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 .
Claims 26-46 are pending in the application. Claims 40-46 are withdrawn. Claims 26-39 are currently under examination.
This office action is in response to the amendment filed on 6/5/2026.
All previous rejection not reiterated in this office action are withdrawn.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 26-39 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.
Regarding claim 26, the recitation of “wherein the MHC-H polypeptide comprises cysteine substitutions at position 84 and 139 that form an intrachain disulfide bond, based on the numbering of SEQ ID NO: 39 when the sequence comprises an HLA-A sequence, SEQ ID NO: 47 when the sequence comprises an HLA-B sequence, SEQ ID NO: 57 when the sequence comprises an HLA-C sequence, and SEQ ID NO: 58 when the sequence comprises HLA-E sequences” renders the claim indefinite because it is unclear how does “based on the numbering of SEQ ID NO: 39, 47, 57, 58” limits the position of the cysteine substitution within the MHC-H if the amino acid sequence encoding MHC-H differs in length and/or structure from the amino acids identified by SEQ ID NO: 39, 47, 57 and 58.
Claims 27-39 are rejected for same reason because they depend on claim 26 and 42 but do not remedy the indefiniteness.
This rejection is maintained for following reason:
The position of 84 and 139 in SEQ ID NO: 39, 47, 57 and 58 is clear because each sequence comprises known amino acids so that each position is clearly defined. However, the claimed MHC-H does not comprise a known structure and/or amino acid sequence. Naming HLA-A, B, C and E does not limit the claimed polypeptide to any structure, including the length of the sequence. It is thus unclear how a cysteine substitution within the claimed polypeptide is considered to meet the requirement that corresponds to position 39 and 139 in SEQ ID NO: 39 when it is named HLA-A, for example. Therefore, this amendment does not overcome the indefiniteness rejection.
Regarding claim 31, the recitation of “the variant IL-2 MOD sequences comprises an amino acid at X1 16 other than His and amino acid at X2 other than Phe” renders the claim indefinite because it is unclear what “X1 16” stands for. Does it mean at position X1 and 16, or at position X1 or 16? This is a new rejection necessitated by amendment.
Regarding claim 35, the recitation of “the MHC H chain comprises a cysteine substitution at position 236” renders the claim indefinite because it is unclear how does “cysteine substitution at position 236” limits the position of the cysteine substitution within the MHC-H if the amino acid sequence encoding MHC-H differs in length and/or structure from the amino acids identified by SEQ ID NO: 39, 47, 57 and 58. This is a new rejection necessitated by amendment.
Regarding claim 27, the recitation of “wherein the unconjugated T-Cell-MP comprises at least one MOD sequence as part of element (i) or (ix)” renders the claim indefinite because it is unclear whether it is referring to the T-Cell-MP comprises at least (i) or (ix), or (i) or (ix) comprises at least one MOD sequence.
Applicant argues there is no conflicting in the recitation to say the MOD are individually optional, but at least one must be present.
The above argument is not persuasive because the claim is ambiguous and may be interpreted differently as discussed above. If Applicant meant to state the MOD are individually optional but at least must be present, appropriate correction is required.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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)(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.
Claim(s) 26-31, 33-39 is/are rejected under 35 U.S.C. 102(a2) as being anticipated by Wu et al (WO2021/127495). This rejection has been rewritten to address the amendment.
Claim 26 is drawn to a single chain, unconjugated T cell modulatory polypeptide (T-Cell-MP), comprising: (1) a β2M polypeptide sequence; (2) a class I MHC heavy chain (MHC-H) polypeptide sequence that comprises cysteine substitution; (3) a linker joining the β2M and class I MHC-H sequence; (4) a scaffold polypeptide and (5) one or more MOD, wherein the T-Cell-MP comprises a chemical conjugation site for epitope conjugation in (1) or (2). As discussed in the above 112b rejection, the limitation of cysteine substitution at position 84 and 139..that based on the numbering of SEQ ID NOS: 39, 47, 57 and 58 is indefinite because the position of the substitution cannot be determined if the claimed MHC-H differs from the MHC-H identified by SEQ ID NO: 39, 47, 57 and 58. As such, this claim limitation is interpreted as MHC-H comprise cysteine at any position.
