DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/CN2021/081841 filed March 19, 2021.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in the instant application on September 15, 2022. Foreign priority is claimed through China 202010196689.5 filed on March 19, 2020. All claims have been given an effective filing date of March 19, 2020.
Election/Restriction
Applicant’s election of Group I (Claims 1, 3-5, 7-8, 10-11, 17, and 24-27) and species election of:
K35D/E and R38W/E/D
A loop having a sequence of (Q/G)S(K/A)N(F/I)H or GDASIH positioned between position 73 and position 84
AGDASIH between position 72 and position 84
IL-2 mutant: SEQ ID NO: 23
IL-2 mutant fusion: SEQ ID NO: 19
in the reply filed on September 9, 2025 is acknowledged. 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)).
Upon further consideration, Examiner withdraws the restriction requirement between Group I (Claims 1, 3-5, 7-8, 10-11, 17, and 24-27) and Groups II-III (Claims 13-16 and 20) as set forth in the Office action mailed on 07/10/25. Claims 13-16 and 20 are hereby rejoined and fully examined for patentability. In view of the withdrawal of the restriction 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.
Claim 18 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on September 9, 2025.
Claim Status
Claim listing filed on September 9, 2025 is pending. Claims 2, 6, 9, 12, 19, and 21-23 are cancelled. Claims 1 and 20 are amended. Claim 18 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions or species. Claims 1, 3-5, 7-8, 10-11, 13-17, 20, and 24-27 are examined upon their merits.
Information Disclosure Statement
The information disclosure statements filed on 03/07/2024, 05/13/2024, 10/11/2024, 11/25/2024, 01/17/2025, 04/16/2025, and 09/12/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Sequence Compliance in Drawings
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 C.F.R. § 1.821 (a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 C.F.R. § 1.821 through 1.825. Specifically, no sequence identification has been provided for the amino acid sequences presented in Figures 3 and 8-9 of the drawings. MPEP § 2412.04 states that where a sequence is presented in a drawing, reference must be made to the sequence by use of the sequence identifier (§ 1.832(a)), either in the drawing or in the Brief Description of the Drawings, where the correlation between multiple sequences in the drawing and their sequence identifiers (§ 1.832(a)) in the Brief Description is clear.
Should Applicant choose to correct the 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.
Applicant is reminded to comply with sequence rules as stated in MPEP§ 2422 and review the specification to ensure the application is in full sequence compliance in response to this action.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Specifically, there are two hyperlinks on page 5 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:// or other browser-executable code. See MPEP § 608.01.
The disclosure is objected to because the sequence listing is not incorporated by reference at the beginning of the specification. MPEP § 2413.04 states that since the "Sequence Listing XML" is not the text of the specification, but rather is sequence data in an XML file format, an incorporation by reference statement is needed to ensure that the content of the "Sequence Listing XML," submitted to the USPTO as an XML file, is considered part of the disclosure capable of providing 35 U.S.C. 112(a) support for the disclosure and any claims relating to nucleotide and/or amino acid sequences. The required incorporation by reference statement identifies: (i) the name of the file; (ii) the date of creation of the file; and (iii) the size of the file in bytes.
The disclosure is objected to because “Table 13” is referenced on page 36, but no Table 13 is present. Appropriate correction is required. Applicant is urged to carefully review the specification for additional informalities.
Claim Objections
Claims 1, 4, 10-11, and 20 are objected to because of the following informalities:
Claim 1, lines 24-30, currently lists different B’C’ loop regions as (i)-(iii). This list should be labeled (a)-(c) as is presented above in the list of mutations. For consistency and clarity, the indented lists should be in 1(i)(a) format. For example, Claim 1(ii)(a) reads “a loop region having a sequence of (Q/G)S(K/A)N(F/I)H…”
Claim 20 requires corrected subpart labeling as outlined above to follow the 1(i)(a) format. Specifically, “introducing into a wild-type IL-2 mutations” should be labeled Claim 20(i) instead of Claim 20(a). The different B’C’ loop regions should be labeled (j)-(l) instead of (i)-(iii) as they are under Claim 20(i). Subparts (b)-(c) should be relabeled as Claim 20(i)-(ii). The list of improved properties should be labeled as Claims 20(iii)(a)-(c) instead of (i)-(iii).
