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 .
Claims Status
Applicant’s amendments and remarks filed 03/05/2026 are acknowledged.
Claims 1-2, 7, 13, 14, 17, 19-20, 23, 25, 27, 30, 32, 35, 38, 41, 43, 46, 49, 51, 56, 62, 67, 73, 75, 77, 79-81, 85-86, and 90-95 are pending.
Claims 3-6, 8-12, 15-16, 18, 21-22, 24, 26, 28-29, 31, 33-34, 36-37, 39-40, 44-45, 47-48, 50, 52-55, 57-61, 63-66, 68-72, 74, 76, 78, 82-84, 87-89, and 96-133 are canceled.
Claims 38 and 46 are amended.
Applicant’s election of Group I, claims 1-2, 7, 13, 14, 17, 19-20, 23, 25, 27, 30, 32, 35, 38, 41, 43, 46, 49, 51, 56, 62, 67, 73, 75, 77, 79-81, 85-86, 90, and 94, in the reply filed on 03/05/2026 is acknowledged. Applicant’s election of the following species in the reply filed on 03/05/2026 is acknowledged: SEQ ID NO: 350 for the first amino acid sequence, SEQ ID NO: 4 as the third amino acid sequence, SEQ ID NO: 350 for the sixth amino acid sequence, SEQ ID NO: 4 for the eighth amino acid sequence, SEQ ID NO: 355 for the eleventh and twelfth amino acid sequences, (GGGGS)n wherein n is 4 for the second and seventh amino acid sequences, and SEQ ID NO: 185 for the fourth and ninth amino acid sequences. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The elected species of SEQ ID NO: 185 for the fourth amino acid sequence (Species I) and the elected species of SEQ ID NO: 185 for the ninth amino acid sequence (Species J) is free of the art, and consistent with MPEP 803.02, the examiner has extended the search and examination to the non-elected species. Therefore, the election of species for Species I and J is withdrawn. In view of the withdrawal of the election of species requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the election of species requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 27, 32, 91-93 and 95 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/05/2026. It is noted that Applicant referred to claims 27 and 32 as encompassing the elected species. However, Applicant elected [GGGGS]4 for the second and seventh amino acid sequence. Thus, this is 20 amino acid residues in length and therefore, claims 27 and 32 do not read upon the elected species.
Therefore, claims 1-2, 7, 13, 14, 17, 19-20, 23, 25, 30, 35, 38, 41, 43, 46, 49, 51, 56, 62, 67, 73, 75, 77, 79-81, 85-86, 90, and 94 are under examination.
Priority
The instant application claims priority to provisional applications 63/346,593, 63/349,078, 63/355,375, 63/386,999, and 63/501,434. Priority is given with the earliest effective filing date of 05/27/2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 02/06/2025, 05/05/2025, 10/01/2025, and 03/05/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
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 specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Claims 25 and 30 have an amino acid sequence listed (i.e. (GGGGS)n) without any sequence identifier. The specification refers to this sequences as SEQ ID NO: 153 [0105; Table C of the instant specification].
Required response – Applicant must provide:
Amended claims in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers.
Specification
The disclosure is objected to because it contains embedded hyperlinks and/or other forms of browser-executable code (see paragraph [0005] of the specification). 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://, www., or other browser-executable code. See MPEP § 608.01.
Claim Rejections - 35 USC § 112(b)
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 1-2, 7, 80-81, and 85-86 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.
Claims 1-2 and 7 recite “about”. Applicant has provided a definition for “about” meaning “the number is not necessarily exact” [see paragraph 31 of the instant specification]. However, the metes and bounds for “about” are dependent on the interpretation of others for determining what is an acceptable error range for “about”. Given a single value, one person of ordinary skill in the art could determine that the value is acceptably in the error range. Yet, another person of ordinary skill in the art could determine that it is unacceptable, leading to two different interpretations on if the claim infringes with “about.” Therefore, these claims are indefinite.
