Office Action 1: Non-Final Rejection (2024-12-03)
Rejection types: 112 - Written Description/Enablement, Double Patenting

CLAIMS:
What is claimed is:
1\. An isolated molecule comprising a targeting moiety fused with an immunomodulatory moiety, wherein: (a) the targeting moiety comprises an antibody, antibody fragment, scFv, or Fc-containing polypeptide comprising amino acids 1-119 of SEQ ID NO: 2 and amino acids 1-107 of SEQ ID NO: 71, and that specifically binds EGFR; and (b) the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of Transforming growth factor-beta receptor II (TGF-βRII) comprising SEQ ID NO: 87.
2\. The molecule of claim 1, wherein the molecule comprises a light chain, wherein the light chain comprises, from N-terminus to C-terminus, an amino acid sequence comprising SEQ ID NO: 71, a linker comprising SEQ ID NO: 104, and an amino acid sequence comprising SEQ ID NO: 87.
3\. The molecule of claim 2, wherein the molecule further comprises a heavy chain polypeptide, wherein the heavy chain comprises amino acids 1-119 of SEQ ID NO: 2.
4\. A method of treating cancer in a subject in need thereof, comprising: administering a therapeutically effective amount of a molecule comprising a targeting moiety fused with an immunomodulatory moiety, wherein: (a) the targeting moiety comprises an antibody, antibody fragment, scFv, or Fc-containing polypeptide comprising amino acids 1-119 of SEQ ID NO: 2 and amino acids 1-107 of SEQ ID NO: 71, and that specifically binds EGFR; and (b) the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of Transforming growth factor-beta receptor II (TGF-βRII) comprising SEQ ID NO: 87.
5\. The method of claim 4, wherein the molecule comprises a light chain, wherein the light chain comprises, from N-terminus to C-terminus, an amino acid sequence comprising SEQ ID NO: 71, a linker comprising SEQ ID NO: 104, and an amino acid sequence comprising SEQ ID NO: 87.
6\. The method of claim 5, wherein the molecule further comprises a heavy chain polypeptide, wherein the heavy chain comprises amino acids 1-119 of SEQ ID NO: 2.
7\. The method of claim 4, wherein the cancer is selected from the group consisting of: prostate cancer, pancreatic cancer, biliary cancer, colon cancer, rectal cancer, liver cancer, kidney cancer, lung cancer, testicular cancer, breast cancer, ovarian cancer, pancreatic cancer, brain cancer, head and neck cancer, melanoma, sarcoma, multiple myeloma, leukemia and lymphoma.
8\. The method of claim 7, wherein the cancer is head and neck squamous cell cancer (HNSCC).

OFFICE ACTION:
DETAILED ACTION
Notice of Pre-AIA  or AIA  Status
The present application is being examined under the pre-AIA  first to invent provisions.
Status of Application, Amendments and/or Claims
Claims 1-8 are pending.
Election/Restriction
1.	Restriction to one of the following inventions is required under 35 U.S.C. 121:
I. Claims 1-3, drawn to an isolated molecule comprising a targeting moiety fused with an immunomodulatory moiety, wherein the targeting moiety comprises an antibody, scFv, or Fc-containing polypeptide that targets EGFR; and the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of TGF-βRII, classified in C07K 16/2863, for example.
II. Claims 4-8, drawn to a method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a molecule comprising a targeting moiety fused with an immunomodulatory moiety, wherein the targeting moiety comprises an antibody, scFv, or Fc-containing polypeptide that targets EGFR; and the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of TGF-βRII, classified in A61K 39/39558.
2.	The inventions are independent or distinct, each from the other because:
a.	Inventions I and II are related as product and process of use.  The inventions can be shown to be distinct if either or both of the following can be shown: (1) the process for using the product as claimed can be practiced with another materially different product or (2) the product as claimed can be used in a materially different process of using that product. See MPEP § 806.05(h).  In the instant case, the isolated molecule comprising a targeting moiety fused with an immunomodulatory moiety claimed in Group I can be used in materially different methods, such as in protein purification methods or cell culture assays.