Claim 4 repeats “QSANFH”.
Claims 10-11 and 20 have a hyphen missing between “IL” and “2” and should be corrected to “IL-2” or “IL-2Rα” or “IL-2Rβ” as appropriate.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1, 3-5, 7-8, 10-11, 13-17, 20, and 24-27 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, 8, and 26 recite “preferably” or “e.g.” These phrases render the claims indefinite because it is unclear whether the limitations following the phrases are part of the claimed invention. See MPEP § 2173.05(d). For the purpose of compact prosecution, all claim limitations following the phrases “preferably” or “e.g.” will be interpreted as optional limitations.
Claim 7 recites wherein the IL-2 mutant protein has at least 85% identity to the wild-type human IL-2 and/or the wild-type IL-2 is a human IL-2 or comprises a sequence having at least 85% identity to SEQ ID NOs: 1, 2, or 3. Claim 7 can be interpreted in two ways. First, the IL-2 mutant has at least 85% identity to the wild-type human IL-2 which is understood in the art to be SEQ ID NO: 3. Second, the IL-2 mutant has at least 85% identity to a sequence that has at least 85% identity to SEQ ID NOs: 1, 2, or 3. The scope of the two interpretations are very different, and the metes and bounds of Claim 7 cannot be determined. For the purpose of compact prosecution, Claim 7 will be interpreted as wherein the IL-2 mutant has at least 85% identity to the wild-type human IL-2 which is understood in the art to be SEQ ID NO: 3.
Claim 16 recites the limitations "the host cell" in line 2 and “the conjugate” in line 4. There is insufficient antecedent basis for these limitations in the claim. For the purpose of compact prosecution, Claim 16 will be interpreted as “the host cell comprising the polynucleotide according to claim 15” and “the immunoconjugate.”
Claim 20 recites wherein identifying the IL-2 mutant protein having “improved” expression, “reduced” binding to IL-2Rα, or “enhanced” binding to IL-2Rβ. These phrases are considered indefinite relative terminology because it is unclear what the improved expression, reduced binding, or enhanced binding is in comparison to (MPEP § 2173.05(b)). For the purpose of compact prosecution, it is interpreted that the IL-2 mutant protein is being compared to the wild type IL-2 comprising SEQ ID NOs: 1, 2, or 3.
Claim 26 recites “a mutation that reduces or eliminates binding of the Fc to FcγR.” This phrase is considered functional language because the feature (the mutation) is defined by what it does (reduces or eliminates binding of the Fc to FcγR) rather than by what it is (MPEP § 2173.05(g)). To determine if functional language is ambiguous, the following factors are considered: (1) whether there is a clear cut indication of the scope of the subject matter covered by the claim; (2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and (3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim. These factors are examples of points to be considered when determining whether language is ambiguous and are not intended to be all inclusive or limiting (MPEP § 2173.05(g)). The instant claim states a result obtained without any required structure for the mutations, and the metes and bounds of the mutations are unclear. Further, Claim 26 uses indefinite relative terminology by reciting “reduces or eliminates binding” (MPEP § 2173.05(b)), because it is unclear what the reduction is in comparison to.
Note, wherein “reduced,” “enhanced,” or “increased” binding affinity is in comparison to the wild-type human IL-2, the altered binding affinity is interpreted with the broadest reasonable interpretation as any increase or decrease (even a non-significant change) in binding affinity as measured by methods known in the art prior to the time of filing such as KD.
Note, Claim 1 is interpreted to mean that residues 72 and 84 are unchanged, and residues 73-83 are shortened to 7 amino acids. Wherein the shortened sequence is defined by GDASIH positioned between residues 73 and 84, it is interpreted that the seventh amino acid at residue 73 is the naturally occurring residue of SEQ ID NO: 1, specifically an alanine. Therefore, the sequence would read aa72-AGDASIH-aa84.