Claims 2 and 7 recite “SEQ ID NO: 355”. However, it is unclear what sequence SEQ ID NO: 355 is referring to because the specification refers to SEQ ID NO: 355 as two different sequences: a protease-cleavable linker sequence [page 37, Table D] and a hIgG4 CH1 [page 93, Table S]. Therefore, the scope of this claim is indefinite.
For purposes of examination, the Examiner is interpreting SEQ ID NO: 355 as referring to the hIgG4 CH1 as set forth on page 93, Table S of the specification as this sequence for SEQ ID NO: 355 matches the sequence of SEQ ID NO: 355 in the sequence listing.
Claim 7 recites the limitation “wherein the second polypeptide comprises, N-terminal to the first amino acid sequence”. There is insufficient antecedent basis for the limitation of this claim. The lack of antecedent basis arises from claim 7’s dependence on claim 1 wherein there is no “first amino acid sequence” recited for the second polypeptide. There is only a first amino acid sequence recited for the first polypeptide of claim 1.
For examination purposes, the Examiner has interpreted “wherein the second polypeptide comprises, N-terminal to the first amino acid sequence” as referring to the sixth amino acid sequence.
Claims 80 and 85 recite the negative limitations that the first and sixth amino acid sequences lack additional sequences on their C-terminal ends. It is unclear how the first and sixth amino acid sequences (of the first and second polypeptide chains, respectively), lack additional sequences on their C-terminal ends because the first amino acid sequence has a second amino acid sequence (i.e. a linker) on its C-terminal end and the sixth amino acid sequence has a seventh amino acid sequence (i.e. a linker) on its C-terminal end, and therefore, the first and sixth amino acid sequences have additional amino acids attached which are C-terminal. Thus, the Examiner cannot infer what Applicant is trying to exclude in this claim. Additionally, the first and sixth amino acid sequences only require 95% sequence identity to the recited SEQ ID NOs. So, it is further unclear with the 95% sequence identity if Applicant intends for the 95% identity to occur only at the end of the recited SEQ ID NOs and therefore, the first and sixth amino acid would lack additional sequences at the C-terminal ends relative to the % identity. Thus, the scope of this claim is indefinite.
For purposes of examination, the Examiner is interpreting this claim as there being no additional sequences on the C-terminal end of SEQ ID NO: 350 individually (for the first and sixth amino acid sequences as elected).
Claims 81 and 86 recite the negative limitations that there are no additional sequences between the first and second, second and third, third and fourth, fourth and fifth, sixth and seventh, seventh and eighth, eighth and ninth, and ninth and tenth amino acid sequences of the first and second polypeptide chains, respectively. The first, third, fifth, sixth, eighth, and tenth amino acid sequences only require 95% sequence identity to the recited SEQ ID NOs. Thus, it is unclear with the 95% sequence identity where Applicant intends for the 95% identity to occur within each of the recited sequences if there are no additional sequences between each of the amino acid sequences listed. Therefore, the scope of this claim is indefinite.
