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
The remarks filed 01/07/2026 are acknowledged.
Claims 1-24 are canceled.
Claims 25-48 are pending.
Applicant’s election without traverse of Group I, claims 25-44 and 47, in the reply filed on 01/07/2026 is acknowledged. Applicant’s election of the following species in the reply filed 01/07/2026 is acknowledged: W142H (contained in SEQ ID NO: 5) for the specific IL-7 variant, L234A/L235A for the optional substitutions of the binding moiety, an exhausted T-cell for immune cell, anti-PD-1 for the target of the binding moiety, the structure set forth in claim 37 for the structure of the bifunctional molecule, and SEQ ID NOs: 51, 53, and 61 for the HCDRs 1-3, respectively, and SEQ ID NOs: 65, 66, and 16 for the LCDRs 1-3, respectively.
The elected species for Species Group F, the specific sequences for the antigen-binding domain (i.e. HCDRs 1-3 and LCDRs 1-3), 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 Therefore, the election of species for Species Group F is withdrawn.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 Once the election of species requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable.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.
Further, Applicant requested an additional species election for Species Group A, specifically requesting D74Q of SEQ ID NO: 13. The Examiner is acknowledging the first elected species of W142H of SEQ ID NO: 5 but will not be expanding the search to include the second requested election. Further, Applicant elected without traverse but seems to have presented arguments as if electing with traverse. Since Applicant explicitly stated the election was made without traverse, the arguments will not be responded to.
Claims 27-28, 39-40, 45-46, and 48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species there being no allowable generic or linking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 01/07/2026.
Therefore, claims 25-26, 29-38, 41-44, and 47 are under examination.
Priority
The instant application is a 371 of PCT/EP2020/086600 and claims priority to European Application EP19306671.9. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Therefore, priority is given with the earliest effective filing date of 12/17/2019.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/15/2022, 06/06/2023, 08/15/2024, and 10/25/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because Figures 12A-D contain sequences that are not identified by sequence identifiers (i.e. SEQ ID NO: X or the like) in accordance with 37 CFR 1.831(c), either in the Figure itself or in the specification in the brief description of drawings. 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.
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). See the following for specific locations of deficiencies: Page 6, Description for Figure 1; Page 7, Descriptions for Figures 3-5; Page 8, Description for Figure 7; Page 9, Description for Figure 12; Page 10, Description for Figure 14; Page 11, Descriptions for Figures 15-16; Page 12, Descriptions for Figures 18-19; Page 13, Descriptions for Figures 21-22; page 15, line 7; page 43, lines 14-21; page 46, lines 2-3, 13-14, 32; page 47, line 15; page 48, lines 8-9, 29-30; page 49, lines 19-20; page 50, lines 4-5; page 84, lines 22, 27.
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.
Claim Objections
Claim 25 is objected to because of the following informalities: Claim 25 recites the limitation “specifically expressed on immune cells surface”. This is grammatically awkward and the Examiner recommends amending the claim to recite “specifically expressed on the surface of an immune cell”. Appropriate correction is required.
Claim 34 is objected to because of the following informalities: Claim 34 recites “T exhausted cells”. However, claim 32 recites “exhausted T cell”. To maintain consistent claim language, the Examiner recommends amending claim 34 to recite “exhausted T cell”. Appropriate correction is required.
Claim 38 is objected to because of the following informalities: Claim 38 recites the limitation “Fc chain covalently linked.” This is grammatically awkward and the Examiner recommends amending the claim to recite “Fc chain is covalently linked”. Appropriate correction is required.
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 30-31, 37-38, and 41-44 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.
Claim 30 recites specific IgG1 heavy chain constant domain substitutions and claim 31 recites specific IgG4 light chain constant domain substitutions. However, there is no reference to the numbering scheme, making the claims unclear. That is, if the numbering scheme is by EU numbering or by another scheme. The specification does use EU numbering, e.g. page 41, legend of Table E in the instant specification. Clarifying that the numbering is according to EU numbering (if that was the Inventors’ intention) would overcome this rejection. Further, claim 30 recites “P257I/Q311”. It is unclear if residue 311 is to remain as Q, can be substituted to be any amino acid other than Q, or is supposed to be a specific amino acid substitution. Therefore, the scope of this claim is indefinite.
Claim 31 recites “T256E.17”. It is unclear what amino acid substitution this is referring to as this is not standard nomenclature. Additionally, “T256E.17” does not occur in the specification. Therefore, the scope of this claim is indefinite.
Claim 37 recites the limitation “a first heterodimeric Fc chain” and “a complementary second heterodimeric Fc chain”. It is unclear how the first or second Fc chain by itself can be “heterodimeric” because it is the pair of Fc chains that is heterodimeric. Therefore, the scope of this claim is indefinite.
Claims 38 and 41-44, which depend from claim 37, are therefore indefinite for the same reasons set forth above.
Note: The Examiner recommends amending the claim to recite “a first Fc chain” and “a second Fc chain” and “wherein the first and second Fc chains are heterodimeric” to overcome the rejection.