Note, the IL-2/CD25 binding interface mutations listed in Claims 1 and 20 are interpreted as closed groups (ie selected from a group consisting of) as is proper for a Markush group (MPEP § 2117.I).
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 4-5 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 1 teaches wherein the shortened B’C’ loop comprises (Q/G)S(K/A)N(F/I)H or GDASIH, a B’C’ loop sequence from IL-15, or a C-terminal truncation of 4 amino acids. Note, Chirifu et al. Nat Immunol. 2007 teaches that the B’C’ loop of IL-15 comprises SGDAS (Figure 2C). The C-terminal truncation of 4 amino acids results in aa72-AQSKNFH-aa84. Claims 4-5 recite wherein the shortened B’C’ loop comprises QSDNFH or AQSDNFH. These B’C’ loops fail to include the limitations of Claim 1 on which they depend. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 3-5, 7-8, 10-11, 13-17, 20, and 24-27 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 claims contain 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.
Claims 1 and 20 are directed to an IL-2 mutant comprising a shortened B’C’ loop sequence comprising a substitution of a sequence at position 74 to position 83 with a B’C’ loop sequence from IL-15. The specification teaches one B’C’ loop sequence from IL-15 comprising SGDASIH (page 28 and Table 4), but does not provide a definition of a B’C’ loop sequence “from IL-15.” Chirifu et al. Nat Immunol. 2007 teaches that the B’C’ loop of IL-15 comprises SGDAS (Figure 2C). Therefore, a B’C’ loop sequence from IL-15 is understood with the broadest reasonable interpretation as any fragment of two or more amino acids in SGDAS wherein the remaining residues are maintained from wild-type IL-2 to total a B’C’ loop comprising 7 residues. Thus, the claims are directed to a genus of possible B’C’ loops from IL-15. Claims 4-5 recite the B’C’ loop QSDNFH or AQSDNFH which were not evaluated in the specification. Claim 7 recites wherein the IL-2 mutant comprises at least 90% identity to an amino acid sequence selected from SEQ ID NOs: 22-26, resulting in a genus of possible IL-2 mutant sequences. Claim 27 recites wherein the IL-2 mutant fusion protein comprises at least 85% identity to an amino acid sequence selected from SEQ ID NOs: 15-19, resulting in a genus of possible IL-2 mutant fusion protein sequences.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. In order to provide adequate written description and evidence of possession of the claimed genus, the specification must provide 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 the instant case, the specification teaches 5 species of B’C’ loop regions: SGDASIH, AQSKNFH, AGSKNFH, AQSANFH, and AQSANIH (Table 4). The B’C’ loop regions improved the expression yield and purity of IL-2 fusion proteins (page 30 and Table 5). Nine different mutation combinations were evaluated and showed reduced or eliminated binding to IL-2Rα and maintained binding to IL-2Rβ (Table 3 and Fig. 4). When the B’C’ loop regions were combined with a mutation combination that blocks binding to IL-2Rα (K35E, T37E, R38E, F42A), the IL-2 mutants achieved the eliminated IL-2Rα binding and also the improved expression yield and purity (Tables 6-7) which shows that the B’C’ loop regions can be combined with the IL-2Rα blocking mutations and both alterations retain their functions. Therefore, there is proper written description for 5 species of B’C’ loop regions and 9 species of IL-2Rα binding interface mutation combinations.
However, the claims are broader than these species. The claims encompass a genus of possible B’C’ loops from IL-15 and B’C’ loops QSDNFH or AQSDNFH that were not evaluated in the specification. Further, the specification does not teach how 10% of the amino acids can be varied in the IL-2 mutant or how 15% of the amino acids can be varied in the IL-2 mutant fusion protein. For example, SEQ ID NO: 19 comprises 366 amino acids, and 15% variation in 366 amino acids means that any 54 amino acids could be inserted, deleted, or substituted.