Claim Rejections - 35 USC § 112(a)
Written Description
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, 7, 13, 14, 17, 19-20, 23, 25, 30, 35, 38, 41, 43, 46, 49, 51, 56, 62, 67, 73, 75, 77, 79-81, 85-86, 90, and 94 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 is drawn to an IL2 proprotein, comprising (a) a first polypeptide chain comprising, in N- to C- terminal order: (i) a first amino acid sequence having at least about 95% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 346, 347, 348, 349, 350, and 351; (ii) a second amino acid sequence comprising a non-cleavable linker sequence; (iii) a third amino acid sequence having at least about 95% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 3, 4, and 5; (iv) a fourth amino acid sequence comprising a protease cleavable linker sequence; and (v) a fifth amino acid sequence having at least about 95% sequence identity to the amino acid sequence of SEQ ID NO: 2; and (b) a second polypeptide chain comprising, in N- to C-terminal order: (i) a sixth amino acid sequence having at least about 95% sequence identity to any one of SEQ ID NOs: 346, 347, 348, 349, 350, and 351; (ii) a seventh amino acid sequence comprising a non-cleavable linker sequence; (iii) an eighth amino acid sequence having at least about 95% sequence identity to any one of SEQ ID NOs: 3, 4, and 5; (iv) a ninth amino acid sequence comprising a protease cleavable linker sequence; and (v) a tenth amino acid sequence having at least about 95% sequence identity to the amino acid sequence of SEQ ID NO: 2. Claim 2 further limits claim 1 to wherein the first polypeptide comprises, N-terminal to the first amino acid sequence, an eleventh amino acid sequence having at least about 95% sequence identity to any one of SEQ ID NOs: 352, 353, 354, and 355. Claim 7 further limits claim 1 to wherein the second polypeptide comprises, N-terminal to the first amino acid sequence, a twelfth amino acid sequence having at least about 95% sequence identity to any one of SEQ ID NOs: 352, 353, 354, and 355.
The specification states that any of the IL2 moieties (i.e. SEQ ID NO:2 of the instant claims) comprises an amino acid sequence having at least 90-99% or 100% to mature human IL2 [0090] and lists exemplary amino acid deletions and/or substitutions [0086-0089]. The specification further states that the IL2Ra moiety (i.e. SEQ ID NO: 4 of the instant claims) can comprise or consist of an amino acid sequence having at least about 90-99% or 100% sequence identity to an IL2 binding portion of human IL2Ra [0094-0096] and lists exemplary amino acid substitutions. However, these are only exemplary and the claims do not set forth any requirement for what amino acid or where the amino acid can be substituted, deleted, or inserted in order to have 95% identity and still retain any specified function. The specification does not provide any example for what amino acid or where the amino acid can be substituted, deleted, or inserted for SEQ ID NO: 350 (i.e. hIgG4s Fc) and SEQ ID NO: 355 (i.e. protease-cleavable linker PCL94), as elected and set forth in instant claims 1-2 and 7, in order to have 95% identity and still retain any specified function.
One means of providing adequate written description and evidence of
possession of a claimed genus is through providing sufficient distinguishing identifying
characteristics of the genus. The factors to be considered include disclosure of
complete or partial structure, physical and/or chemical properties, functional
characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, the claim does not require that the modifications be made at specific amino acid residues or in a particular region of the sequence, and thus, the claims are drawn to a broad genus of an IL2 proprotein comprising an IL2 moiety (i.e. SEQ ID NO: 2) with up to 6 substitutions, deletions, or insertions, an IL2Ra moiety (i.e. SEQ ID NO: 4 as elected) with up to 8 substitutions, deletions, or insertions, a hIgG4s Fc (i.e. SEQ ID NO: 350 as elected) with up to 11 substitutions, deletions, or insertions, and a protease-cleavable linker PCL94 (i.e. SEQ ID NO: 355 as elected) with up to 4 substitutions, deletions, or insertions.
The claims are drawn to variable sequences for the IL2 moiety, IL2Ra moiety, hIgG4s Fc, and protease-cleavable linker of the IL2 proprotein without any requirement for where these modifications occur within the sequences. Making deletions, insertions, or substitutions to a polypeptide sequence, while requiring the polypeptide to still maintain its function, is highly unpredictable. Bhattacharya et al., 2017 (instant PTO-892) teaches that the range of possible effects of even single variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge [page 18, third paragraph]. Fenton et al., 2020 (instant PTO-892) teaches that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at nonconserved positions (which they call “rheostat” positions) are equally capable of affecting protein function, and that each substitution has a different functional outcome, and the set of substitutions spans a range of outcomes [see Abstract]. Further, Guo et al., 2004 (instant PTO-892) teaches that the effects of mutations on protein function are largely additive [page 9207, left column, third paragraph], supporting that when multiple mutations are introduced, there is even less predictability. Thus, it is clear that the structure of variable sequences of proteins does not predictably correlate with the function thereof.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must
describe an invention and does so in sufficient detail that one skilled in the art can
clearly conclude that "the inventor invented the claimed invention." Lockwood v.
