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 .
Election/Restrictions
Applicant’s election without traverse of Group I, encompassing claims 1-3 in the reply filed on 01 February 2026 is acknowledged. Claims 4-7 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-3 are pending and being examined on the merits.
Priority
This application is a continuation of PCT/KR2022/011256 filed 07/29/2022. Acknowledgment is made of applicant's claim for foreign priority based on an application filed in Korea on 7/29/2021. It is noted, however, that applicant has not filed a certified copy of the KR10-2021-0100059 application as required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement filed 3/18/2024 has been acknowledged.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities: The specification contains the recitation of both AUTTM and AUTTM throughout. A cursory search did not reveal AUT to be a trademark. It would be remedial to be consistent with the term designation thought the specification.
Appropriate correction is required.
The use of the term Sigma-Aldrich, HiPrep, Sepahacryl, Thermo Fisher Scientific, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. A cursory review of the specification has revealed these trademarks or names. It would be remedial to check the specification for additional trademarks or names and amend all upon amendment.
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.
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 3 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.
Claim 3 recites “wherein the conjugate of AUT-FGF-1 and AUT-EGF has an amino acid sequence of SEQ ID NO: 1, and lysine residues at position 106 from an N-terminus of FGF-1 and position 28 from an N-terminus of EGF are each substituted with arginine. SEQ ID NO: 1 does not possess a lysine at position 106 from “the” N-terminus of FGF-1. It comprises a glutamic acid at position 106. There is a lysine at position 115, 116, and 120 from the N-terminus of FGF-1. The specification teaches a linker sequence of GGGGS in SEQ ID NO: 1 of which an amino acid sequence of EGF is to follow [0016]. Based on this designation, SEQ ID NO: 1 does not comprise a lysine at position 28 from “the” N-terminus of EGF. It comprises a leucine at position 28. There is a lysine at position 30 and 50 from “the” N-terminus of EGF. Therefore, the it is unclear which lysines are being mutated in the AUT-FGF-1 and AUT-EGF defined by SEQ ID NO: 1.
Figure 1 underlines two lysine residues in the amino acid sequence of FGF-l-linker-EGF and Figure 2 demonstrates an amino acid sequence of AUT-FGF-1-linker-AUT-EGF of which those same lysines have been mutated to arginine. These lysines reside at positions 120 and 190 of SEQ ID NO:1. Therefore, the claims will be given the BRI that the lysines at positions 120 and 190 of SEQ ID NO:1 are to be substituted with an arginine residue.
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 1-2 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.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).”
Claim 1 is drawn to “a method for extending a half-life of a protein, a peptide, or a polypeptide, comprising: substituting at least one lysine binding to glycine at a C-terminus of ubiquitin in a protein, a peptide or a polypeptide with arginine; wherein the protein is a conjugate of AUT-FGF-1 and AUT-EGF”. Possession of this claim requires the possession of the genus of any protein, or a conjugate of AUT-FGF-1 and AUT-EGF, wherein the protein or conjugate has an extended half-life and wherein at least one of the lysine residues of the protein or conjugate (at any position) is substituted with arginine and the lysine residue to be substituted binds to the C-terminal glycine of ubiquitin.
The claims appears to be asserting that any lysine in any protein or the conjugate can be involved in ubiquitination. Stringer (Stringer and Piper. Cell Cycle 10.18 (2011): 3067-3071) discloses that it can be difficult to predict which lysine(s) within a given protein of interest are susceptible to ubiquitination [pg. 3067, col. 2, para 2]. Stringer teaches that a common method of studying ubiquitination is to mutate a lysine and check for ubiquitination [pg. 3067, col. 2, para 2]. Stringer teaches that this can lead to unintended consequences such as having another lysine that is not normally ubiquitinated getting ubiquitinated instead [pg. 3067, col. 2, para 2]. Stringer also teaches that due to this consequence and the fact that lysines aren’t just for
ubiquitination and may be critical for protein folding, protein/protein interactions or as a target for other post-translational modifications, it is virtually impossible to generate any
mutant protein that is completely resistant to ubiquitination [pg. 3067, col. 2, para 2 – pg. 3067, col. 1, para 1].
The specification teaches the specific lysine to arginine substitution and identification of extended half-life of a conjugate of AUT-FGF-1 and AUT-EGF [0025]. However, such disclosure is not representative of the claimed genus, which encompasses an unlimited number of proteins with individual and combination substitutions of lysine residues (at any position) with arginine residues and having the function of "an extended half-life" and "the lysine residue to be substituted binding to the C-terminal glycine of ubiquitin". The specification does not describe any structural features of the instant proteins that would have been expected to be shared by members of the claimed genus. The level of knowledge and skill in the art does not allow the skilled artisan to structurally envisage or recognize a nucleic acid encoding any protein with the claimed function because it is known that genes differ in sequence and the amount and type of sequence variation is unpredictable. The specification does not disclose structural features shared by members of the genus or common structural attributes or features shared by members of the genus that structurally distinguish the members of the genus from other materials at the time of filing. The specification does not describe other species in the genus by structure, or physical and/or chemical characteristics. The level of skill and knowledge in the art is such that one of ordinary skill would not be able to identify without further testing which of those proteins have the claimed function.
Therefore, considering the extremely large variation in the genus, the failure of the specification to describe or provide predictability for achieving any lysine to arginine substitution of any protein or the conjugate thereof, and the lack of predictability provided by the art for the full scope of the claimed genus, it is reasonable to conclude that Applicant did not possess the invention as claimed at the time of filing.
Claim 2 do not further limit the genus of proteins so as to resolve the issues above, and are therefore not sufficiently described for at least the reasons above.
