Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I (i.e., claims 1-9 and 14 drawn to a fusion protein) in the reply filed on November 21, 2025, is acknowledged. Additionally, Applicant’s election without traverse of Species A (i.e., a single and specific fusion protein as an antibody comprising SEQ ID NOs: 1-3 as the HCDRs, SEQ ID NOs: 5-7 as the LCDRs; two IL-2 proteins that are variants having the amino acid sequence of SEQ ID NO: 20; and a linker having the amino acid sequence of SEQ ID NO: 19) in the reply filed on November 21, 2025, is acknowledged.
Please note that a single and specific linker as it pertains to Species A is hereby removed in light of the Examiner’s search.
Status of Claims
Claims 1-18 were originally filed on December 22, 2022.
The amendment received on December 22, 2022, canceled claims 15-17; amended claims 10, 14, and 18; and added new claim 19. The amendment received on November 21, 2025, amended claim 6.
Claims 1-14 and 18-19 are currently pending and claims 1-9 and 14 are under consideration as claims 10-13 and 18-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on November 21, 2025.
Priority
The present application claims status as a 371 (National Stage) of PCT/KR2021/008198 filed June 29, 2021, and claims priority under 119(a)-(d) to Korean Application No. 10-2020-0079978 filed on June 30, 2020.
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d) for Korean Application No. 10-2020-0079978, which papers have been placed of record in the file. Please note that the Korean application is NOT in English and therefore cannot be verified.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on December 22, 2022; April 11, 2024; and August 15, 2025, are being considered by the examiner.
Claim/Sequence Interpretation
For claims 1 and 5, it is noted that an antibody that specifically binds to LAG-3 encompasses any full length antibody without a defined sequence or a fragment of a full length antibody as long as the antibody fragment contains an antigen-binding domain capable of specifically binding to LAG-3 (i.e., CD223 or lymphocyte activation gene 3) (See instant, pg. 5, 7th to last paragraph to pg. 6, 1st paragraph). However, the antibody of claim 1 does not specify or require an antigen-binding domain capable of specifically binding to LAG-3.
Furthermore, it is noted that IL-2 or interleukin-2 refers to any wild-type IL-2 obtained from any vertebrate source (See instant, pg. 6, 3rd paragraph). The specification also teaches that a IL-2 protein can be wild-type IL-2, a variant thereof, or a fragment of wild-type IL-2 in which a portion of the N-terminus or C-terminus is truncated (See instant, pg. 6, 3rd and 5th paragraph). An IL-2 variant refers to a form in which a portion of amino acids in the full-length IL-2 or a IL-2 fragment is substituted (See instant, pg. 6, 6th paragraph). That is, an IL-2 variant can have an amino acid sequence different from wild-type IL-2 or a fragment thereof (See instant, pg. 6, 6th paragraph). However, an IL-2 variant can have activity equivalent or similar to the wild-type IL-2 such as specific binding to an IL-2 receptor (See instant, pg. 6, 6th paragraph). Thus, an IL-2 protein of claim 1 encompasses any fragment of a wild-type IL-2 protein or any IL-2 variant.
For claim 2, please note that the Examiner is interpreting the scope as open-ended requiring 100% identity to each recited sequence with any N- and/or C-terminal additions.
For claim 3, please note that the Examiner is interpreting the scope as open-ended requiring 100% identity to each recited sequence with any N- and/or C-terminal additions.
For claim 6, please note that the Examiner is interpreting the scope as closed-ended (i.e., “is” as the transitional phrase) requiring 100% identity and the same length to SEQ ID NO: 22 except with one or more of the recited substitutions.
For claim 7, please note that the Examiner is interpreting the scope as open-ended requiring 100% identity to either SEQ ID NO: 20 or 21 with any N- and/or C-terminal additions.
Specification
The disclosure is objected to because of the following informalities: on page 11, paragraph 5, teaches a peptide linker can be (G4S)n where n is an integer of 1 to 10 without an accompanying SEQ ID NO. Pursuant to MPEP 2422 and 37 CFR 1.821(a), any amino acid sequence with at least 4 defined amino acids in length requires a sequence identifier. Additionally, update the Sequence Listing, if necessary. Appropriate correction is required.