American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re
Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he
description must clearly allow persons of ordinary skill in the art to recognize that [the
inventor] invented what is claimed."). Thus, an applicant complies with the written
description requirement "by describing the invention, with all its claimed limitations, not
that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention."
Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
A "representative number of species" means that the species, which are
adequately described, are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species
to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if
the disclosure "indicates that the patentee has invented species sufficient to constitute
the gen[us]. "See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v.
Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir.
2004) "[A] patentee of a biotechnological invention cannot necessarily claim a genus
after only describing a limited number of species because there may be unpredictability
in the results obtained from species other than those specifically enumerated."). "A
patentee will not be deemed to have invented species sufficient to constitute the genus
by virtue of having disclosed a single species when ... the evidence indicates ordinary
artisans could not predict the operability in the invention of any species other than the
one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir.
2004).
Thus, for all the reasons set forth above, Applicant has failed to meet the written description requirement.
Claims 13, 14, 17, 19-20, 23, 25, 30, 35, 38, 41, 43, 46, 49, 51, 56, 62, 67, 73, 75, 77, 79-81, 85-86, 90, and 94, which depend from claim 1, also fail to meet the written description requirement for the same reasons as set forth above.
It is noted claims 13-14, 19-20, 35, 38, 43, and 46 require 100% sequence identity. However, the claims do not remedy the written description deficiencies of claim 1 as a whole.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 13-14, 17, 19-20, 23, 25, 30, 35, 38, 43-44, 46, 49, 73, 75, 77, 79-81, 85-86, 90, and 94 are rejected under 35 U.S.C. 103 as being unpatentable over Zijuan (WO2021011353; 02/06/2025 8 page IDS) in view of Kirshner (WO2017023761; instant PTO-892).
Regarding claims 1, 13-14, 19-20, 25, 30, 35, 38, 43, 46, 73, 77, and 90, Zijuan teaches an activatable IL2 proprotein homodimer (i.e. first and second polypeptide are identical as claimed in instant claim 90) [page 1, lines 16-19, 32-34] comprising a first and second polypeptide as depicted in Figures 3C and 3D (Figure 3D is reproduced below):
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144
670
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Greyscale
The first and second polypeptides of Zijuan correspond to the instantly claimed first and second polypeptide chains as follows: (i) CH2CH3, (ii) Linker 1, (iii) IL-2Ra, (iv) Linker 2, (v) IL-2. Applicant defines SEQ ID NO: 350 (as elected) of the (i) first and sixth amino acid sequences as an hIgG4s Fc (i.e. CH2CH3) [page 92, Table S], SEQ ID NO: 4 (as elected) of the (iii) third and eighth amino acid sequences as hILRa extracellular domain [0092], and SEQ ID NO: 2 for the (v) fifth and tenth amino acid sequences as mature hIL2 [0076]. Thus, the structure depicted in Figures 3C and 3D of Zijuan is the identical to the overall structure claimed in instant claim 1.
Zijuan further teaches that the fusion of the C-terminus of the Fc to the N-terminus of the IL-2Ra is with a cleavable or non-cleavable linker, and the fusion of the C-terminus of the IL-2Ra to the N-terminus of the IL-2 is with a cleavable or non-cleavable linker and that full activity can be restored after protease cleavage between the IL-2 and IL-2Ra [page 8, lines 33-36] thereby indicating a protease cleavable linker is necessary between the IL-2 and IL-2Ra to restore full activity. Zijuan also teaches that the cleavable linker comprises a protease cleavage site [page 5, lines 1-7]. Zijuan further teaches that the first and second IL-2 proteins optionally comprise or consist of amino acids 21-153 of SEQ ID NO: 1 (i.e. full-length wild-type human IL-2) [page 2, lines 27-30] and that the IL-2Ra can be human IL-2Ra-sushi comprising SEQ ID NO: 6 [page 30, lines 24-26; Table S2].
