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 .
Claim Status
Claim listing filed on January 5, 2026 is pending. Claims 1-97, 100, 103, 106-109, and 114-115 are canceled. Claims 98-99, 101-102, 104-105, 110-112, and 116 are amended. Claims 118-125 are new. Claims 110-113, 116-117, and 120-125 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions or species. Claims 98-99, 101-102, 104-105, and 118-119 are examined upon their merits.
Information Disclosure Statement
The information disclosure statement filed on January 5, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objections and Rejections
Applicant’s cancelation of Claims 100, 103, and 106-108 has rendered all previous rejections directed to these claims moot.
Applicant’s amendments to the specification have overcome the objections of record, and the specification objections are withdrawn.
The provisional rejection of Claims 98-99, 101-102, and 104 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 22, 26, and 28-29 of copending U.S. App. No. 18/417,047 is withdrawn in view of Applicant’s amendments. Amended Claim 98 is directed to an IL-2 pro-cytokine which is distinct from the IL-12 pro-cytokine of the copending claims.
Claim Objections (New, necessitated by amendment)
Applicant is advised that should Claim 98 be found allowable, Claim 104 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. Claim 98 recites wherein the inhibitory polypeptide sequence comprises “an IL-2 binding domain of an IL-2 receptor (IL-2R)” and Claim 4 recites “wherein the inhibitory polypeptide sequence comprises the IL-2 binding domain of the IL-2Rα.” When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112 (New, necessitated by amendment)
Claim 105 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 105 recites the limitation "the cytokine-binding domain" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. For the purpose of compact prosecution, “the cytokine-binding domain” is interpreted as “the IL-2 binding domain.”
Claim Rejections - 35 USC § 112 (Maintained)
The rejection of Claims 98-99, 101-102, 104, and 118-119 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 is maintained. Note, the rejection applies to newly added Claims 118-119.
Claims 98 and 104 recite “an IL-2 binding domain of an IL-2 receptor.” It is of record in the non-final rejection filed 07/03/3035 that the specification defines “an IL-2 binding domain of an IL-2 receptor” as an extracellular portion of a cytokine receptor or a fragment or truncation thereof that can bind a cytokine polypeptide sequence (specification paragraph [0078]). This term is defined by using indefinite functional language because the feature (the domain) is only defined by what it does (binds the cytokine) rather than by what it is (MPEP § 2173.05(g)). The specification teaches that the domain can be a portion, fragment, or truncation of an IL-2 receptor and multiple IL-2 receptors are known in the art (IL-2Rα, IL-2Rβ, IL-2Rγ). It is unclear what structure of the IL-2 receptor needs to be conserved to maintain cytokine binding and blocking function as required by the claims. For example, would a fragment comprising amino acid residues 1-5 of human wild-type IL-2Rα be capable of binding IL-2? Because experimentation would be required to understand what structures (portions, fragments, truncations) are encompassed by the claim language, the claims are rejected for indefinite functional language. The structural metes and bounds of the IL-2 binding domains cannot be determined from the claim language.
Applicant's arguments filed January 5, 2025 have been fully considered but they are not persuasive. Applicant argues that the IL-2 receptor and its IL-2 binding domain are well-defined in the art. While the structures of IL-2Rα, IL-2Rβ, and IL-2Rγ are known in the art, the specification defines “an IL-2 binding domain of an IL-2 receptor” as an extracellular portion of a cytokine receptor or a fragment or truncation thereof that can bind a cytokine polypeptide sequence (specification paragraph [0078]). As explained above, it is unclear what portions, fragments, or truncations of the known receptors are capable of binding and blocking IL-2 as required by the claims. The rejection is maintained.
The rejection of Claims 98-99, 101-102, 104, and 118-119 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 is maintained. 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. Note, the rejection applies to newly added Claims 118-119.
The claims are directed to an inhibitory polypeptide sequence comprising an IL-2 binding domain of an IL-2 receptor which is defined as an extracellular portion of an IL-2 receptor or a fragment or truncation thereof that can bind IL-2 (specification paragraph [0078]). As of record in the non-final office action filed 07/03/2025, the specification teaches 16 species of pro-cytokines (Constructs B-Q in Table 3). Of these pro-cytokine species, only 3 IL-2 binding domain portions, fragments, or truncations are evaluated: full-length IL-2Rα (residues 1-219), truncated IL-2Rα (residues 1-178), and IL-2Rα (residues 1-192) (Table 3). Three species of IL-2 binding domains are not sufficient to describe the genus of IL-2 binding domains claimed that comprises any portion, fragment, or truncation of any IL-2R.
Applicant's arguments filed January 5, 2025 have been fully considered but they are not persuasive. Applicant argues that amended claim 98 recites elements (i)-(iv) (as defined on page 8 of Applicant remarks) which is directed to a specific genus that finds written support in the specification. Elements (i), (iii), and (iv) do have proper written description. Element (ii) lacks proper written description for the reasons outlined in the paragraph above, and the rejection is maintained.
The rejection of Claims 98-99, 101-102, 104, and 118-119 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is maintained because the specification, while being enabling for the specific species of pro-cytokines outlined in Table 3 and those known in the art prior to filing, does not reasonably provide enablement for the genus of pro-cytokines encompassed by the claims. 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. Note, the rejection applies to newly added Claims 118-119.