Claim Objections
Claim 1 is objected to because of the following informalities: claim 1 recites, “…antibody that specifically binds to LAG-3; and an IL-2 protein.” Although, the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The Examiner respectfully requests that Applicant uses lymphocyte activation gen 3 (LAG-3) and interleukin-2 (IL-2) for the first recitation, thereafter LAG-3 and IL-2 may be utilized. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4-9, and 14 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 1 includes an “antibody that specifically binds to LAG-3”. The interpretation of this phrase is described above in the “Sequence Interpretation” section where the antibody structure encompasses any full length antibody or fragment thereof as long as the fragment contains an antigen-binding domain capable of specifically binding to LAG-3. However, the full length, antibody fragment, and antigen-binding domain(s) do not require any core structure or sequence that each would require in order to specifically bind to LAG-3. In particular, there is no limit with respect to the antigen-binding domain(s) as a necessary sequence that each antibody or fragment thereof needs in order to be capable of specifically binding to LAG-3. Thus, the scope of the claimed antibody encompasses an enormous array of antibody structures and/or sequences linked by only functional language.
The written description requirement may be met by provided a representative number of species of the genus and/or in light of the state of the art. With regard to the state of the art, US Publication No. 2021/0238283 A1 teaches a monoclonal antibody or an antigen-binding fragment thereof that binds to LAG-3 including a heavy and light chain variable region (See ‘283, abstract; [0008]) (cited in the IDS received on 12/22/22). ‘283 teaches that the heavy chain variable region comprises SEQ ID NO: 1 or 27 as HCDR1, SEQ ID NO: 2 as HCDR2, and SEQ ID NO: 3 as HCDR3 (See ‘283, [0012], [0040]). Moreover, the light chain variable region comprises SEQ ID NOs: 8, 53, or 57 as LCDR1, DAS as LCDR2, and SEQ ID NO: 10, 33, or 60 as LCDR3 (See ‘283, [0012], [0040]). ‘283 teaches that a heavy chain variable region comprises SEQ ID NO: 114, 116 or 118; and a light chain variable region comprises SEQ ID NOs: 115, 117, or 119 (See ‘283, [0042]). ‘283 also teaches that “CDR” indicates a loop-shaped region that is involved in antigen recognition, and according to a variation in the sequence of this region, the specificity of an antibody for an antigen is decided (See ‘283, [0048]). As such, ‘283 teaches that the CDR regions of an antibody are critical structures for an antibody or fragment thereof to bind to a specific antigen/target. Furthermore, Kramen et al. teaches a bispecific, tetravalent antibody (i.e., referred to as FS118) that specifically binds to LAG-3 (See Kramen et al., Clin. Cancer Res. 26:333-3344 (2020) at abstract) (cited in the IDS received on 12/22/22). Thus, the art has identified specific antibody sequences including specific CDR sequences, but does not identify a necessary sequence that each antibody needs to contain in order to specifically bind to LAG-3 and/or does not constitute a representative number of antibodies to establish possession of the breadth of the claimed genus.
Alternatively, the written description requirement may be met by provided a representative number of species of the genus. In this, the specification teaches an anti-hLAG-3(1E09)VH and CH1 antibody fragment comprising SEQ ID NO: 12, which contains a heavy chain variable region comprising SEQ ID NO: 4, and which contains SEQ ID NO: 1 as HCDR1, SEQ ID NO: 2 as HCDR2, and SEQ ID NO: 3 as HCDR3 (See instant, pg. 6, 1st paragraph; Table 2). Moreover, the instant specification teaches an anti-hLAG-3(1E09)VL-kappa and CL antibody fragment comprising SEQ ID NO: 16, which contains a light chain variable region comprising SEQ ID NO: 8, and which contains SEQ ID NO: 5 as the LCDR1, SEQ ID NO: 6 as the LCDR2, and SEQ ID NO: 7 as the LCDR3 (See instant, pg. 6, 1st paragraph; Table 1). Notably, instant SEQ ID NO: 4 is 100% identical to ‘283’s SEQ ID NO: 114, and instant SEQ ID NO: 8 is 100% identical to ‘283’s SEQ ID NO: 115. As such, the species taught in the specification do not constitute a representative number of species of antibodies and/or fragments thereof containing a representative number of antigen-binding domains that would specifically bind to LAG-3. Thus, the specification is not sufficient for the skilled artisan to envisage a core structure or sequence necessary for the claimed antibody to preserve function.
The Examiner further notes that the Federal Circuit decided in Amgen v Sanofi that the “newly characterized antigen” test should not be used in determining whether there is adequate written description under 35 USC 112(a) for a claim drawn to an antibody (See Amgen v Sanofi, 872 F.3d 1367, 1378-79 (Fed. Cir. 2017)). Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent (See Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010)). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional. In the instant case, without an indication of a core structure, sequence or residues that would be necessary in order for an antibody or fragment thereof to bind to LAG-3, it would be difficult for a skilled artisan to envision the correlation between structure and function for the whole genus and/or to predict what would be covered by the functionally claimed genus because Applicants have failed to provide a representative number of species to support the scope of the whole genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “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, what 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). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of polypeptides which preserve the required function, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Therefore, claims 1, 4-9 and 14 do not meet the written description requirement.