3.	Restriction for examination purposes as indicated is proper because all the inventions listed in this action are independent or distinct for the reasons given above and there would be a serious search and/or examination burden if restriction were not required because one or more of the following reasons apply:
• the inventions have acquired a separate status in the art in view of their different classification
• the inventions require a different field of search (e.g., searching different classes /subclasses or electronic resources, or employing different search strategies or search queries)
• the inventions are likely to raise different non-prior art issues under 35 U.S.C. 101 and/or 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
Applicant is advised that the reply to this requirement to be complete must include (i) an election of an invention to be examined even though the requirement may be traversed (37 CFR 1.143) and (ii) identification of the claims encompassing the elected invention.
The election of an invention may be made with or without traverse. To reserve a right to petition, the election must be made with traverse. If the reply does not distinctly and specifically point out supposed errors in the restriction requirement, the election shall be treated as an election without traverse. Traversal must be presented at the time of election in order to be considered timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are added after the election, applicant must indicate which of these claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA  35 U.S.C. 103(a) of the other invention.
4.	During a telephone conversation with Pamela Hwang on 22 November 2024, a provisional election was made without traverse to prosecute the invention of Group I, claims 1-3.  Affirmation of this election must be made by applicant in replying to this Office action.  Claims 4-8 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with  37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
The examiner has required restriction between product or apparatus claims and process claims. Where applicant elects claims directed to the product/apparatus, and all product/apparatus claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product/apparatus claims should be considered for rejoinder. All claims directed to a nonelected process invention must include all the limitations of an allowable product/apparatus claim for that process invention to be rejoined.
In the event of rejoinder, the requirement for restriction between the product/apparatus claims and the rejoined process claims will be withdrawn, and the rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to be allowable, the rejoined claims must meet all criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103 and 112. Until all claims to the elected product/apparatus are found allowable, an otherwise proper restriction requirement between product/apparatus claims and process claims may be maintained. Withdrawn process claims that are not commensurate in scope with an allowable product/apparatus claim will not be rejoined. See MPEP § 821.04. Additionally, in order for rejoinder to occur, applicant is advised that the process claims should be amended during prosecution to require the limitations of the product/apparatus claims. Failure to do so may result in no rejoinder. Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the examiner before the patent issues. See MPEP § 804.01.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12 September 2024 is in compliance with the provisions of 37 CFR 1.97.  Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
5.	Claims 1 and 2 are objected to because of the following informalities:
5a.	Claim 1 recites the acronyms “EGFR” without first defining what it represents. While the claims can reference acronyms, the material presented by the acronym must be clearly set forth at the first use of the acronym and/or in each independent claim.
5b.	In claim 2, the linker is an amino acid sequence, not a sequence identifier (SEQ ID NO:).  Thus, for clarity, the claim should be amended to recite, for example, …a linker comprising the amino acid sequence of SEQ ID NO: 104”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b)  CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
6.	Claims 2 and 3 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.
6a.	Claims 2 and 3 are rejected as being indefinite because the elements comprising the isolated molecule are unclear, as well as the structure of the molecule. Claim 2 recites the molecule of claim 1, wherein the molecule comprises a light chain, from N-terminus to C-terminus, an amino acid sequence comprising SEQ ID NO: 71, a linker comprising SEQ ID NO: 104, and an amino acid sequence comprising SEQ ID NO: 87.
For reference, claim 1 recites a targeting moiety fused with an immunomodulatory moiety, wherein (a) the targeting moiety comprises an antibody, antibody fragment, scFv, or Fc-containing polypeptide comprising amino acids 1-119 of SEQ ID NO: 2 and amino acids 1-107 of SEQ ID NO: 71, and that specifically binds EGFR; and (b) the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of TGF-βRII comprising SEQ ID NO: 87.
Therefore, regarding claim 2, it is not clear how a light chain comprises an amino acid sequence of SEQ ID NO: 87. The amino acid sequence of SEQ ID NO: 87 is an immunomodulatory moiety, specifically, the extracellular domain of TGF-βRII, and not a light chain.