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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (MPEP § 2163.05.Ib). In the absence of sufficient recitation of distinguishing identifying characteristics or structure-to-function attributes for the entire genus of B’C’ loop regions, the genus of IL-2 mutant sequences, or the genus of IL-2 mutant fusion protein sequences, the specification does not provide adequate written description of the claimed genera. Therefore, in view of the case law directed to an appropriate number of representative species, claims 1, 3-5, 7-8, 10-11, 13-17, 20, and 24-27 are rejected for insufficient written description.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claims 1, 3-5, 7-8, 10-11, 13-17, 20, and 24-27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the specific species of B’C’ loop regions listed in specification Table 4, does not reasonably provide enablement for the genus of B’C’ loop regions from IL-15 (Claims 1 and 20). Similarly, the specification, while being enabling for the specific species of B’C’ loop regions listed in specification Table 4 and the specific mutations listed in Table 3 and Fig. 4, does not reasonably provide enablement for the genus of IL-2 mutant sequences and the genus of IL-2 mutant fusion protein sequences encompassed by Claims 7 and 27. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
MPEP § 2164.01(a) states that there are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure
does not satisfy the enablement requirement and whether any necessary experimentation is “undue”. These factors include, but are not limited to:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims and nature of the invention:
The nature of the invention is complex. As understood with the broadest reasonable interpretation, Claims 1 and 20 are directed to an IL-2 mutant comprising a shortened B’C’ loop sequence comprising any fragment of two or more amino acids in the IL-15 B’C’ loop SGDAS wherein the remining residues are maintained from wild-type IL-2 to total a B’C’ loop comprising 7 residues. Thus, the claims are directed to a genus of possible B’C’ loops from IL-15. Claims 4-5 recite the B’C’ loop QSDNFH or AQSDNFH which were not evaluated in the specification. Claim 7 recites wherein the IL-2 mutant comprises at least 90% identity to an amino acid sequence selected from SEQ ID NOs: 22-26, resulting in a genus of possible IL-2 mutant sequences. Claim 27 recites wherein the IL-2 mutant fusion protein comprises at least 85% identity to an amino acid sequence selected from SEQ ID NOs: 15-19, resulting in a genus of possible IL-2 mutant fusion protein sequences.
When analyzing the scope of enablement, the claims are analyzed with respect to the teachings of the specification and are to be "given their broadest reasonable interpretation consistent with the specification." See MPEP 2111 [R-5]; Phillips v. AWH Corp., 415 F.3d 1303, 75 USPQ2d 1321 (Fed. Cir. 2005); and In re Hyatt, 211 F.3d 1367, 1372, 54 USPQ2d 1664, 1667 (Fed. Cir. 2000). Applicant always has the opportunity to amend the claims during prosecution, and broad interpretation by the examiner reduces the possibility that the claim, once issued, will be interpreted more broadly than is justified. In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550- 51 (CCPA 1969).
The state of the prior art and level of predictability in the art:
The level of predictability in the art depends, most importantly, on whether the claimed invention can be practiced by one of ordinary skill in the art. In AMGEN INC. ET AL. v. SANOFI ET AL. (No. 21-757, decided May 18, 2023), the Supreme Court held that Amgen was not enabled for “the entire genus” of antibodies that (1) “bind to specific amino acid residues on PCSK9,” and (2) “block PCSK9 from binding to [LDL receptors]” (872 F. 3d 1367, 1372) even though Amgen identified the amino acid sequences of 26 antibodies that perform these two functions. The case law applies to the instant claims which encompass a genus of B’C’ loop regions, yet the inventors have only disclosed 5 species: SGDASIH, AQSKNFH, AGSKNFH, AQSANFH, and AQSANIH (Table 4). Further, the inventors have disclosed a genus of IL-2 mutant sequences (Claim 7) and IL-2 mutant fusion protein sequences (Claim 27) with no guidance on what structural features need to be maintained such that the functional properties of the IL-2 mutants are preserved.
In Amgen, the Supreme Court has stated that despite recent advances, aspects of antibody science remain unpredictable. For example, scientists understand that changing even one amino acid in the sequence can alter an antibody's structure and function. See id., at 14. But scientists cannot always accurately predict exactly how trading one amino acid for another will affect an antibody's structure and function. Ibid. The unpredictability of polypeptide structure and function extends to the IL-2 mutant structure and binding function in the instant application.