Claim Rejections - 35 USC § 112(a)
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 25-26, 30-38, 41-44, and 47 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 25 is drawn to a bifunctional molecule comprising an IL-7 variant conjugated to a binding moiety, wherein: the binding moiety binds to a target specifically expressed on the surface of an immune cell, and the IL-7 variant presets at least 75% identity with a wild type human IL-7 (wth-IL-7). Claims 26-29 further limit the variant to specific single substitutions or combination of single substitutions compared to wth-IL-7.
The specification teaches that the IL-7 variant (IL-7m) differs by at least one amino acid mutation which i) reduces affinity of the IL-7 variant for IL-7 receptor (IL-7R) and ii) improves pharmacokinetics of the IL7 variant in comparison to wt-IL7 [page 25, lines 7-10] and that the variant presents at least 75% identity with wth-IL-7 [page 27, lines 4-8]. However, the specification only discloses the specific variants comprising SEQ ID NOs: 2-15 [page 29, lines 1-5], which have at least 95% sequence identity to SEQ ID NO: 1 (hwt-IL-7). The specification does not disclose any other examples of IL-7 “variants” that i) reduces affinity of the IL-7 variant for IL-7 receptor (IL-7R) and ii) improves pharmacokinetics of the IL7 variant in comparison to wt-IL7, that has less than 95% sequence identity to SEQ ID NO: 1. The specification further does not provide any guidance on which residues, other than those comprised in SEQ ID NOs: 2-15, could be modified and have less than 95% sequence identity while still maintaining the function of reducing affinity of the IL-7 variant for IL-7 receptor (IL-7R) and ii) improving pharmacokinetics of the IL7 variant in comparison to wt-IL7.
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, other than those specifically listed, 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 IL-7 variants with up to 38 substitutions and/or deletions in SEQ ID NO: 1 (SEQ ID NO: 1 consists of 152 amino acid residues; 25% of 152 is 38).
Claim 25 is drawn to a variable sequence for the IL-7 variant (up to 38 substitutions and deletions in SEQ ID NO: 1). 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, based on the lack of teachings in the specification and the teachings in the art, Applicant has failed to meet the written description requirement of an IL-7 variant that has less than 95% sequence identity to SEQ ID NO: 1. Therefore, one of skill in the art would not conclude that Applicant was in possession of an IL-7 variant that has anything less than 95% sequence identity to SEQ ID NO: 1 (hwt-IL-7), and retains its function of reducing affinity of the IL-7 variant for IL-7 receptor (IL-7R) and ii) improving pharmacokinetics of the IL7 variant in comparison to wt-IL7.
Claims 26, 30-38, 41-44, and 47, which depend from claim 25, do not meet the written description requirement for the same reasons set forth above.
The Examiner notes that instant claim 29 sets forth specific sequences for the IL-7 variant, with all listed sequences of SEQ ID NOs: 2-15 having at least 95% sequence identity to instant SEQ ID NO: 1. Therefore, claim 29 does meet the written description requirement.
Claim Interpretation
Claims 30-31, 35, and 37-38 recite the word “optionally.” The Examiner is interpreting everything that succeeds the “optionally” as optional and not required claim limitations, and as such, these limitations are not necessarily included in the rejections below.
Claim 38 recites that the second Fc chain is linked to the IL-variant, thereby clearly requiring that the bifunctional molecule has only a single IL-7 variant. Thus, this excludes construct 4 in Figure 1 of the instant specification.
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 25-26, 29-31, 35-36, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Fang (WO2019144945; instant PTO-892).
Regarding claims 25, 26, and 29, Fang teaches a PD-L1 inhibitor (binding moiety) fused to an IL-7 protein through a peptide linker (bifunctional molecules) [page 2, third paragraph], wherein the IL-7 has an amino acid residue other than Trp at location 142 [page 4, first paragraph]. Fang also teaches that IL7 variants with a different activity level may have better synergism with the anti-PDL1 function [page 29, first paragraph]. Fang further teaches that a series of single site mutations on W142 of IL7 were generated, with amino acids divided into four categories: non-polar (inclusive of F), polar (inclusive of Y), positively charged (inclusive of H), and negatively charged, with a few representative amino acids from each group selected to construct the anti-PDL1-IL7 molecules [page 29, fourth paragraph]. Fang also teaches that the IL7 variants have different and attenuated IL7 activities by modifying a single site mutation of W142 [page 30, second paragraph]. Fang also teaches that PD-L1 is expressed on T cells, NK cells, and macrophages (immune cells) [page 2, second paragraph]. This is further evidenced by Chinai et al., 2015 (instant PTO-892) that teaches PD-L1 is seen on T cells, B cells, monocytes, macrophages, and DCs (immune cells) [page 587, right column, second paragraph]. Thus, the anti-PDL1 inhibitor (binding moiety) of Fang would necessarily bind to PDL1 (a target) specifically expressed on immune cells surface.
However, Fang does not explicitly teach the claim limitations in a manner as required by 35 U.S.C. 102.