Claims 1-5, 8-9 and 14 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 1 includes an “IL-2 protein”, and dependent claim 5 includes an “IL-2 variant”. The interpretation of these phrases are described above in the “Sequence Interpretation” section where an IL-2 protein encompasses any wild-type IL-2 full length protein, any fragment of a wild-type IL-2 full length protein thereby ranging from any dipeptide (i.e., any two contiguous residues) to a peptide with one deleted residue at the N- or C-terminus, and any variant of a wild-type IL-2 full length protein or fragment thereof thereby including a sequence with every residue substituted and a sequence with any single residue substituted. A IL-2 variant can have activity equivalent or similar to the wild-type IL-2 such as specific binding to an IL-2 receptor. Thus, the scope of the claimed IL-2 protein encompasses an enormous array of sequences without a common core structure and/or sequence that each IL-2 protein needs in order to exhibit activity equivalent or similar to a wild-type IL-2.
The written description requirement may be met by provided a representative number of species of the genus and/or in light of the state of the art. With regard to the state of the art, WO 2020/146221 A1 teaches a modified IL-2 comprising at least one substitution at, at least one amino acid position where the position to be substituted is T3, F42, Y45, L72, P65, D84, E95, M23, C125, E15, and/or H16 (See ‘221, [0006]) (cited in the IDS received on 4/11/24). However, ‘221 only teaches a few specific IL-2 variant sequences with at most 5 to 6 substitutions and most of the 5 to 6 substitutions are located at the same position, e.g., T3A-H16A-P65R-D84S-C125S and T3A-H16A-P65R-D84S-E95Q-C125S (See ‘221, [0006], embodiment 25). Similarly, WO 2018/184964 A1 teaches a fusion protein comprising an anti-PD1 antibody, a mutant IL-2, and a IL-15 (See ‘964, abstract; pg. 6, 5th paragraph) (cited in the IDS received on 4/11/24). ‘964 teaches that the mutant IL-2 polypeptide comprises the amino acid substitutions F42A, Y45A and L72G (See ‘964, abstract; pg. 6, 5th to 6th paragraph). Moreover, ‘964 teaches that the mutant IL-2 polypeptide further comprises the amino acid substitution T3A and/or C125A (See ‘964, abstract; pg. 7, 3rd paragraph). Thus, the art has identified IL-2 variant sequences, but does not identify a necessary sequence/residues that each variant sequence needs to contain in order to exhibit IL-2 activity and/or does not constitute a representative number of IL-2 variant sequences to establish possession of the breadth of the claimed genus.
Alternatively, the written description requirement may be met by provided a representative number of species of the genus. In this, the specification teaches that the IL-2 variant contains at least one substitution at the residue at position 38, 42, 45, 61, and 72 of instant SEQ ID NO: 22 (See instant, pg. 6, last paragraph; pg. 7, 1st paragraph). The specification teaches that the IL-2 variant contains two or three amino acid substitutions at the aforementioned positions (See instant, pg. 7, 2nd paragraph; pg. 9, last paragraph). Two specific species of IL-2 variant sequences are SEQ ID NO: 20 (i.e., F42A and R38A substitutions) and 21 (i.e., F42A, R38A, and E61R substitutions) (See instant, pg. 10, 1st paragraph). While these examples of a substitution are provided including in dependent claims 6-7, these substitutions are not representative of the scope of claims 1 and 5 because these substitutions encompass 5 positions out of the 133 possible positions of the mature full length IL-2 protein (i.e., instant SEQ ID NO: 22) whereas the scope of claims 1 and 5 encompass any number of substitutions at any positions. Further, three of the positions, i.e., 42, 45, and 72, are the same as the positions known in the art (See discussion supra). Other than these specific positions for substitution, the specification does not indicate a core structure/sequence that a variant sequence needs in order to exhibit similar activity as the wild-type IL-2 protein. Thus, this is not sufficient for the skilled artisan to envisage other substitutions at other residue sites (other than those taught in the art) which preserve function.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “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, what 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). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of polypeptides which preserve the required function, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Therefore, claims 1-5, 8-9 and 14 do not meet the written description requirement.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 5, 8-9, and 14 are rejected under 35 U.S.C. 102(a)(1) and/or 102(a)(2) as being anticipated by Timmer et al. WO 2020/146221 A1 published on July 16, 2020 (effective filing date of January 7, 2019) (cited in the IDS received on 4/11/24).