It is also not clear how amino acids 1-119 of SEQ ID NO: 2 recited in claim 1 are structured/associated with the light chain of claim 2. Or, is the light chain recited in claim 2 an additional component of the isolated molecule of claim 1?  Likewise, regarding claim 3, is the heavy chain an additional component of the isolated molecule of claim 1? Or, is Applicant attempting to limit the structure of the targeting moiety? One of ordinary skill in the art would not be apprised of the scope of the invention.
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.
7.	Claims 1-3 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 9,441,044. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are directed to an isolated molecule comprising a targeting moiety fused with an immunomodulatory moiety.
Claim 1 of the instant application is directed to an isolated molecule comprising a targeting moiety fused with an immunomodulatory moiety, wherein: (a) the targeting moiety comprises an antibody, antibody fragment, scFv, or Fc-containing polypeptide comprising amino acids 1-119 of SEQ ID NO: 2 and amino acids 1-107 of SEQ ID NO: 71, and that specifically binds EGFR; and (b) the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of TGF-βRII comprising SEQ ID NO: 87.
Meanwhile, claim 1 of the ‘044 patent recites an isolated molecule comprising a targeting moiety fused with an immunomodulatory moiety, wherein: (a) the targeting moiety specifically binds EGFR; and (b) the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of TGF-βRII. Claim 2 of the ‘044 patent recites that the targeting moiety comprises an antibody, antibody fragment, scFv, or Fc-containing polypeptide that specifically binds EGFR or a fragment thereof. Claim 3 of the ‘044 patent recites that the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of TGF-βRII selected from the group consisting of SEQ ID NO: 79-91. Claim 41 of the ‘044 patent recites that the immunomodulatory moiety comprises the amino acid sequence corresponding to SEQ ID NO: 87 or a binding fragment thereof. It is noted that the amino acid sequence of SEQ ID NO: 87 of the ‘044 patent is 100% identical the amino acid sequence of SEQ ID NO: 87 of the instant claims.
Furthermore, claim 5 of the ‘044 patent recites that the molecule comprises the amino acid sequence of SEQ ID NO: 2 or a binding fragment thereof. It is noted that the amino acid sequence of SEQ ID NO: 2 of the ‘044 patent is 100% identical to the amino acid sequence of SEQ ID NO: 2 of the instant application.
Lastly, claims 7-9 of the ‘044 patent recite that the isolated molecule comprises a linker at the CH3 region of the Fc, wherein the linker comprises the amino acid sequence of SEQ ID NO: 104 (GGGGSGGGGSGGGGS). It is noted that the amino acid sequence of SEQ ID NO: 104 of the ‘044 patent is 100% identical to the amino acid sequence of SEQ ID NO: 104 as recited in instant 2.
8.	Claim 1-3 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of copending Application No. 18/811,627 in view of Huang et al. (App Environ Microbiol 72(12): 7748-7759, 2006).
Instant claim 1 is directed to an isolated molecule comprising a targeting moiety fused with an immunomodulatory moiety, wherein: (a) the targeting moiety comprises an antibody, antibody fragment, scFv, or Fc-containing polypeptide comprising amino acids 1-119 of SEQ ID NO: 2 and amino acids 1-107 of SEQ ID NO: 71, and that specifically binds EGFR; and (b) the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of TGF-βRII comprising SEQ ID NO: 87.
Meanwhile, claim 1 of the ‘627 application recites a method of treating a subject having cancer, comprising: administering to the subject a therapeutically effective amount of (a) a fusion protein comprising a targeting moiety fused to an immunomodulatory moiety, wherein:
(i) the targeting moiety comprises amino acids 1-119 of SEQ ID NO: 225 and amino acids 1-107 of SEQ ID NO: 226, and
(ii) the immunomodulatory moiety comprises a ligand binding fragment of the extracellular domain (ecd) of transforming growth factor β receptor II (TGFβRIIecd) having the amino acid sequence of SEQ ID NO: 6,
and (b) pembolizumab.