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 among the various embodiments of Fang to have arrived at the claimed bifunctional molecule (i.e. IL7 variant conjugated to a binding moiety) wherein the IL-7 variant comprises the amino acid mutation of W124H, W142F, or W142Y, because Fang teaches that these are mutations that could be chosen for W142 and generally suggests that IL7 variants have different and attenuated IL7 activities by modifying a single site mutation of W142. Additionally, it would have been obvious to try specifically selecting the W142H mutation for the IL7 variant as a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. See MPEP 2143. One of ordinary skill in the art would have been motivated to try the W142H substitution because Fang teaches that IL7 variants with a different activity level may have better synergism with the anti-PDL1 function. Further, since the structure of the IL7 variant is 100% identical to that as claimed, than the IL7 variant would necessarily i) reduce affinity for IL-7 and ii) improve pharmacokinetics, as claimed in instant claim 1, since function flows from structure. See MPEP 2112.01(II).
The Examiner notes that SEQ ID NO: 5 of instant claim 29 comprises only a W142H mutation compared to wth-IL-7 (i.e. SEQ ID NO: 1 of instant claim 25), SEQ ID NO: 6 of instant claim 29 comprises only a W142Y mutation compared to wth-IL-7, and SEQ ID NO: 7 of instant claim 29 comprises only a W142F mutation to wth-IL-7. Thus, the teachings of Fang above would result in an IL-7 variant comprising SEQ ID NO: 5, 6, or 7.
Claims 30 and 31 are included in this rejection because Fang teaches that the antibody (binding moiety) comprises a heavy chain constant domain (i.e. CH1, CH2, and CH3) [page 10, third paragraph] and that the antibody molecules of the disclosure can be human and can be IgG1 or IgG4 [page 10, first paragraph]. Thus,
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 among the various embodiments of Fang to have arrived at the claimed binding moiety structures.
Claim 35 is included in this rejection because Fang teaches that the C-terminal of the heavy chain constant domain of the PD-L1 inhibitor is fused to the N-terminal residue of the IL-7 protein by a peptide linker, and that the PD-L1 inhibitor is an anti-PD-L1 antibody [page 20, second-third paragraphs; page 27, Example 1].
Claim 36 is included in this rejection because Fang teaches that the peptide linker may be SEQ ID NO: 1 or 2 [page 16, third paragraph; claim 6].
SEQ ID NOs: 1-2 of Fang have 100% sequence identity to SEQ ID NOs: 69 and 70, respectively, of the instant claim.
Claim 47 is included in this rejection because Fang teaches a pharmaceutical composition comprising an effective amount of the fusion (bifunctional) molecule and an acceptable carrier [page 26, fourth paragraph].
Claims 25-26, 29-36, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Fang (WO2019144945; instant PTO-892), as applied to claims 25-26, 29-31, 35-36, and 47 above, and further in view of Zhan et al., 2016 (instant PTO-892).
The teachings of Fang are above.
However, Fang does not specifically teach that the target is expressed by exhausted T cells and that the binding moiety binds to PD-1.
Regarding claims 32-34, Zhan teaches that antibodies that bind to either PD-1 or PD-L1 block the interactions between PD-1/PD-L1 and thus may enable T cells to attack tumor cells [page 1028, right column, second paragraph].
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 bifunctional molecule of Fang to comprise a binding moiety that binds to a target of PD-1, as taught by Zhan. One would have been motivated to have made this modification because Zhan teaches that antibodies that bind to either PD-1 or PD-L1 block the interactions between PD-1/PD-L1 and thus may enable T cells to attack tumor cells. It is prima facie obvious to substitute equivalents known for the same purpose (see MPEP 2144.06 (II)).
Further, regarding the limitations of the immune cell is an exhausted T cell and wherein the target is expressed by exhausted T cells, as set forth in instant claims 32-34, the bifunctional molecule comprising an IL-7 variant and an antibody that binds to PD-1, as taught by Fang and Zhan above, would necessarily bind to PD-1 on exhausted T cells. This is evidenced by Chinai et al., 2015 (instant PTO-892) that teaches that PD-1 is observed on exhausted T cells and upregulated selectively on exhausted CD8 T cells [page 587, left column, second paragraph; page 589, left column, fourth paragraph].
Claims 25-26, 29-31, 35-38, 41, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Fang (WO2019144945; instant PTO-892), as applied to claims 25-26, 29-31, 35-36, and 47 above, and further in view of Kim (WO2018030806; instant PTO-892).
The teachings of Fang are above. To reiterate, Fang teaches a PD-L1 inhibitor (binding moiety) fused to an IL-7 protein through a peptide linker (bifunctional molecules) [page 2, third paragraph], wherein the IL-7 has an amino acid residue other than Trp at location 142 (IL-7 variant) [page 4, first paragraph]. Fang further teaches that the antibody (binding moiety; antigen binding domain) comprises a heavy chain constant domain (i.e. CH1, CH2, and CH3; i.e. comprises the Fc domain) [page 10, third paragraph] and that the C-terminal of the heavy chain constant domain of the PD-L1 inhibitor is fused to the N-terminal residue of the IL-7 protein by a peptide linker, and that the PD-L1 inhibitor is an anti-PD-L1 antibody [page 20, second-third paragraphs; page 27, Example 1]. Thus, Fang teaches the first monomer as claimed in instant claim 37.
