thus, claims 1-4 and 13 describe a broad genus of fusion polypeptides, but the specification only describes a narrow species (i.e., HSA-cpIL-2 and HSA-cpIL-15) with no evidence that the genus that includes structures other than HSA-cpIL-2 and HSA-cpIL-15 that have the disclosed functions are contemplated. See MPEP 2163.03 (V).
The state of the art around the effective filing date of the claimed invention demonstrates that while carrier proteins having a plurality of helical domains linked with loops exist and that carrier proteins having functions related to half-life extension, protein delivery, and facilitating immunogenicity are known in the art, the prior art does not teach a carrier harboring all properties indicated by the instant disclosure.
Berger, et al. Fusion protein technologies for biopharmaceuticals: applications and challenges. mAbs (2015), 7:3, p.456-460, herein referred to as Berger, teaches carriers such as albumin- and antibody Fc-conjugation for fusion proteins are classical examples of carrier protein usage for half-life extension (p.456, col2, para.3). Further, Berger teaches fusion carriers can also function to target the fusion partner to a specific molecule, cell, or location (p.458, col.1, para.3; p.458, col.2, paras.3-4). However, it is not apparent from the prior art which carriers are to be encompassed by the claims and it is not apparent how all carriers having a plurality of helical domains linked with loops would function to shield a site of interest or how to circularly permutate each of them so as to result in the claimed function.
For example, Goedhart. Fluorescent proteins 101: GFP fusion proteins – Making the right connection. Addgene (2019), p.1-10 Internet -- https://blog.addgene.org/gfp-fusion-proteins-making-the-right-connection, herein referred to as Goedhart, teaches insertion of a GFP between alpha helices (p.4). However, Bendezu, et al. Spontaneous Cdc42 polarization independent of GDI-mediated extraction and actin-based trafficking. PLOS Biology (2015), 13:4, p.1-30, herein referred to as Bendezu, teaches that when GFP is inserted between two alpha helices on a solvent exposed loop of Cdc42 (i.e., a protein having a plurality of helical domains linked with loops), GFP forms a structure separate from Cdc42 and it is unclear how Cdc42 has a structure that shields a site of interest on GFP to block accessibility of the site as required by the claims (p.3, [5]; Fig.1A).
Overall, it is not evident from the disclosure or the prior art that applicant was in possession of any fusion polypeptides other than HSA-cpIL-2 and HSA-cpIL-15. There is no support providing that applicant had possession nor did applicant provide a sufficient description for the fusion polypeptide.
The claimed subject matter was not described in the specification in such a way as to reasonably convey to one of ordinary skill in the art that applicant was in possession of the claimed invention at the time of filing and, therefore, the claims do not meet the written description requirement.
Allowable Subject Matter
Claim 24 is allowed.
The following concepts of the invention are novel:
Producing a fusion protein by inserting a polypeptide of interest (PPI) into a protein that has a plurality of helical domains by inserting the PPI into a loop of a carrier that has a plurality of helical domains in order to block a site of interest is novel.
The specific sequences for the circularly permutated cytokines (i.e., IL-2 and IL-15) defined by the orientation of the helical domains (i.e., H1, H2, H3, and H4) and the removal of additional amino acids.
The use of albumin as both a carrier and the blocking moiety via the joining of the PPI and albumin via specific recited loop sites on albumin is also novel.
The following is a statement of reasons for the indication of allowable subject matter based on the closest prior art:
Alvarez and Chamoun. Ligands modified by circular permutation as agonists and antagonists – US9359415B2, herein referred to as Alvarez, teaches fusion polypeptides that comprise circularly permutated cytokines of the 4-helical domain cytokine family, including circular permutations for IL-2 and IL15, using GS linkers between 1-10 amino acids, for the treatment of cancer and autoimmune disorders (title; abstract; p.16, col.2, para.1; Fig.8; Fig.13; p.22, col.1, para.5; p.24, col.1, para.4); and, pharmaceutical compositions, isolated nucleic acids, vectors, and host cells thereof (p.17, col.2, para.2-3). Alvarez also teaches that the fusion partner for the cytokine can be a carrier that extends half-life, such as albumin (p.16, col.2, para.4; p.24, col.1, para.8 – p.25, col.2, para.1). Alvarez also conceives of linking the first and second fusion partners oriented in a way as to antagonize via steric hinderance or super agonize the function of the target receptor (p.17, col.2, para.6; p.21, col.2, para.5); and teaches dimeric and trimeric receptor binding for IL-2 and IL-15 receptor complexes, including IL-2Rα (i.e., CD25) and IL-15Rα (i.e., CD215). However, Alvarez does not teach linkage via a loop of albumin wherein albumin also blocks a binding site of interest.
Goedhart. Fluorescent proteins 101: GFP fusion proteins – Making the right connection. Addgene (2019), p.1-10 Internet -- https://blog.addgene.org/gfp-fusion-proteins-making-the-right-connection, herein referred to as Goedhart, teaches fusion protein production strategies for GFP, including the concept that “…the best site for the insertion is a loop in between secondary structure (beta-sheets or alpha helices).” However, Goedhart does not teach the concept of using GFP to block a binding site for the PPI, nor does Goedhart teach fusion proteins comprising cytokines or carriers such as albumin. Thus, it is not obvious why one would look to Goedhart’s GFP fusion protein to produce the fusion polypeptides recited in the invention.
Dijkstra et al. Identification of a gene for an ancient cytokine, interleukin 15-like, in mammals; interleukins 2 and 15 co-evolved with this third family member, all sharing binding motifs for IL-15Rα. Immunogenetics (2014), 66:93, p.93-103, herein referred to as Dijkstra, teaches the helical domain sequences for IL-2 and IL-15 (p.97, Fig.3). However, a simple rearrangement of the helical domains does not produce the circularly permutated cytokines recited by the instant SEQ ID NOs as amino acid residues in instant sequences have been removed. Further, while Dijkstra discusses binding of IL-2 and IL-15 to their respective α receptors, Dijkstra does not provide for creation of fusion constructs involving a carrier such as albumin.
Sugio, et al. Crystal structure of human serum albumin at 2.5 Å resolution. Protein Engineering (1999), 12:6, p.439-446, herein referred to as Sugio, teaches the structure of human serum albumin (Fig.1) and identifies the loop domains and residues for HSA (Fig.3). However, Sugio does not provide for production of a fusion protein by inserting a PPI such as a cytokine into any of the specific loop domains/residues of HSA.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jami M Gurley whose telephone number is (571)272-0117. The examiner can normally be reached Monday - Friday, 8am - 4pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at 571-272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JAMI MICHELLE GURLEY/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647