The case law shows a continued lack of predictability even after the effective filing date of the instant invention, and there is no support in the Applicant’s disclosure leading one of ordinary skill to overcome the lack of predictability in the genus of IL-15 B’C’ loops claimed and the genus of IL-2 mutant and fusion protein sequences claimed. The specification provides no guidance or direction for structure that must be maintained such that the functional properties of the invention are preserved (reduced binding affinity to IL-2Rα, enhanced binding affinity to IL-2Rβγ, and improved expression yield and/or purity).
Level of skill in the art:
The level of skill would be high encompassing protein design, protein purification, immunology, binding assays, etc.
Amount of direction provided by inventor and the existence of working examples:
The specification teaches 5 species of B’C’ loop regions: SGDASIH, AQSKNFH, AGSKNFH, AQSANFH, and AQSANIH (Table 4). The B’C’ loop regions improved the expression yield and purity of IL-2 fusion proteins (page 30 and Table 5). Nine different mutation combinations were evaluated and showed reduced or eliminated binding to IL-2Rα and maintained binding to IL-2Rβ (Table 3 and Fig. 4). When the B’C’ loop regions were combined with a mutation combination that blocks binding to IL-2Rα (K35E, T37E, R38E, F42A), the IL-2 mutants achieved the eliminated IL-2Rα binding and also the improved expression yield and purity (Tables 6-7) which shows that the B’C’ loop regions can be combined with the IL-2Rα blocking mutations and both alterations retain their functions. Therefore, the specification is enabling for IL-2 mutants comprising 5 species of B’C’ loop regions and 9 species of IL-2Rα binding interface mutation combinations.
However, these species do not adequately represent the scope of IL-2 mutants that are claimed. A person having ordinary skill in the art would have to make a substantial inventive contribution in order to make and characterize a representative number of IL-2 mutants with various B’C’ loop regions and various amino acid sequence variations and evaluate their functional properties to encompass the claimed genera.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
In light of the unpredictability surrounding the claimed subject matter, the undue breadth of the claimed invention’s intended use, and the lack of adequate guidance, one wishing to make and practice the presently claimed invention would be unable to do so without engaging in undue experimentation. Given that structure is essential to function, a person having ordinary skill in the art would have to perform further experimentation to make the IL-2 mutants encompassed by the claims and screen their characteristics in order to practice the invention commensurate with the scope of the claims.
The instant specification does not enable the invention to make and use the entire genus of IL-2 mutants comprising shortened B’C’ loop regions from IL-15 or 10-15% sequence variation. Therefore, Claims 1, 3-5, 7-8, 10-11, 13-17, 20, and 24-27 are rejected.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 3-5, 7-8, 10-11, 13-17, 20, and 24-26 are rejected under 35 U.S.C. 103 as being unpatentable over Kang et al. US 2021/0213102 (filed Sept. 2019 and not a prior art exception due to a different inventive entity) in view of Gu et al. US 12,269,855 (filed Sept. 2019 and not a prior art exception due to a different inventive entity).
In regard to Claims 1, 4-5, 8, and 20, Kang teaches that IL-2 mutants comprising truncated B’C’ loops not only have increased binding to IL-2Rβ but also improve the expression and/or purification of the IL-2 mutant as compared to wild-type IL-2 (paragraph [0076]). The truncated B’C’ loop can comprise SGDASIH, AQSKNFH, AGSKNFH, AQSANFH, or AQSANIH between amino acid positions 72 and 84 (paragraph [0077]). The IL-2 mutant can comprise a mutated glycosylation motif at the binding interface of IL-2 and IL-2Rα to reduce or eliminate binding to IL-2Rα (paragraphs [0009]-[0010]). The amino acid positions are numbered according to SEQ ID NO: 26 (Claim 1) which is 100% identical to instant SEQ ID NO: 1. IL-2 mutants with improved expression yield and/or purity can be identified by SEC-HPLC, and binding affinity to IL-2Rα and IL-2Rβ can be identified by measuring the equilibrium dissociation constant (KD) (Tables 3, 4a, 4b, and paragraph [0173]). Note, Claim 8 is interpreted as inherent properties of the IL-2 mutant protein of claim 1 (MPEP § 2112.01).