However, Fang does not teach that the bifunctional molecule comprises a second monomer comprising a Fc domain that is heterodimeric with the first Fc domain and is devoid of an antigen binding domain or that the second monomer is covalently linked to the IL-7 variant.
Regarding claims 37 and 38, Kim teaches heterodimeric Fc-fused proteins comprising a first Fc region and a second Fc region of a Fc region pair of an immunoglobulin while a subunit of a biologically active protein is bound to at least one of N-terminal or C-terminal of the first Fc region and/or the second Fc region, the first Fc region and the second Fc region are CH3 domains modified to promote the formation of a heterodimer [see Abstract]. Kim further teaches that the use of the heterodimeric Fc-fused protein increases the in vivo half-life of the biologically active protein, and thus, various types of biological activities can be maintained for a long time in the body [see Abstract]. Kim further teaches that the first Fc region, the second Fc region, and a subunit of a physiologically active protein may be bonded in a linker-mediated form, wherein the linker is preferably an amino acid (peptide) linker [page 13, paragraph 155].
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 bifunctional molecule comprising a first monomer of Fang to specifically comprise a second monomer comprising a second Fc chain (domain) that is heterodimeric with the first Fc chain (domain) and that is also covalently linked to the IL-7 variant, as taught by Kim. One would have been motivated to make this modification because Kim teaches that the heterodimeric Fc-fused proteins comprising a first Fc region and a second Fc region of a Fc region pair of an immunoglobulin while a subunit of a biologically active protein is bound to at least one of N-terminal or C-terminal of the first Fc region and/or the second Fc region, the first Fc region and the second Fc region are CH3 domains modified to promote the formation of a heterodimer, that the first Fc region, the second Fc region, and a subunit of a physiologically active protein may be bonded in a linker-mediated form, wherein the linker is preferably an amino acid (peptide) linker, and that the use of the heterodimeric Fc-fused protein increases the in vivo half-life of the biologically active protein, and thus, various types of biological activities can be maintained for a long time in the body. Thus, there would be a reasonable expectation of success in making this modification because this is a known structural format in the art for immunocytokines and it is obvious to use known variations in the prior art for predictable outcomes. See MPEP 2143 (F).
Claim 41 is included in this rejection because Fang teaches that the anti-PD-L1 antibody is a single-chain fragment (scFv) or a Fab fragment [page 3, first paragraph].
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Copending Application No. 17/414,970
Claims 25-26, 29-36, and 47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 34-35, 37, 39, 41-47, and 54 of copending Application No. 17/414,970 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 25, 26, and 32-34 of the instant application, claim 34 the reference application teaches a bifunctional molecule comprising: (a) an anti-human PD-1 antibody or an antigen-binding fragment thereof, which anti-human PD-1 antibody or antigen-binding fragment comprises a full-length lgG Fc domain and a constant light chain, wherein the C-terminus of the lgG Fc domain and/or the C-terminus of the constant light chain of the anti-human PD-1 antibody or antigen-binding fragment is covalently linked to, (b) a human interleukin 7 (IL-7) variant having at least 90% sequence identity to SEQ ID NO: 51, wherein said IL-7 variant comprises the mutation W142H, and binds to an IL-7 receptor; and further wherein the covalent linkage of the IL-7 variant to the C-terminus of the lgG Fc domain and/or to the C-terminus of the constant light chain of the anti-human PD-1 antibody or antigen-binding fragment thereof is direct or by a flexible linker peptide, claim 41 of the reference application teaches the IL-7 variant which comprises said W142H mutation comprises or consists of an amino acid sequence having at least 95% identity with a wild type human IL-7 (wth-lL-7) having SEQ ID NO: 51, claim 42 of the reference application teaches that the IL-7
variant comprises or consists of an amino acid sequence which only differs from the amino acid sequence set forth in SEQ ID NO: 51 by said a W142H mutation, claim 43 of the reference application teaches that the IL-7 variant comprises said W142H mutation i) possesses reduced affinity for the IL-7 receptor (IL-7R) in comparison to the affinity of wild-type IL-7 for IL-7R, and ii) said IL-7 variant improves the pharmacokinetics of the bifunctional molecule comprising the IL-7 variant in comparison with a bifunctional molecule comprising wild-type IL-7 wherein said wild-type IL-7 consists of the amino acid sequence of SEQ ID NO: 51, and claim 44 of the reference application teaches that the IL-7 variant which comprises said W142H mutation further comprises another amino acid substitution or a group of amino acid substitutions selected from the group consisting of (i) C2S, C141S and C47S, C92S, C2S, C141S and C34S, C129S, or C47S, C92S and C34S, C129S, (ii) D74E, D74Q or D74N, (iii) Q11E, Y12F, M17L, Q22E and/or K81R; or any combination thereof.
SEQ ID NO: 51 of the reference application has 100% sequence identity to SEQ ID NO: 1 of the instant application.