Applicant's arguments filed January 5, 2025 have been fully considered but they are not persuasive. Applicant argues that amended claim 98 recites elements (i)-(iv) (as defined on page 8 of Applicant remarks) which is directed to a specific genus that is sufficiently enabled by the specification. Elements (i), (iii), and (iv) are enabled by the specification and the state of the art prior to filing; however, element (ii) is not enabled. An inhibitory polypeptide sequence comprising an IL-2 binding domain of an IL-2 receptor is defined as an extracellular portion of an IL-2 receptor or a fragment or truncation thereof that can bind IL-2 (specification paragraph [0078]) which results in a genus of IL-2 binding domains comprising any portion, fragment, or truncation of any IL-2R. As of record in the non-final office action filed 07/03/2025, the specification teaches 16 species of pro-cytokines (Constructs B-Q in Table 3). Of these pro-cytokine species, only 3 IL-2 binding domain portions, fragments, or truncations are evaluated: full-length IL-2Rα (residues 1-219), truncated IL-2Rα (residues 1-178), and IL-2Rα (residues 1-192) (Table 3). 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 binding domain variants encompassed by the claims and screen their binding and blocking capabilities in order to practice the invention commensurate with the scope of the claims. This amount of experimentation is considered undue, and the rejection is maintained.
Claim Rejections - 35 USC § 102 (Maintained)
The rejection of Claims 98-99, 101-102, 104-105, and 118 under 35 U.S.C. 102(a)(2) as being anticipated by Winston et al. US 10,696,724 (filed June 11, 2019; of record) is maintained. Note, the rejection applies to newly added Claim 118.
Applicant's arguments filed January 5, 2025 have been fully considered but they are not persuasive. Applicant argues that Claim 98 is novel over Winston because Winston at least does not disclose or suggest an amino acid sequence consisting of SEQ ID NO: 2. It is of record in the non-final office action filed 07/03/2025 that Winston teaches that the IL-2 comprises SEQ ID NO: 1 with a C125S substitution (col. 20, lines 27-34) which is 100% identical to instant SEQ ID NO: 2. This section of art specifically recites “any of the mutant IL-2 polypeptides disclosed herein can include the sequences described; they can also be limited to the sequences described and otherwise identical to SEQ ID NO: 1. Moreover, any of the mutant IL-2 polypeptides disclosed herein can optionally include a substitution of the cysteine residue at position 125 with another residue ( e.g. , serine ) … of SEQ ID NO: 1” (col. 20, lines 27-34; emphasis added). Therefore, Winston teaches that the IL-2 can be limited to and otherwise identical to SEQ ID NO: 1 with a C125S mutation. This teaching reads on a cytokine polypeptide sequence consisting of the amino acid sequence of SEQ ID NO: 2. The rejection is maintained.
Claim Rejections - 35 USC § 103 (New, necessitated by amendment)
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 98-99, 101-102, 104-105, and 118-119 are rejected under 35 U.S.C. 103 as being unpatentable over Winston et al. US 10,696,724 (filed June 11, 2019; of record) in view of Ha et al. Front Immunol. 2016.
The teachings of Winston as they apply to Claims 98-99, 101-102, 104-105, and 118 are outlined in the rejection above. Winston fails to teach wherein the immunoglobulin Fc region is a knob-into-hole heterodimeric Fc region (Claim 119).
Ha teaches that “knob-into-hole” mutations in Fc regions are well understood in the art wherein a knob is introduced as a bulky substitution on one side of a Fc homodimer, and to accommodate the knob, a complementary hole is created in the other side of a Fc homodimer by replacing the neighboring residues with smaller ones (page 3, paragraph 1) which results in an Fc heterodimer. Specific knob-into-hole amino acid substitutions are listed in Fig. 2 and Table 1. The knob-into-hole Fc regions have a high yield of heterodimerization and improved stability (page 3, paragraph 1). The knob-into-hole Fc regions can specifically be fused to cytokines (page 12, last paragraph).
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 apply the known knob-into-hole Fc substitutions taught by Ha to the Fc region of the pro-cytokine taught by Winston. The motivation to apply the known knob-into-hole Fc substitutions is because Ha teaches that the knob-into-hole system increases Fc region stability. The substitutions could be made with a reasonable expectation of success, because Ha teaches knob-into-hole Fc regions fused to cytokines.
Double Patenting (Modified, necessitated by amendment)
1. The provisional rejection of Claims 98-99, 101-102, 104-105, and 118-119 on the ground of nonstatutory double patenting as being unpatentable over claims 7, 9, 38, 80, 101, 177, and 211 of copending U.S. App. No. 18/416,736 is maintained. Note, the rejection applies to newly added Claims 118-119.
Copending claim 38 is directed to immunoglobulin Fc regions comprising knob-into-hole heterodimeric Fc regions which reads on newly added Claim 119. Copending Claim 101 recites wherein the IL-2 polypeptide sequence has at least 99% identity to SEQ ID NO: 2 which makes obvious an IL-2 polypeptide consisting of SEQ ID NO: 2 as in instant Claim 98.
Applicant's arguments filed January 5, 2025 have been fully considered but they are not persuasive. Applicant requests that the obviousness-type double patenting rejection be reconsidered in view of the amendments. The double patenting rejection has been reconsidered and is maintained for the reasons of record and the explanation above.
Applicant requests that the rejection be held in abeyance until the claims are otherwise allowable. MPEP § 804.I.B.1 states that “as filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance.” As no terminal disclaimer has been filed and no showing has been made that the claims are patentably distinct, the provisional double patenting rejection is maintained.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH COOPER PATTERSON whose telephone number is (703)756-1991. The examiner can normally be reached Monday - Friday 8:00am - 5:00pm EST.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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