In regard to Claims 10-11, 20, and 24-26, the IL-2 mutant can be a fusion protein linked to the Fc domain of human IgG1 comprising the L234A and L235A mutations via a linker comprising GSGS or 2X(G4S) (paragraphs [0158]-[0159]). The IL-2 mutant can be an immunoconjugate comprising the IL-2 mutant protein and an antigen-binding molecule (paragraph [0092]).
In regard to Claims 13-17 and 20, Kang teaches a nucleic acid encoding the IL-2 mutant protein, a vector comprising the nucleic acid, and a host cell comprising the nucleic acid wherein the host cell can be a mammalian cell (paragraphs [0095]-[0097]). Kang teaches a method comprising culturing a host cell comprising the nucleic acid encoding the IL-2 mutant under suitable conditions for IL-2 mutant protein expression (paragraph [0099]). Kang teaches pharmaceutical compositions that comprise the IL-2 mutant and a pharmaceutical carrier or excipient including buffers (paragraph [0124]).
Kang fails to teach wherein the IL-2 mutant comprises the mutations K35E+T37E+R38E+F42A that reduce binding to IL-2Rα (Claims 1, 3, 5, 7, and 20).
However, Gu teaches IL-2 mutants with reduced or eliminated IL-2Rα binding compared to wild-type IL-2 wherein the IL-2 mutant comprises mutations K35E+T37E+R38E+F42A relative to SEQ ID NO: 1 (Claims 1-2). Note, Gu SEQ ID NO: 1 is 100% identical to instant SEQ ID NO: 1.
Instant Claim 7 is directed to an IL-2 mutant comprising SEQ ID NO: 23. The specification teaches that SEQ ID NO: 23 is wild-type IL-2 SEQ ID NO: 1 further comprising mutations K35E+T37E+R38E+F42A and the IL-15 B’C’ loop SGDASIH (pages 40-41, Table 4, and last paragraph on page 28) which is made obvious by the teachings of Kang and Gu above.
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to substitute equivalents, each of which is taught by the prior art to be useful for the same purpose. Specifically, the mutated glycosylation motif at the binding interface of IL-2 and IL-2Rα taught by Kang could be replaced with the K35E+T37E+R38E+F42A mutation combination taught by Gu because both mutations occur at the IL-2Rα binding interface and both mutations are known to reduce or eliminate binding to IL-2Rα. The motivation to apply the mutations taught by Gu is because Gu teaches that the mutations cause activation of CD25- cells over CD25+ cells (col. 36, lines 32-37) which upregulates CD8+ cytotoxic T cells and NK cells over T regulatory cells, thus achieving therapeutic immunostimulation (col. 6, lines 45-54).
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Kang et al. US 2021/0213102 (filed Sept. 2019 and not a prior art exception due to a different inventive entity) in view of Gu et al. US 12,269,855 (filed Sept. 2019 and not a prior art exception due to a different inventive entity) as applied to Claims 1, 3-5, 7-8, 10-11, 13-17, 20, and 24-26 above, and further in view of Ast et al. US 2012/0244112.
The teachings of Kang and Gu as they apply to Claims 1, 3-5, 7-8, 10-11, 13-17, 20, and 24-26 are outlined in the rejection above. Instant Claim 27 is directed to an IL-2 mutant fusion protein comprising SEQ ID NO: 19. The specification teaches that SEQ ID NO: 19 is wild-type IL-2 SEQ ID NO: 1 further comprising mutations K35E+T37E+R38E+F42A, mutation T3A, and the IL-15 B’C’ loop SGDASIH all linked to a human IgG1 Fc domain comprising mutations L234A and L235A wherein the linker is 2X(G4S) (page 40, Table 4, and last paragraph on page 28). Kang and Gu teach all the components of an IL-2 mutant fusion protein comprising SEQ ID NO: 19 except for the T3A mutation.