It is noted that amino acids 1-119 of SEQ ID NO: 225 of the ‘627 application are 100% identical to amino acids 1-119 of SQ ID NO: 2 of the instant application (see sequence alignment, below).
Qy=instant SEQ ID NO: 2
Db= SEQ ID NO: 225 of 18/811,627
RESULT 1
US-18-811-627-225
Query Match             100.0%;  Score 3253;  DB 1;  Length 601;
Best Local Similarity   100.0%;
Matches  601;  Conservative    0;  Mismatches    0;  Indels    0;  Gaps    0;
Qy          1 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYN 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db          1 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYN 60
Qy         61 TPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSAA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db         61 TPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSAA 120
Qy        121 STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db        121 STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG 180
Qy        181 LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db        181 LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGP 240
Qy        241 SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db        241 SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS 300
Qy        301 TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db        301 TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL 360
Qy        361 TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db        361 TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ 420
Qy        421 QGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSTIPPHVQKSVNNDMIV 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db        421 QGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSTIPPHVQKSVNNDMIV 480
Qy        481 TDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLE 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db        481 TDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLE 540
Qy        541 TVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNP 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db        541 TVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNP 600
Qy        601 D 601
|
Db        601 D 601
Additionally, amino acids 1-107 of SEQ ID NO: 226 of the ‘627 application are 100% identical to amino acids 1-107 of SQ ID NO: 71 of the instant application (see sequence alignment, below).
Qy=instant SEQ ID NO: 71
Db= SEQ ID NO: 226 of 18/811,627
RESULT 1
US-18-811-627-226
Query Match             100.0%;  Score 1109;  DB 1;  Length 379;
Best Local Similarity   100.0%;
Matches  214;  Conservative    0;  Mismatches    0;  Indels    0;  Gaps    0;
Qy          1 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db          1 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPS 60
Qy         61 RFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db         61 RFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPP 120
Qy        121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db        121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
Qy        181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
||||||||||||||||||||||||||||||||||
Db        181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
Lastly, the amino acid sequence of SEQ ID NO: 6 of the ‘627 application is 100% identical to the amino acid sequence of SEQ ID NO: 87 of the instant application (see sequence alignment, below).
Qy=instant SEQ ID NO: 87
Db= SEQ ID NO: 6 of 18/811,627
RESULT 1
US-18-811-627-6
Query Match             100.0%;  Score 764;  DB 1;  Length 137;
Best Local Similarity   100.0%;
Matches  137;  Conservative    0;  Mismatches    0;  Indels    0;  Gaps    0;
Qy          1 TIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQE 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db          1 TIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQE 60
Qy         61 VCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDE 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db         61 VCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDE 120
Qy        121 CNDNIIFSEEYNTSNPD 137
|||||||||||||||||
Db        121 CNDNIIFSEEYNTSNPD 137
Claims 5 and 6 of the ‘627 application recite that the fusion protein comprises a linker fused between the targeting moiety and the immunomodulatory moiety; and that the linker comprises the amino acid sequence of SEQ ID NO: 4.
The only difference between the fusion protein of the ‘627 claims and the fusion protein of the instant application is that the claims of the ‘627 application do not recite that the linker comprises the amino acid sequence of SEQ ID NO: 104 (GGGGS)3, as required by instant claim 2.