Wu teaches a IL2 agonist that comprises an IL2 moiety, a multimerization moiety and a stabilization moiety and an optional tumor targeting moiety (paragraph [0015]). Wu teaches the targeting moiety may comprise a class I MHC heavy chain α polypeptide and a β2M polypeptide (paragraph [0190]). Wu teaches the MHC polypeptide and the β2M is linked to each other by a peptide linker (paragraph [0191], lines 1-4). Wu teaches the IL2 agonist can further comprise multimerization moiety that comprises Fc domains (paragraph [0206]), which meets the limitation of a scaffold polypeptide. Since the specification describes MOD or MOD polypeptide as immunomodulatory polypeptide (paragraph [0003]), the IL2 moiety taught by Wu meets this limitation. Since amino acids comprise sites for chemical conjugation, for example, cysteine, the wild type β2M amino acid sequence thus comprises chemical conjugation sites (see attached sequence). Therefore, the teaching from Wu anticipates the claimed polypeptide claimed in claim 26.
Regarding claim 27, Wu teaches the linker may be 10 to 25 amino acids in length (paragraph [0262]), which falls within the range of 10-50 aa as claimed.
Regarding claim 28, the β2M sequence comprises 100% sequence identity with amino acid 21-119 of SEQ ID NO: 61 (see attached alignment).
Regarding claim 29, Wu teaches the HLA-A sequence can be an HLA-A*0201 sequence (paragraph [0188]). Although Wu does not teach it comprises 200 contiguous aas of SEQ ID NO: 27, Wu incorporates the information from WO 2015/195531 (paragraph [0192]), which teaches MHC class I heavy chain sequence HLA-A02 (see attached alignment).
Regarding claim 30, Wu teaches IL-2 moiety, which meets the limitation of MOD.
Regarding claims 31, Wu teaches the IL-2 moiety is a full length IL-2 molecule, a human IL-2 molecule, or variants including deletion and substitution (paragraph [0138]-[0142]). This teaching meet the limitation of wild type IL-MOD.
Regarding claims 33-36, Wu teaches human β2M wild type sequence, which comprises at least two cysteine amino acids, one at position 45 of SEQ ID NO: 61 (see attached alignment), and it meets the limitation of amino acid conjugation sites.
Regarding claim 37, Wu teaches the Fc region may be immunoglobulin heavy chain constant region from IgA, IgD and IgG (paragraph [0211]).
Regarding claims 38, Wu teaches the IL-2 agonists may be homodimers upon expression of the component monomers in a suitable cell line (paragraph [0083]).
Regarding claim 39, Wu teaches the IL-2 agonists may be heterodimers (paragraph [0094]).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 31 and 32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wu, in view of the sequence having accession number (BFL45791, SEQ ID NO: 84 disclosed in WO2018119114). This is a new ground of rejection necessitated by amendment.
The teaching from Wu has been discussed above. However, Wu does not teach a IL-2 variant that comprises SEQ ID NO: 110 with X1 being A or T, and X2 being A.
BFL45791 (SEQ ID NO: 84) comprises A at X1 and A at position X2. WO2018119114 teaches IL-2 variant polypeptide or multimeric polypeptide H16A and F42A used for preparing pharmaceutical composition for selectively activating an epitope-specific T cell (see attached alignment).
It would have been obvious to an ordinary skilled in the art the one or more MOD sequence taught by Wu may comprise variant IL-2 that comprises H16A and F42A as disclosed in ‘114 application. The ordinary skilled in the art would be motivated to use this variant for its ability to selectively activating an epitope specific T cell as disclosed by ‘114 application. Therefore, the claimed invention would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Response to Arguments
Applicant argues that Wu only mentions a disulfide bond involving cysteine substitution at Y84C in paragraph [0193], and none of the constructs there are described as having intrachain disulfide within the MHC-H sequence from position 84 to position 139.