Claims 1-2 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 for extending the half-life of a protein, a peptide, or a polypeptide, comprising substituting each lysine at positions 120 and 190 of the sequence of SEQ ID NO: 1 with arginine, does not reasonably provide enablement for a method for extending a half-life of a protein, a peptide, or a polypeptide, comprising: substituting at least one lysine binding to glycine at a C-terminus of ubiquitin in a protein, a peptide or a polypeptide with arginine; wherein the protein is a conjugate of AUT-FGF-1 and AUT-EGF. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Nature of the Invention and Breadth of Claims
The claims are directed to “method for extending a half-life of a protein, a peptide, or a polypeptide, comprising: substituting at least one lysine binding to glycine at a C-terminus of ubiquitin in a protein, a peptide or a polypeptide with arginine; wherein the protein is a conjugate of AUT-FGF-1 and AUT-EGF”. This recitation broadly encompass the amino acid substitution of any lysine to arginine at any position in any protein or in the conjugate of AUT-FGF-1 and AUT-EGF. Enablement of the claims turns on whether one of ordinary skill in the art could substituting anv number of lvsines, at anv position in any protein or in the conjugate of AUT-FGF-1 and AUT-EGF, with an arginine and achieve an extended half-life and reduced binding to glycine at a C-terminus of ubiquitin without undue experimentation.
• State of the Art
Stringer (Stringer and Piper. Cell Cycle 10.18 (2011): 3067-3071) discloses that it can be difficult to predict which lysine(s) within a given protein of interest are susceptible to ubiquitination [pg. 3067, col. 2, para 2]. Stringer teaches that a common method of studying ubiquitination is to mutate a lysine and check for ubiquitination [pg. 3067, col. 2, para 2]. Stringer teaches that this can lead to unintended consequences such as having another lysine that is not normally ubiquitinated getting ubiquitinated instead [pg. 3067, col. 2, para 2]. Stringer also teaches that due to this consequence and the fact that lysines aren’t just for
ubiquitination and may be critical for protein folding, protein/protein interactions or as a target for other post-translational modifications, it is virtually impossible to generate any
mutant protein that is completely resistant to ubiquitination [pg. 3067, col. 2, para 2 – pg. 3067, col. 1, para 1].
Batonnet (Batonnet et al. Journal of Biological Chemistry 279.7 (2004): 5413-5420) teach regions of MyoD that target it for destruction by the ubiquitin--proteasome pathway [abstract]. Batonnet teach MyoD contains nine lysine residues at positions 58, 99, 102, 104. 112, 124, 133, 146 and 241, which were all mutated to arginine [pg. 5415, col. 2, para 3]. Batonnet teach the replacement of five lysines (at positions 58, 99, 102, 104, and 112) did not affect either the half-life or the ubiquitination of MyoD in vivo or in vitro [pg. 5415, col. 2, para 3 – 5416, col. 1, para 1; Figs. 2-3]. However, Batonnet teach that the replacement of lysine at positions 99, 102 and 104, and 112 resulted in MyoD mutants that cannot be acetylated and that these mutants were impaired in their ability to promote transcriptional and myogenic potency although their half-lives and ubiquitination were similar to wild-type MyoD [5416, col. 1, para 1; Fig. 4D]
• Guidance of the Specification
The specification teaches the specific lysine to arginine substitution and identification of extended half-life of a conjugate of AUT-FGF-1 and AUT-EGF [0025; Fig. 3; example 1].
• Experimentation Required
In order to practice the claimed invention, an immense amount of experimentation would be required. To practice the invention as broadly claimed, it would be necessary for one of ordinary skill in the art to systematically mutate every lysine to arginine single and all different combination in every protein or mutate every lysine to arginine single and all different combination in AUT-FGF-1 and AUT-EGF. However, such experimentation would be highly unpredictable in view of the prior art which teaches that mutation in lysines will not only affect ubiquitination but also affect the functionality of the protein. Accordingly, practicing the invention as broadly claimed would require a massive amount of highly unpredictable experimentation.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an undue experimentation would be required to make and use the invention as claimed.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by KR924 (KR 20180122924).
Regarding claim 1, KR924 teach methods for increasing EGF half-life (EGF). KR924 teach that the 28th and 48th lysine residues from the N-terminus in the amino acid sequence of EGF represented by SEQ ID NO: 1 is substituted with an arginine residue which resulted in an increased half-life of EGF [pg. 2; para 12]. KR924 teaches ubiquitination and polyubiquitination of wild type of EGF that was abolished in the EGF K28R mutant [pg. 3; para 5-7; Figs. 4-5].
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by KR652 (KR 20180055652).
Regarding claim 1, KR652 teaches a method for increasing the half-life of a protein wherein one of the lysine residues that bind to the C-terminal glycine of ubiquitin is replaced by arginine in Fibroblast growth factor-1 (FGF-1) [abstract, claim 1].
Allowable Subject Matter
The following is an examiner’s statement of reasons for allowance: A conjugate comprising AUT-FGF-1 and AUT-EGF separated by a linker is free of the art. The closest art to this conjugate is Herbert (Herbert et al. J Tissue Eng Regen Med 2009; 3: 553–561). Herbert teaches that human adipose-derived stromal/stem cells (hASCs) supplemented with EGF and bFGF (FGF-2) significantly increased proliferation and that that bFGF and EGF can be used as culture supplements to optimize the proliferative capacity of cryopreserved human ASCs and their adipogenic differentiation potential. [abstract; Fig. 1]. Herbert does not teach FGF-1 nor does he teach conjugating EGF to FGF-2 via a linker. Furthermore, the prior art as a whole does not teach or suggest conjugating EGF to any FGF via a linker for the purpose of extending the half-life of the conjugate.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIFFANY N GROOMS whose telephone number is (571)272-3771. The examiner can normally be reached M-F 830-530.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637