Huang et al. teach the generation of scFv and single-chain TCR fused to GFP via a linker, (GGGGS)3 (abstract; page 7749, column 1, 1st full paragraph; page 7751, column 1; Figure 1 (Type II, III); Table 1). Huang et al. disclose that secretion yields were not substantially different, but fusion proteins with the extended linker of (GGGGS)3 demonstrated higher fluorescence per molecule, indicating less interference between the folded protein domains (page 7757, top of column 2).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the administered fusion protein comprising a targeting moiety fused to an immunomodulatory moiety, wherein the fusion protein comprises a linker fused between the two moieties as required by the claims of the ‘627 application by fusing the moieties with a (GGGGS)3 (instant SEQ ID NO: 104) linker as taught by Huang et al. The person of ordinary skill in the art would have been motivated to make that modification because the (GGGGS)3 linker is flexible, increasing spatial separation between the domains and minimizing potential folding interference (see Huang et al., page 7751, column 1, 1st full paragraph). The person of ordinary skill in the art reasonably would have expected success because the (GGGGS)3 linker was a common flexible linker for fusion proteins at the time the invention of the ‘627 claims was made.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowable.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Schmidt et al. Oncogene 18: 1711-1721, 1999 (teach a fusion protein comprising the variable domains of anti-EGFR antibody, 14E1, fused to a truncated form of Pseudomonas exotoxin A via a (GGGGS)3 linker (abstract; page 1712, column 1, 1st paragraph under Results)

APPLICANT REBUTTAL: REMARKS
Prior to this Communication, claims 1-9 were pending. With the present communication, claims 1 and 2 have been amended, claims 3-8 have been canceled without prejudice or disclaimer and new claims 9-15 have been added. Support for the claim amendments and new claims may be found generally throughout the application and claims as originally filed. No new matter is added. After entry of the amendments, claims 1-2 and 9-15 will be pending and under consideration.
Examiner's Interview
Applicant thanks Examiner Bunner for the telephone interview with Applicant's representatives on December 17, 2024. During the interview, proposed claim amendments were discussed to address clarity and indefiniteness rejections and the submission of a terminal disclaimer to address the obviousness type double patenting rejection were discussed. The Examiner stated that the proposed amendments and filing of a terminal disclaimer were reasonable to overcome the objections/rejections, but that such would be considered once the response is made of record.
Election/Restriction
The Examiner contacted Applicant's representative regarding a telephonic restriction requirement. The Examiner restricted the claims into two groups:
I. Claims 1-3 drawn to an isolated molecule comprising a targeting moiety fused
with an immunomodulatory moiety, wherein the targeting moiety comprises an antibody, scFv, or Fe-containing polypeptide that targets EGFR; and the immunomodulatory moiety comprises an amino acid sequence of extracellular
domain of TGF-BRII; and
II. Claims 4-8 drawn to a method of treating cancer in a subject in need thereof
comprising administering a therapeutically effective amount of a molecule comprising a targeting moiety fused with an immunomodulatory moiety,
wherein the targeting moiety comprises an antibody, scFv, or Fc-containing polypeptide that targets EGFR; and the immunomodulatory moiety comprises
an amino acid sequence of extracellular domain of TGF-BRII.
During a telephone conversion with Applicant's representative on November 22, 2024, a provisional election to pursue the invention of Group I, claims 1-3, without traverse was made. Applicant affirms the election of Group I, claims 1-3 without traverse.
Applicant reserves the right to pursue prosecution of non-elected subject matter and/or species upon an indication of allowance of any generic claims and to request rejoinder in the present application or in a later filed application claiming the benefit of priority of the above- identified application.
Claim Objections
The Examiner objected to claim 1 stating that the acronym "EGFR" is recited without first defining what it represents.
Applicant amended claim 1 to define "EGFR" as Epidermal Growth Factor Receptor". submits that this amendment renders the objection moot and respectfully requests withdrawal of the objection.
The Examiner objected to claim 2 not reciting a sequence identifier for the amino acid sequence of the linker and suggested that the claim be amended to recite "... linker comprising the amino acid sequence of SEQ ID NO: 104."
Applicant amended claim 2 to recite "wherein the targeting moiety comprises an antibody fragment selected from a Fab or scFv." Applicant submits that these amendments render the objection moot and respectfully request withdrawal of the objection.
Rejections under 35 USC
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second
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graph
Claims 2 and 3 stand rejected under 35 USC § 112, second paragraph as being indefinite for failing to particularly point out and distinctly claim the subject matter of the invention. Applicant respectfully traverses this rejection.
The Examiner states that claims 2 and 3 are indefinite because the elements comprising the isolated molecule are unclear, as well as the structure of the molecule.