Regarding the limitations of “the binding moiety binds to a target specifically expressed on immune cells”, as set forth in instant claim 25, and wherein the immune cell is an exhausted T cell and wherein the target is expressed by exhausted T cells, as set forth in instant claims 32-34, the bifunctional molecule comprising an IL-7 variant and an antibody that binds to PD-1, as taught by the reference application above, would necessarily bind to PD-1 on exhausted T cells (i.e. immune cells). This is evidenced by Chinai et al., 2015 (instant PTO-892) that teaches that PD-1 is observed on exhausted T cells and upregulated selectively on exhausted CD8 T cells [page 587, left column, second paragraph; page 589, left column, fourth paragraph].
Regarding claim 29 of the instant application, claim 45 of the reference application teaches that the IL-7 variant comprises or consists of the amino acid sequence set forth in SEQ ID NO: 56.
SEQ ID NO: 56 of the reference application has 100% sequence identity to SEQ ID NO: 5 of instant claim 29.
Regarding claim 30 of the instant application, claim 46 of the reference application teaches that the anti-human PD-1 antibody or antigen-binding fragment thereof comprises a light chain constant domain derived from a human kappa light chain constant domain and a heavy chain constant domain derived from a human lgG1 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of T2S0Q/M428L; M252Y/S254T/T256E + H433K/N434F; E233P/L234V/L235A/G236A + A327G/A330S/P331S; E333A; S239D/A330L/1332E; P2571/Q311; K326W/E333S; S239D/1332E/G236A; N297A;
L234A/L235A; N297A + M252Y /S254T/T256E; K322A; and wherein numbering for each of the afore-identified substitutions is according to EU numbering.
Regarding claim 31 of the instant application, claim 47 of the reference application teaches that the antihuman PD-1 antibody or antigen-binding fragment thereof comprises a light chain constant domain derived from a human kappa light chain constant domain and a heavy chain constant domain derived from a human lgG4 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of S228P, L234A/L235A, S228P + M252Y/S254T/T256E; and K322A; and wherein for each of the afore-identified substitutions the numbering is according to EU numbering.
Regarding claim 35 of the instant application, claim 35 of the reference application teaches that the N-terminus of the human IL-7 variant is connected to the C-terminus of said full-length lgG Fc domain and/or to the constant light chain of said anti-human PD-1 antibody or antigen-binding fragment thereof.
Regarding claim 36 of the instant application, claim 49 of the reference application teaches that the C terminus of the of the IgG Fc domain in the anti-human PD-1 antibody or antigen binding fragment thereof is linked to IL-7 variant by the flexible peptide linker (GGGGS)3 (SEQ ID NO. 70).
SEQ ID NO: 70 of the reference claim has 100% sequence identity to SEQ ID NO: 70 of the instant claim.
Regarding claim 47 of the instant application, claim 54 of the reference application teaches a pharmaceutical composition comprising the bifunctional molecule according to of claim 34 and a pharmaceutically acceptable carrier.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
It is noted that nonelected claims 27-28, 45-46 and 48 correspond to claims 44, 50-52 and 55-59 of the reference application, respectively.
Claims 25-26, 29-38, 41-44, and 47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 34-35, 37, 39, 41-47, and 54 of copending Application No. 17/414,970 (reference application), as applied to claims 25-26, 29-36, and 47, and further in view of Kim (WO2018030806; instant PTO-892).
The teachings of the reference application are above. To reiterate, claim 34 of the reference application teaches a bifunctional molecule comprising: (a) an anti-human PD-1 antibody or an antigen-binding fragment thereof, which anti-human PD-1 antibody or antigen-binding fragment comprises a full-length lgG Fc domain and a constant light chain, wherein the C-terminus of the lgG Fc domain and/or the C-terminus of the constant light chain of the anti-human PD-1 antibody or antigen-binding fragment is covalently linked to, (b) a human interleukin 7 (IL-7) variant having at least 90% sequence identity to SEQ ID NO: 51, wherein said IL-7 variant comprises the mutation W142H, and binds to an IL-7 receptor; and further wherein the covalent linkage of the IL-7 variant to the C-terminus of the lgG Fc domain and/or to the C-terminus of the constant light chain of the anti-human PD-1 antibody or antigen-binding fragment thereof is direct or by a flexible linker peptide
However, the reference application does not specifically teach that the bifunctional molecule comprises a second monomer comprising a Fc domain that is heterodimeric with the first Fc domain and is devoid of an antigen binding domain.
Regarding claims 37 and 38, Kim teaches heterodimeric Fc-fused proteins comprising a first Fc region and a second Fc region of a Fc region pair of an immunoglobulin while a subunit of a biologically active protein is bound to at least one of N-terminal or C-terminal of the first Fc region and/or the second Fc region, the first Fc region and the second Fc region are CH3 domains modified to promote the formation of a heterodimer [see Abstract]. Kim further teaches that the use of the heterodimeric Fc-fused protein increases the in vivo half-life of the biologically active protein, and thus, various types of biological activities can be maintained for a long time in the body [see Abstract]. Kim further teaches that the first Fc region, the second Fc region, and a subunit of a physiologically active protein may be bonded in a linker-mediated form, wherein the linker is preferably an amino acid (peptide) linker [page 13, paragraph 155].