Regarding Timmer as 102(a)(1) prior art, Applicant cannot rely upon the certified copy of the foreign priority application to overcome this rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216. However, please note that the Timmer reference would still be applicable as a 102(a)(2) reference.
For claims 1, 5, and 8-9, Timmer et al. discloses a fusion protein comprising an antibody specific for LAG3 (i.e., LAG3-Mab xELL-Knob Fc) and a IL-2 variant amino acid sequence with at least a substitution of T3G where the antibody and the IL-2 variant are linked via a GGSGGS peptide linker (See Timmer, pg. 71; SEQ ID NO: 95). Thus, Timmer’s specific species of fusion protein constitutes a fusion protein comprising an antibody that specifically binds to LAG-3 and an IL-2 protein in light of the scope of each component as discussed in the “Claim/Sequence Interpretation” supra as recited in instant claim 1; constitutes an IL-2 variant in light of the scope discussed in the “Claim/Sequence Interpretation” supra as recited in instant claim 5; constitutes where the antibody that specifically binds to LAG-3 and the IL-2 protein are attached to each other via a linker such as a peptide linker as recited in instant claims 8-9.
For claim 14, Timmer et al. discloses pharmaceutical compositions comprising modified IL-2 polypeptides in combination with a pharmaceutically acceptable carriers (See Timmer, [00146]-[00147]). Additionally and/or alternatively, it is noted that the claimed pharmaceutical composition only requires one component; namely, the fusion protein of claim 1. As such, it would then follow that Timmer’s SEQ ID NO: 95 constitutes a pharmaceutical composition. Thus, Timmer’s disclosure satisfies the claim limitation as recited in instant claim 14.
Accordingly, Timmer’s disclosure anticipates instant claims 1, 5, 8-9, and 14.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Timmer et al. WO 2020/146221 A1 published on July 16, 2020 (effective filing date of January 7, 2019) (cited in the IDS received on 4/11/24) as applied to claim 1 above, and further in view of Lee et al. WO 2020/005003 A1 published on January 2, 2020 (effective filing date of June 28, 2019) (note: US 2021/0238283 A1 as English language equivalent and will be cited in the rejection below) (US 2021/0238283 A1 cited in the IDS received on 12/22/22), as applied to instant claims 2-4 herewith.
For claim 1, please see discussion of Timmer et al. supra.
For claims 2-3, with respect to the antibody sequence:
Timmer et al. teaches that a modified IL-2 polypeptide is fused to the C-terminus of a Fc region or heavy chain constant region via a peptide linker where the polypeptide further comprises at least one antigen binding domain where the antigen binding domain specifically binds to LAG3 (See Timmer, [0006], embodiments 30, 50, 55-56, 62, 78; [00112]). The at least one antigen binding domain comprises a VH domain and a VL domain (See Timmer, [0006], embodiment 68). Plus, Timmer et al. teaches that the modified IL-2 polypeptide comprises a heavy chain constant region where the VH domain is fused to the heavy chain constant region and where the VL domain is associated with the VH domain (See Timmer, [0006], embodiment 71). However, Timmer et al. does not expressly teach specific amino acid sequences for the VL and VH domains, which necessarily contain the CDRs for each region.
Lee et al. teaches an antibody for LAG-3 or an antigen-binding fragment thereof (See Lee, [0008]). Lee teaches that the heavy chain variable region comprises SEQ ID NO: 1 or 27 as HCDR1, SEQ ID NO: 2 as HCDR2, and SEQ ID NO: 3 as HCDR3 (See Lee, [0012], [0040]). Moreover, the light chain variable region comprises SEQ ID NOs: 8, 53, or 57 as LCDR1, DAS as LCDR2, and SEQ ID NO: 10, 33, or 60 as LCDR3 (See Lee, [0012], [0040]). Lee teaches that a heavy chain variable region comprises SEQ ID NO: 114, 116 or 118; and a light chain variable region comprises SEQ ID NOs: 115, 117, or 119 (See Lee, [0042]). When comparing Lee’s SEQ ID NO: 114 with instant SEQ ID NO: 4, there is 100% identity. When comparing Lee’s SEQ ID NO: 115 with instant SEQ ID NO: 8, there is 100% identity. As such, Lee et al. suggests an antibody that specifically binds to LAG-3 and comprises a VH domain comprising instant SEQ ID NO: 4 and a VL domain comprising instant SEQ ID NO: 8, each necessarily containing instant SEQ ID NOs: 1-3 as HCDRs1-3 and instant SEQ ID NOs: 5-7 as LCDRs1-3, respectively, as recited in instant claims 2-3.
Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of Timmer et al. and utilize a fusion protein comprising a modified IL-2 polypeptide and an antibody comprising a heavy chain constant region where the VH domain is fused to the heavy chain constant region and where the VL domain is associated with the VH domain such that the VH and VL domains comprise instant SEQ ID NOs: 4 and 8, respectively in order for the antibody to specifically bind to LAG-3. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because an antibody comprising a VH domain of instant SEQ ID NO: 4 and a VL domain of instant SEQ ID NO: 8 was known to specifically bind to LAG-3 as taught by Lee et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the fusion protein of Timmer et al. comprised a modified IL-2 polypeptide and an antibody that specifically binds to LAG-3 comprising a heavy chain constant region where the VH domain is fused to the heavy chain constant region and where the VL domain is associated with the VH domain, and therefore, substituting instant SEQ ID NO: 4 as the VH domain and instant SEQ ID NO: 8 as the VL domain would support the antibody component of the fusion protein specifically binding to LAG-3 by constituting a simple substitution of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
For claim 4, with respect to where the fusion protein comprises two IL-2 proteins:
Timmer et al. teaches that the modified IL-2 polypeptide forms a homodimer under physiological conditions (See Timmer, [0006], embodiment 79). By forming a homodimer necessarily constitutes where Timmer’s fusion protein contains two IL-2 proteins. Furthermore, Timmer et al. depicts a fusion protein comprising an antibody containing Fab and Fc regions where each Fc region each is fused to an IL-2 protein thereby constituting two IL-2 proteins. Thus, the teachings of Timmer et al. satisfy the claim limitation as recited in instant claim 4.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1 and 5-7 are rejected under 35 U.S.C. 103 as being unpatentable over Timmer et al. WO 2020/146221 A1 published on July 16, 2020 (effective filing date of January 7, 2019) (cited in the IDS received on 4/11/24) as applied to claims 1 and 5 above, and further in view of Li et al. WO 2020/088459 A1 published on May 7, 2020, and Keane et al., Blood Adv. 4:1367-1377 (April 2020), as applied to instant claims 6-7 herewith.
For claims 1 and 5, please see discussion of Timmer et al. supra.
For claims 6-7, with respect to the IL-2 variant amino acid sequence being SEQ ID NO: 20:
As discussed supra for claims 1 and 5, Timmer et al. teaches a modified IL-2 polypeptide comprising at least one substitution at, at least one amino acid position (See Timmer, [0006]). However, Timmer et al. does not expressly teach where the at least one substitution at, at least one amino acid position is a combination of R38A and F42A.
Li et al. teaches fusion proteins comprising an anti-checkpoint antibody or fragment thereof and a mutant IL-2 polypeptide (See Li, [0008]-[0009]). The IL-2 mutant is less selective towards the high affinity receptor (See Li, [0009]). The mutant IL-2 polypeptide sequence is selected from SEQ ID NOs: 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, or 57 (See Li, [00012]). These mutant polypeptide sequences include the following substitutions: K35E; R38A; F42K, F42A; Y45R; E62R, E62K; L72G; and C125S (See Li, [000155]-[000205]).
Keane et al. teaches that LAG3 is a novel immune checkpoint that was most highly expressed on CD4+ Tregs and CD8+ TILs and typically co-expressed with PD1 and TIM3 (See Keane, pg. 1373, col. 2, last paragraph). Thus, Keane et al. demonstrates that an antibody that specifically targets LAG3 would constitute an anti-checkpoint antibody.
Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of Timmer et al. and utilize a fusion protein comprising instant SEQ ID NO: 20 as a modified IL-2 polypeptide and an antibody that specifically binds to LAG-3 as an anti-checkpoint antibody. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because a modified IL-2 polypeptide fused to an anti-checkpoint antibody was known to have the amino acid sequence of instant SEQ ID NO: 20, which was known to be less selective towards the high affinity receptor as taught by Lee et al.; and because an antibody that specifically targets LAG-3 was known to constitute an anti-checkpoint antibody as taught by Keane et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the fusion protein of Timmer et al. comprised a modified IL-2 polypeptide and an antibody that specifically binds to LAG-3, and therefore, substituting instant SEQ ID NO: 20 as the modified IL-2 polypeptide would support the IL-2 protein being less selective towards the high affinity receptor by constituting a simple substitution of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654