Ast teaches an IL-2 mutant comprising mutations designed to disrupt binding to IL-2Rα in combination with the T3A mutation (paragraphs [0291]-[0295]). Ast teaches that the T3A mutation was chosen to eliminate the O-glycosylation site and obtain a protein product with higher homogeneity and purity when the IL-2 mutant polypeptide is expressed in eukaryotic cells such as CHO or HEK293 cells (paragraph [0298]).
It would have been prima facie obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the IL-2 mutant protein taught by Kang and Gu to further comprise the T3A mutation as taught by Ast. Ast teaches that the T3A mutation can be combined with mutations that disrupt binding to IL-2Rα, providing one of ordinary skill a reasonable expectation of success. The motivation to add the T3A mutation is to eliminate an O-glycosylation site and obtain a protein product with higher homogeneity and purity when expressed in eukaryotic cells (Ast paragraph [0298]).
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.
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1. Claims 1, 3-5, 7-8, 10-17, 20, and 24-25 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claim 30, 32, 36, 43-44, 46-50, and 52 of copending U.S. App. No. 17/059,539 in view of Gu et al. US 12,269,855 (filed Sept. 2019 and not a prior art exception due to a different inventive entity).
The instant claims recite an IL-2 mutant protein comprising mutation combination K35E+T37E+R38E+F42A and a shortened B’C’ loop positioned between position 73 and 84 comprising (Q/G)S(K/A)N(F/I)H or GDASIH (Claims 1 and 3-5). Dependent claims recite: wherein the IL-2 mutant comprises SEQ ID NO: 23 which is wild-type IL-2 SEQ ID NO: 1 further comprising mutations K35E+T37E+R38E+F42A and the IL-15 B’C’ loop SGDASIH (Claim 7); wherein the IL-2 mutant inherently has reduced or eliminated binding to IL-2Rα and enhanced binding to IL-2Rβ (Claim 8); the IL-2 mutant as a fusion protein or an immunoconjugate (Claims 10-11); a polynucleotide encoding the IL-2 mutant protein (Claim 13); a vector or host cell comprising the polynucleotide (Claims 14-15); a method of producing the IL-2 mutant by culturing the host cell in conditions suitable for protein expression (Claim 16); a pharmaceutical composition comprising the IL-2 mutant (Claim 17); a method for obtaining the IL-2 mutant of Claim 1 as an Fc fusion protein (Claim 20); and the IL-2 mutant protein fused to an Fc domain through a linker comprising GSGS (Claims 24-25).
The copending claims recite an IL-2 mutant protein comprising a shortened B’C’ loop region having a sequence of A(Q/G)S(K/A)N(F/I)H or SGDASIH substituted between aa72 and aa84 (Claim 30). Dependent claims recite: wherein the IL-2 mutant comprises a mutated glycosylated motif and has reduced or eliminated binding to IL-2Rα (Claim 32); the IL-2 mutant protein has enhanced binding to IL-2RBγ (Claim 36); the IL-2 mutant is a fusion protein fused to an Fc antibody fragment optionally with a linker comprising GSGS (Claims 43-44); the IL-2 mutant as an immunoconjugate (Claim 46); a polynucleotide encoding the IL-2 mutant protein (Claim 47); a vector or host cell comprising the polynucleotide (Claims 48-49); a pharmaceutical composition comprising the IL-2 mutant (Claim 50); a method of obtaining the IL-2 mutant by expressing the protein in a mammalian cell and identifying its binding properties (Claim 52).
The copending claims do not teach wherein the IL-2 mutant comprises the mutations K35E+T37E+R38E+F42A.
However, Gu teaches IL-2 mutants with reduced or eliminated IL-2Rα binding compared to wild-type IL-2 wherein the IL-2 mutant comprises mutations K35E+T37E+R38E+F42A relative to SEQ ID NO: 1 (Claims 1-2). Note, Gu SEQ ID NO: 1 is 100% identical to instant SEQ ID NO: 1.