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 bifunctional molecule comprising a first monomer of the reference application to specifically comprise a second monomer comprising a second Fc chain that is heterodimeric with the first Fc chain and that is also covalently linked to the IL-7 variant, as taught by Kim. One would have been motivated to make this modification because Kim teaches that the heterodimeric Fc-fused proteins comprising a first Fc region and a second Fc region of a Fc region pair of an immunoglobulin while a subunit of a biologically active protein is bound to at least one of N-terminal or C-terminal of the first Fc region and/or the second Fc region, the first Fc region and the second Fc region are CH3 domains modified to promote the formation of a heterodimer, that the first Fc region, the second Fc region, and a subunit of a physiologically active protein may be bonded in a linker-mediated form, wherein the linker is preferably an amino acid (peptide) linker, and that the use of the heterodimeric Fc-fused protein increases the in vivo half-life of the biologically active protein, and thus, various types of biological activities can be maintained for a long time in the body. Thus, there would be a reasonable expectation of success in making this modification because this is a known structural format in the art for immunocytokines and it is obvious to use known variations in the prior art for predictable outcomes. See MPEP 2143 (F).
Claim 41 is included in this rejection because claim 34 of the reference application teaches that the PD-1 antibody or antigen-binding fragment thereof comprises a full-length lgG Fc domain and a constant light chain, and claim 39 of the reference application teaches that the anti-human PD-1 molecule a VH and a VL. Therefore, the antigen binding domain (i.e. PD-1 antibody) is necessarily a Fab.
Claims 42 is included in this rejection because claim 37 of the reference application teaches that the anti-human PD-1 antibody or antigen-binding fragment thereof, comprises: (i) a heavy chain variable domain (VH) comprising HCDR1, HCDR2 and HCDR3, and (ii) a light chain variable domain (VL) comprising LCDR1, LCDR2 and LCDR3, wherein: the heavy chain CDR1 (HCDR1) comprises or consists of an amino acid sequence of SEQ ID NO: 1; the heavy chain CDR2 (HCDR2) comprises or consists of an amino acid sequence of SEQ ID NO: 2; the heavy chain CDR3 (HCDR3) comprises or consists of an amino acid sequence of SEQ ID NO: 3 wherein X1 is D or E and X2 is selected from the group consisting of T, H, A, Y, N, E and S; the light chain CDR1 (LCDR1) comprises or consists of an amino acid sequence of SEQ ID
NO: 12 wherein X is G or T; the light chain CDR2 (LCDR2) comprises or consists of an amino acid sequence of SEQ ID NO: 15; the light chain CDR3 (LCDR3) comprises or consists of an amino acid sequence of SEQ ID NO:16, and claim 39 of the reference application teaches that the anti-human PD-1 antibody antigen-binding fragment thereof, comprises or consists of (i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence of SEQ ID NO: 24; and (ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence of SEQ ID NO: 28.
SEQ ID NOs: 1-2, SEQ ID NO: 3 wherein X1 is D and X2 is N, SEQ ID NO: 12 wherein X is T, and SEQ ID NOs: 15-16 of the reference application have 100% sequence identity to SEQ ID NOs: 51, 53, 61, 65, 66, and 16, respectively, of the instant claim, and SEQ ID NOS: 24 and 28 of the reference application comprise CDRs with 100% sequence identity to SEQ ID NOs: 51, 53, 61, 65, 66, and 16, respectively, of the instant claim.
Claims 43 and 44 are included in this rejection because claim 39 of the reference application teaches that the anti-human PD-1 antibody antigen-binding fragment thereof, comprises or consists of (i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence of SEQ ID NO: 24; and (ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence of SEQ ID NO: 28.
SEQ ID NOs: 24 and 28 of the reference application have 100% sequence identity to SEQ ID NOs: 24 and 28 of the instant claims.
This is a provisional nonstatutory double patenting rejection.
Copending Application No. 18/267,795
Claims 25-26, 29-35, 37, 41-44, and 47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43-48, 50, 54, 56-58, and 63 of copending Application No. 18/267,795 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 25-26, 32-34, and 37 of the instant application, claim 43 of the reference application teaches a bifunctional molecule comprising a single antigen binding domain and a wherein the bifunctional molecule comprises a first monomer comprising an antigen binding domain covalently linked via C-terminal end to N-terminal end of a first Fc chain, optionally via a peptide linker, and a second monomer comprising a complementary second Fc chain devoid of antigen-binding domain and of the IL-7 variant; wherein either i) the IL-7 variant is covalently linked to the C-terminal end of said first Fc chain, optionally via a peptide linker; or ii) the single antigen binding domain comprises a heavy variable chain and a light variable chain and the IL-7 variant is covalently linked to the C-terminal end of the light chain; wherein the antigen binding domain binds to PD- 1; and wherein the IL-7 variant presents at least 75% identity with a wild type human IL-7 (wth-IL-7) comprising SEQ ID NO: 1, and the IL-7 variant i) reduces affinity of the IL-7 variant for IL-7 receptor (IL-7R) in comparison to the affinity of wth-IL-7 for IL-7R, and ii) improves pharmacokinetics of the bifunctional molecule comprising the IL-7 variant in comparison with a bifunctional molecule comprising wth-IL-7, claim 44 of the reference application teaches that the IL-7 variant comprises
at least one amino acid mutation selected from the group consisting of (i) W142G, W142A, W142V, W142C, W142L, W1421, W142M, W142H, W142Y and W142F, (ii) C2S-C141S and C47S-C92S, C2S-C141S and C34S-C129S, or C47S-C92S and C34S-C129S, (iii) D74E, D74Q or D74N, iv) Q11E, Y12F, M17L, Q22E and/orK81R; or any combination thereof, the amino acid numbering shown in SEQ ID NO: 1, claim 45 of the reference application teaches that the IL-7 variant is linked at the C-terminal end of first Fc chain by its N-terminal end, claim 46 of the reference application teaches that the IL-7 variant comprises an amino acid substitution selected from the group consisting of W142H, W142F and W142Y, the amino acid numbering being as shown in SEQ ID NO: 1, and claim 50 of the reference application teaches that the first Fc chain and the second Fc chain form a heterodimeric Fc domain.