Residues 21-153 of SEQ ID NO: 1 of Zijuan has 100% sequence identity to SEQ ID NO: 2 of instant claim 1. SEQ ID NO: 6 of Zijuan has 100% sequence identity to SEQ ID NO: 4 of instant claims 1, 35, 38, 43, and 46.
Zijuan also teaches examples of non-cleavable linkers such as [GGGGS]x, wherein x can be 4 [page 40, lines 32-36]. This linker has 100% sequence identity to the linker as elected in instant claims 25 and 30.
However, Zijuan does not specifically teach that the Fc domain (i.e. CH2CH3; the first amino acid sequence of the first polypeptide chain and the sixth amino acid sequence of the second polypeptide chain as claimed) comprises SEQ ID NO: 350 (as elected).
Kirschner teaches a heavy chain constant region Fc domain comprising the sequence of SEQ ID NO: 1681 [0155].
SEQ ID NO: 1681 of Kirschner has 100% sequence identity to SEQ ID NO: 350 of instant claims 1, 13, 14, 19, and 20.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have picked upon the various embodiments of Zijuan, specifically to have chosen a non-cleavable linker between the Fc domain and the IL2Ra and a protease cleavable linker between the IL2Ra and IL2, and arrived at the overall structure of the claimed IL2 proprotein because Zijuan teaches this is a suitable structure for the IL2 proprotein. Second, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the CH2CH3 (Fc domain) of Zijuan to be SEQ ID NO: 1681, a heavy chain constant region Fc domain, of Kirschner. One would have been motivated to use this sequence for the Fc domain because it is a known sequence in the art, and it is obvious to use known variations in the prior art for predictable outcomes. See MPEP 2143 (F).
Claims 17 and 23 are included in this rejection because SEQ ID NO: 1681 of Kirschner (which has 100% sequence identity to SEQ ID NO: 350 as elected for the first and sixth amino acid sequences as claimed) is 228 amino acid residues in length.
Claims 41 and 49 are included in this rejection because SEQ ID NO: 6 of Zijuan (which has 100% sequence identity to SEQ ID NO: 4 as elected for the third and eight amino acid sequences as claimed) is 166 amino acid residues in length.
Claims 75 and 79 are included in this rejection because residues 21-153 of SEQ ID NO: 1 of Zijuan (which has 100% sequence identity to SEQ ID NO: 2 for the fifth and tenth amino acid sequences as claimed) is 133 amino acid residues in length.
Claims 80-81 and 85-86 are included in this rejection because as depicted in Figures 3C and 3D of Zijuan, the polypeptide chains lack any additional sequences between each of the individual amino acid sequences (i.e. the Fc domain, Linker 1, IL-2Ra, Linker 2, and IL2), absent evidence to the contrary.
Claim 94 is included in this rejection because Zijuan teaches a pharmaceutical composition comprising the activatable proprotein homodimer and a pharmaceutically acceptable carrier (excipient) [page 6, lines 16-17].
12. Claims 1-2, 7, 13-14, 17, 19-20, 23, 25, 30, 35, 38, 43-44, 46, 49, 73, 75, 77, 79-81, 85-86, 90, and 94 are rejected under 35 U.S.C. 103 as being unpatentable over Zijuan (WO2021011353; 02/06/2025 8 page IDS) in view of Kirshner (WO2017023761; instant PTO-892), as applied to claims 1, 13-14, 17, 19-20, 23, 25, 30, 35, 38, 43-44, 46, 49, 73, 75, 77, 79-81, 85-86, 90, and 94 above, and further in view of Presta (U.S. 6,121,022; instant PTO-892).