As an initial matter, claim is canceled. Applicant amended claim 2 to recite "wherein the targeting moiety comprises an antibody fragment selected from a Fab or scFv." Applicant submits that these amendments and cancelations render the rejection moot and respectfully requests reconsideration and withdraw of the rejection.
Double Patenting Re
j
ection
Claims 1-3 are provisionally rejected on the ground of non-statutory obviousness-type double patenting over claims 1-9 of U.S. Patent No. 9,441,044. Applicants respectfully traverse this rejection.
Without acquiescing to the Examiner's assertion and to expedite prosecution of the claimed invention, a terminal disclaimer is hereby submitted together with this paper to overcome the non-statutory obviousness-type double patenting rejections over U.S. Patent No. 9,441,044. Accordingly, withdrawal of the double patenting rejection is respectfully requested.
Claims 1-3 are provisionally rejected on the ground of non-statutory obviousness-type double patenting over claims 1-12 of U.S. Patent Appl. Serial No. 18/811,627 in view of Huang et al. (App Environ Microbiol 72(12):7748-7759, 2006). Applicants respectfully traverse this rejection.
Without acquiescing to the Examiner's assertion and to expedite prosecution of the claimed invention, a terminal disclaimer is hereby submitted together with this paper to overcome the non-statutory obviousness-type double patenting rejections over U.S. Patent Appl. Serial No. 18/811,627. Accordingly, withdrawal of the double patenting rejection is respectfully requested.
CONCLUSION

NEXT OFFICE ACTION: DETAILED ACTION
Notice of Pre-AIA  or AIA  Status
The present application is being examined under the pre-AIA  first to invent provisions.
Status of Application, Amendments and/or Claims
The amendment of 23 December 2024 has been entered in full.  Claims 1 and 2 are amended. Claims 3-8 are cancelled. Claims 9-15 are added.
Claims 1, 2, and 9-15 are under consideration in the instant application.
Withdrawn Objections and/or Rejections
1.	The objections to claims 1 and 2 as set forth at page 6 of the previous Office Action of 03 December 2024 are withdrawn in view of the amended claims (23 December 2024).
2.	The rejection of claims 2 and 3 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as set forth at pages 6-7 of the previous Office Action of 03 December 2024 is withdrawn in view of amended claim 2 and cancelled claim 3 (23 December 2024).
3.	The rejection of claims 1-3 on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 9,441,044 as set forth at pages 9-10 of the previous Office Action of 03 December 2024 is withdrawn in view of the submission of a terminal disclaimer (23 December 2024).
4.	The provisional rejection of claims 1-3 on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of copending Application No. 18/811,627 in view of Huang et al. (App Environ Microbiol 72(12): 7748-7759, 2006) as set forth at pages 10-14 of the previous Office Action of 03 December 2024 is withdrawn in view of the submission of a terminal disclaimer (23 December 2024).
Conclusion
Claims 1, 2, and 9-15 are allowed.

CITED REFERENCE SUMMARIES: Ref US8993524B2: Claims:
An isolated molecule comprising a targeting moiety fused with an immunomodulatory moiety, wherein: (a) the targeting moiety specifically binds Cytotoxic T-lymphocyte associated antigen-4 (CTLA-4); and (b) the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of Transforming growth factor-beta receptor (TGF-Î²R).
(a) the targeting moiety specifically binds Cytotoxic T-lymphocyte associated antigen-4 (CTLA-4); and
(b) the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of Transforming growth factor-beta receptor (TGF-Î²R).
The molecule of claim 1 , wherein the targeting moiety comprises an antibody, antibody fragment, scFv, or Fc-containing polypeptide that specifically binds CTLA-4.
The molecule of claim 1 , wherein the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of Transforming growth factor-beta receptor selected from the group consisting of SEQ ID NO: 79-91.
The molecule of claim 3 , wherein the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of Transforming growth factor-beta receptor II (TGF-Î²RII).