SEQ ID NO: 1 of the reference application has 100% sequence identity to SEQ ID NO: 1 of the instant application.
Regarding the limitations of “the binding moiety binds to a target specifically expressed on immune cells”, as set forth in instant claim 25, and wherein the immune cell is an exhausted T cell and wherein the target is expressed by exhausted T cells, as set forth in instant claims 32-34, the bifunctional molecule comprising an IL-7 variant and an antibody that binds to PD-1, as taught by the reference application above, would necessarily bind to PD-1 on exhausted T cells (i.e. immune cells). This is evidenced by Chinai et al., 2015 (instant PTO-892) that teaches that PD-1 is observed on exhausted T cells and upregulated selectively on exhausted CD8 T cells [page 587, left column, second paragraph; page 589, left column, fourth paragraph].
Regarding claim 29 of the instant application, claim 47 of the reference application teaches that the IL-7 variant comprises any one of SEQ ID NOs: 2-15.
SEQ ID NO: 5 of the reference application has 100% sequence identity to SEQ ID NO: 5 of the instant claim.
Regarding claims 30-31 of the instant application, claim 48 of the reference application teaches that the bifunctional molecule comprises a) a heavy chain constant domain or a Fc domain of a human IgG1, optionally with a substitution or a combination of substitutions selected from the group consisting of T250Q/M428L; M252Y/S254T/T256E + H433K/N434F; E233P/L234V/L235A/G236A + A327G/A330S/P331S; E333A; S239D/A330L/1332E; P2571/Q311; K326W/E333S;
S239D/1332E/G236A; N297A; L234A/L235A; N297A + M252Y/S254T/T256E;
N297A+N298A+ M252Y/S254T/T256E+ K444A, K322A, K444A, K444E, K444D, K444G, K444S, P329G, L234A/L235A/P329G, M428L, L309D, Q311H, N434S, M428L + N434S and L309D + Q311H + N434S; or b) a heavy chain constant domain or a Fc domain, of a human IgG4, optionally with a substitution or a combination of substitutions selected from the group consisting of S228P, L234A/L235A, S228P + M252Y/S254T/T256 + K444A, P329G, K444E, K444D, K444G, K444S, and L234A/L235A/P329G
Regarding claim 35 of the instant application, claim 45 of the reference application teaches that the IL-7 variant is linked at the C-terminal end of first Fc chain by its N-terminal end.
Regarding claim 41 of the instant application, claim 54 of the reference application teaches that the antigen-binding domain is a Fab domain, a Fab', a single-chain variable fragment (scFV) or a single domain antibody (sdAb).
Regarding claim 42 of the instant application, claim 56 of the reference application teaches that the antigen binding domain comprises b) (i) a heavy chain comprising a CDR1 of SEQ ID NO: 51, a CDR2 of SEQ ID NO: 53 and a CDR3 of SEQ ID NO: 61; and (ii) a light chain comprising a CDR1 of SEQ ID NO: 65, a CDR2 of SEQ ID NO: 66 and a CDR3 of SEQ ID NO: 16.
SEQ ID NOs: 51, 53, 61, 65, 66, and 16 of the reference application have 100% sequence identity to SEQ ID NOs: 51, 53, 61, 65, 66, and 16, respectively, of the instant claim.
Regarding claims 43 and 44 of the instant application, claim 57 of the reference application teaches that the antigen-binding domain comprises a heavy chain variable region (VH) of SEQ ID NO: 24 and a light chain variable region (VL) of SEQ ID NO: 28 and the IL-7 variant comprises the amino acid substitution Wl42H, the amino acid numbering shown in SEQ ID NO: 1, and claim 58 of the reference application teaches that the antigen-binding domain comprises a heavy chain variable region (VH) of SEQ ID NO: 24 and a light chain variable region (VL) of SEQ ID NO: 28.
SEQ ID NOs: 24 and 28 of the reference application have 100% sequence identity to SEQ ID NOs: 24 and 28 of the instant claims.
Regarding claim 47 of the instant application, claim 63 of the reference application teaches a pharmaceutical composition comprising the bifunctional molecule of claim 43 and a pharmaceutically acceptable carrier.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
It is noted that nonelected claims 27-28, 45-46 and 48 correspond to claims 44, 61-62 and 64-66 of the reference application, respectively.