The teachings of Zijuan and Kirschner are above. Further, Zijuan teaches that the binding moiety (i.e. CH2CH3; Fc domain) can also be a CH1CH2CH3 [page 35, lines 12-14]. The Examiner notes that SEQ ID NO: 355 (as elected) for the eleventh and twelfth amino acid sequences on the N-terminal of the first and sixth amino acid sequences, respectively, is defined by Applicant as hIgG4 CH1 [Page 93, Table S].
However, Zijuan and Kirschner do not specifically teach that the CH1 domain of the IL2 proprotein comprises the sequence of SEQ ID NO: 355.
Regarding claims 2 and 7, Presta teaches a sequence for an hIgG4 CH1 domain [see Figures 2a-2b].
The sequence of Presta has 100% sequence identity to SEQ ID NO: 355 of the instant claims.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have attached a CH1 domain to the N terminus of the first and second polypeptides of Zijuan (i.e. an eleventh and twelfth amino acid sequence on the N-terminus of the first and sixth amino acid sequences as claimed). One would have been motivated to have made this modification because Zijuan teaches that this is a suitable structure of the IL2 proprotein. It further would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the CH1 of Zijuan to be the hIgG4 CH1 domain of Presta. One would have been motivated to use this sequence for the CH1 domain because it is a known sequence in the art, and it is obvious to use known variations in the prior art for predictable outcomes. See MPEP 2143 (F).
Claims 1, 13-14, 17, 19-20, 23, 25, 30, 35, 38, 43-44, 46, 49, 51, 62, 73, 75, 77, 79-81, 85-86, 90, and 94 are rejected under 35 U.S.C. 103 as being unpatentable over Zijuan (WO2021011353; 02/06/2025 8 page IDS) in view of Kirshner (WO2017023761; instant PTO-892), as applied to claims 1, 13-14, 17, 19-20, 23, 25, 30, 35, 38, 43-44, 46, 49, 73, 75, 77, 79-81, 85-86, 90, and 94 above, and further in view of Moore (WO2016118629; instant PTO-892).
The teachings of Zijuan and Kirschner are above.
However, Zijuan and Kirschner do not specifically teach that the fourth amino acid sequence and the ninth amino acid sequence (i.e. protease cleavable linkers) comprise the amino acid sequence of SEQ ID NO: 64.
Regarding claims 51 and 62, Moore teaches SEQ ID NO: 481, a matrix metalloprotease-cleavable (MMP) substrate peptide cleavable moiety (CM1) [00018].
SEQ ID NO: 481 of Moore has 100% sequence identity to SEQ ID NO: 64 of the instant claims.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the cleavable linker that comprises a protease cleavage site of Zijuan to specifically comprise the sequence of SEQ ID NO: 481 of Moore. One would have been motivated to have made this modification because Moore teaches that SEQ ID NO: 481 is a MMP substrate peptide cleavable moiety (i.e. protease cleavage site). One would have been motivated to use this sequence for the protease cleavage site in the cleavable linker of Zijuan because it is a known sequence in the art, and it is obvious to use known variations in the prior art for predictable outcomes. See MPEP 2143 (F).
Allowable Subject Matter
The Examiner searched SEQ ID NOs: 185, 189, 207, 338, and 339 for the protease cleavable linker sequence (i.e. (iv) the fourth and (iv) the ninth amino acid sequences of the first and second polypeptides claimed in instant claim 1, respectively), all of which were free of the art. As such, the election of species requirement for Species I and J, set forth in the reply filed on 03/05/2026, is withdrawn as stated above.
Examiner’s Note
The Examiner considered the claims as they currently stand of copending application No. 18/328,327. The sequences in claim 1 of ‘327 did not correspond to the sequences of instant claim 1. As such, no double patenting rejection was made.
Conclusion
No claims are allowed.
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/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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