It would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to substitute equivalents, each of which is taught by the prior art to be useful for the same purpose. Specifically, the mutated glycosylation motif taught by the copending claims could be replaced with K35E+T37E+R38E+F42A mutation combination taught by Gu because both mutations occur at the IL-2Rα binding interface and both mutations are known to reduce or eliminate binding to IL-2Rα. The motivation to apply the mutations taught by Gu is because Gu teaches that mutations cause activation of CD25- cells over CD25+ cells (col. 36, lines 32-37) which upregulates CD8+ cytotoxic T cells and NK cells over T regulatory cells, thus achieving therapeutic immunostimulation (col. 6, lines 45-54). Thus, the instant claims are either anticipated and/or rendered obvious by the copending claims in view of Gu.
This is a provisional nonstatutory obviousness-type double patenting rejection because the patentably indistinct claims have not in fact been patented. However, the notice of allowance for U.S. App. No. 17/059,539 was mailed on October 30, 2025.
2. Claims 1, 3-5, 7-8, 10-17, 20, and 24 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-2, 4, and 7-12 of U.S. Patent No. 12,269,855 in view of Kang et al. US 2021/0213102 (filed Sept. 2019 and not a prior art exception due to a different inventive entity).
The instant claims are recited above.
The patented claims recite an IL-2 mutant protein comprising mutations K35E+T37E+R38E+F42A relative to SEQ ID NO: 1 wherein the IL-2 mutant has reduced or eliminated binding to IL-2Rα and/or enhanced binding to IL-2Rβ as compared to wild-type IL-2 (Claims 1-2). Dependent claims recite: wherein the IL-2 mutant is a fusion protein fused to an Fc antibody fragment and expressed in a mammalian cell (Claim 4); the IL-2 mutant as an immunoconjugate (Claim 7); a polynucleotide encoding the IL-2 mutant protein (Claim 8); a vector or host cell comprising the polynucleotide (Claims 9-10); a pharmaceutical composition comprising the IL-2 mutant (Claim 12); a method of producing the IL-2 mutant comprising culturing the host cell under conditions suitable for protein expression (Claim 11).
The patented claims do not teach an IL-2 mutant protein comprising a shortened B’C’ loop region having a sequence of A(Q/G)S(K/A)N(F/I)H or SGDASIH substituted between aa72 and aa84.
However, Kang teaches that IL-2 mutants comprising truncated B’C’ loops not only have increased binding to IL-2Rβ but also improve the expression and/or purification of the IL-2 mutant as compared to wild-type IL-2 (paragraph [0076]). The truncated B’C’ loop can comprise SGDASIH, AQSKNFH, AGSKNFH, AQSANFH, or AQSANIH between amino acid positions 72 and 84 (paragraph [0077]).
It would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to alter the IL-2 mutant taught by the patented claims to further comprise a truncated B’C’ loop as taught by Kang. The motivation to truncate the B’C’ loop is to improve the expression and/or purification of the IL-2 and to increase binding to IL-2Rβ as taught by Kang. As the patented claims also teach that the IL-2 mutant has enhanced binding affinity for IL-2Rβ, the mutations could be combined with a reasonable expectation of success. Thus, the instant claims are either anticipated and/or rendered obvious by the Patented claims in view of Kang.
Note, no provisional nonstatutory double patenting rejection is made over copending U.S. App. No. 17/911,893. Although the copending claims recite the same IL-2 mutant as in instant Claim 1, the IL-2 mutant in the copending claims further comprises mutations that disrupt IL-2 binding to IL-2Rβγ. This IL-2 structure and function is distinct from the instant IL-2 mutant that has enhanced binding to IL-2Rβ (instant Claim 8).
Similarly, no provisional nonstatutory double patenting rejection is made over copending U.S. App. No. 18/693,453 because the copending claims recite wherein the IL-2 mutant comprises a N88R mutation which reduces the binding of IL-2 to IL-2Rβγ (as evidenced by copending specification page 3). It would not be obvious to further mutate residues K35E+T37E+R38E+F42A as in the instant claims because these mutations are known to have the opposite function (reducing binding to IL-2Rα).
Conclusion
No claim is allowed.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675