Claims 25-26, 29-37, 41-44, and 47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43-48, 50, 54, 56-58, and 63 of copending Application No. 18/267,795 (reference application), as applied to claims 25-26, 29-35, 37, 41-44, and 47 above, and further in view of Fang (WO2019144945; instant PTO-892).
The teachings of the reference application are above.
However, the reference application does not specifically teach that the IL-7 variant is fused to the binding moiety by a peptide linker selected from the group consisting of SEQ ID NOs: 67-70.
Regarding claim 36, Fang teaches a PD-L1 inhibitor (binding moiety) fused to an IL-7 protein through a peptide linker (bifunctional molecules) [page 2, third paragraph] and that the peptide linker may be SEQ ID NO: 1 or 2 [page 16, third paragraph; claim 6].
SEQ ID NOs: 1-2 of Fang have 100% sequence identity to SEQ ID NOs: 69 and 70, respectively, of the instant claim.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have specifically chosen SEQ ID NO: 1 or 2 of Fang to be the linker between the IL-7 and binding moiety of the reference application. One would have been motivated to have chosen one of these linkers because Fang teaches that these linkers can be used to fuse an IL-7 protein and a binding moiety. Further, one would have been motivated to use one of these sequences for the linker because they are known linker sequences in the art, and it is obvious to use variations known in the prior art for predictable outcomes. See MPEP 2143 (F).
This is a provisional nonstatutory double patenting rejection.
Claims 25-26, 29-35, 37-38, 41-44, and 47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43-48, 50, 54, 56-58, and 63 of copending Application No. 18/267,795 (reference application), as applied to claims 25-26, 29-35, 37, 41-44, and 47 above, and further in view of Kim (WO2018030806; instant PTO-892).
The teachings of the reference application are above. To reiterate, claim 43 of the reference application teaches a bifunctional molecule comprising a single antigen binding domain and a wherein the bifunctional molecule comprises a first monomer comprising an antigen binding domain covalently linked via C-terminal end to N-terminal end of a first Fc chain, optionally via a peptide linker, and a second monomer comprising a complementary second Fc chain devoid of antigen-binding domain and of the IL-7 variant; wherein either i) the IL-7 variant is covalently linked to the C-terminal end of said first Fc chain, optionally via a peptide linker; or ii) the single antigen binding domain comprises a heavy variable chain and a light variable chain and the IL-7 variant is covalently linked to the C-terminal end of the light chain, claim 45 of the reference application teaches that the IL-7 variant is linked at the C-terminal end of first Fc chain by its N-terminal end, and claim 50 of the reference application teaches that the first Fc chain and the second Fc chain form a heterodimeric Fc domain.
However, the reference application does not specifically teach that the in the second monomer, the Fc chain is linker to the IL-7 variant by a peptide linker.
Regarding claim 38, Kim teaches heterodimeric Fc-fused proteins comprising a first Fc region and a second Fc region of a Fc region pair of an immunoglobulin while a subunit of a biologically active protein is bound to at least one of N-terminal or C-terminal of the first Fc region and/or the second Fc region, the first Fc region and the second Fc region are CH3 domains modified to promote the formation of a heterodimer [see Abstract]. Kim further teaches that the first Fc region, the second Fc region, and a subunit of a physiologically active protein may be bonded in a linker-mediated form, wherein the linker is preferably an amino acid (peptide) linker [page 13, paragraph 155].
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 bifunctional molecule of the reference application to specifically have the second monomer covalently linked to the IL-7 variant, as taught by Kim. One would have been motivated to make this modification because Kim teaches that the heterodimeric Fc-fused proteins comprising a first Fc region and a second Fc region of a Fc region pair of an immunoglobulin while a subunit of a biologically active protein is bound to at least one of N-terminal or C-terminal of the first Fc region and/or the second Fc region, and that the first Fc region, the second Fc region, and a subunit of a physiologically active protein may be bonded in a linker-mediated form, wherein the linker is preferably an amino acid (peptide) linker. Thus, there would be a reasonable expectation of success in making this modification because this is a known structural format in the art for immunocytokines and it is obvious to use known variations in the prior art for predictable outcomes. See MPEP 2143 (F).
This is a provisional nonstatutory double patenting rejection.
Allowable Subject Matter
The Examiner search all other possible CDR combinations, as claimed in instant claim 42, and all other VH and VL sequences, as claimed in instant claims 43-44. The prior art does not teach an antigen-binding domain (that binds to PD-1) comprising any of the claimed CDR combinations as claimed in instant claim 42. The prior art also does not teach an antigen-binding domain (that binds to PD-1) comprising the sequences listed in instant claims 43 and 44 for the heavy chain variable region and for the light chain variable region. As such, the election of species requirement for Species Group F, set forth in the reply filed 01/07/2026, is withdrawn as stated above.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brittney E Donoghue whose telephone number is (571)272-9883. The examiner can normally be reached Mon - Fri 7:30 - 3:30.
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, Jeffrey Stucker can be reached at (571) 272-0911. 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.
/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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