This argument is not persuasive because naturally occurring human MHC-H such as HLA-B7 and HLA-A comprises cysteine at position 101 and 164, and 203 and 259 forms intrachain disulfide bond (Orr et al. Biochemistry, 1979, vol.18, no.25, pages 5711-5720, abstract) and (Human Immunology, 2006, Vol. 67, no.8, pages 589-596, introduction section). As such, the MHC-H taught by Wu comprises intrachain bisulfide bond even though at different positions than 84 and 139. Since claim 26 (and dependent claims) are indefinite for reason discussed above, the teaching from Wu anticipates the claimed MHC-H polypeptide sequence.
Applicant argues that the mere presence of a cysteine residue in β2M serve as a chemical conjugation site cannot be used to support anticipation because it only references possibilities or probability. Applicant argues that amino acid may be buried within a molecules and not be solvent accessible, rendering them unavailable for conjugation of an epitope, or making the protein unstable.
This argument is not persuasive because claim 26 only recites the existence of a chemical conjugation site for epitope conjugation (i) the β2M polypeptide amino acid sequence or (ii) in the linker, without specifying any specific structure of the claimed conjugation site. Since the prior art known β2M would have the same structure as the claimed β2M, the presence of the cysteine residue meets the limitation of a conjugation site.
Applicant argues that the claimed T cell MPs are unconjugated T cell MPs that lack an epitope conjugated to their chemical conjugation site, but the office does not address this limitation. Applicant states that Wu uses MHC construct as a targeting arm requiring an antigen peptide-MHC construct to direct the constructs to specific T cells, and the rejection did not identify in Wu any construct meeting the limitation of Applicant’s claims, a construct that lacks an epitope bound to it, and to remove the epitope from the molecules of Wu would destroy them for their intended purpose.
This argument is not persuasive because the claimed invention is directed to a product, a single chain polypeptide comprises elements (i)-(v). Since Wu teaches each and every element of (i)-(v), it meets all limitation of the claimed invention. Therefore, for reasons discussed in previous office action and set forth above, this rejection is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 26-32, 37 and 38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 5, 7, 8, 10, 14, 16 and 17 of copending Application No. 18/035,733 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the soluble T-Cell-MP claimed in claims 1 and 5 of ‘733 application anticipates the claimed single chain unconjugated T-Cell-MP claimed in claim 26 and claim 27 of present application.
Claim 7 of ‘733 application recites same limitation of β2M sequence as claim 28 of present application.
Claims 8 and 10 of ‘733 application recites same MHC-H sequence as claim 29 of present application.
Claim 14 of ‘733 application recites same IL2 MOD sequences as claim 30-32 of present application.
Claim 16 of ‘733 application recites same scaffold polypeptide sequence as claim 37 of present application.
Claim 17 of ‘733 application recites same duplex T-Cell-MP as claimed in claim 38 and 39 of present application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant request the rejection to be held in abeyance until allowance matter is identified. Applicant further asserts that ‘733 application are directed to KRAS-epitope conjugates whereas the claims in the present application is directed to unconjugated molecules. Applicant argues that since the conjugated molecules were restricted away in the present application, the double patenting rejection is in conflict with the lack of unity.
The argument is not persuasive because the ‘733 application is not a divisional application of the present application. Therefore, the above rejection does not contradict the lack of unity requirement. Since this rejection cannot be held in abeyance, it is maintained for same reason as discussed above.
Conclusion
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 CELINE X QIAN whose telephone number is (571)272-0777. The examiner can normally be reached M-F (8-4:00).
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/CELINE X QIAN/ Primary Examiner, Art Unit 1637
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