The molecule of claim 4 , wherein the immunomodulatory moiety comprises the amino acid sequence corresponding to SEQ ID NO: 87 or a binding fragment thereof.
The molecule of claim 5 , wherein the molecule comprises the amino acid sequence corresponding to SEQ ID NO: 5 or a binding fragment thereof.
The molecule of claim 6 , wherein the molecule comprises the amino acid sequence corresponding to SEQ ID NO: 5 or a binding fragment thereof and the amino acid sequence corresponding to SEQ ID NO: 74 or a binding fragment thereof.
A method of treating a neoplastic disease comprising: administration to a subject in need thereof one or more molecules of claim 1 , wherein the neoplastic disease is bladder cancer or melanoma.
The method of claim 8 , wherein the subject is administered in combination with another anticancer therapy.
The method of claim 8 , wherein the anticancer therapy comprises a chemotherapeutic molecule, antibody, small molecule kinase inhibitor, hormonal agent, ionizing radiation, ultraviolet radiation, cryoablation, thermal ablation, or radiofrequency ablation.
The method of claim 8 , wherein the subject is administered in combination with a vaccine.
The method of claim 8 , wherein the subject is human.
The isolated molecule of claim 1 , further comprising a linker at the C H 3 region of the Fc.
The isolated molecule of claim 13 , wherein the linker is (GGGGS)n (SEQ ID NO:104), and wherein n is 1, 2, 3, 4, 5, 6, 7 or 8.
The isolated molecule of claim 13 , wherein the linker comprises the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO:104).
Ref US9441044B2: [content unavailable]
Ref US9850306B2: Claims:
An isolated molecule comprising a targeting moiety fused with an immunomodulatory moiety, wherein: (a) the targeting moiety is a polypeptide that specifically binds Programmed Death-1 ligand (PD-1 ligand); and (b) the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of Transforming growth factor-beta receptor (TGFÎ²R).
(a) the targeting moiety is a polypeptide that specifically binds Programmed Death-1 ligand (PD-1 ligand); and
(b) the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of Transforming growth factor-beta receptor (TGFÎ²R).
The molecule of claim 1 , wherein the polypeptide comprises an antibody, antibody fragment, antigen-binding domain of an immunoglobulin, single chain variable fragment (scFv), Fc-containing polypeptide, or fusion protein that specifically binds PD-1 ligand or a fragment thereof.
The molecule of claim 2 , wherein the molecule comprises the amino acid sequence corresponding to the heavy chain or light chain of an antibody that specifically binds PD-L1.
The molecule of claim 1 , wherein the targeting moiety comprises an amino acid sequence of the extracellular domain of PD-1.
The molecule of claim 4 , wherein the targeting moiety comprises the amino acid sequence corresponding to SEQ ID NO: 93 or a binding fragment thereof.
The molecule of claim 1 , wherein the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of Transforming growth factor-beta receptor selected from the group consisting of SEQ ID NO: 79-91.
The molecule of claim 1 , wherein the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of Transforming growth factor-beta receptor II (TGFÎ²RII) or a binding fragment thereof.
The molecule of claim 6 , wherein the immunomodulatory moiety comprises the amino acid sequence corresponding to SEQ ID NO: 87 or a binding fragment thereof.
The molecule of claim 1 , wherein the molecule comprises the amino acid sequence set forth in SEQ ID NOs: 87 and SEQ ID NO:93 or a binding fragment thereof.
The isolated molecule of claim 1 , wherein the targeting moiety is fused to the immunomodulatory moiety via a linker.
The isolated molecule of claim 10 , wherein the targeting moiety is an Fc-containing polypeptide comprising a linker at the CH3 region of the Fc.
The isolated molecule of claim 10 , wherein the linker is (GGGGS)n and wherein n is 1, 2, 3, 4, 5, 6, 7 or 8.
The isolated molecule of claim 12 , wherein the linker comprises the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO:104).
The molecule of claim 9 , wherein the molecule comprises the amino acid sequence set forth in SEQ ID NOs: 11 or SEQ ID NO:12 or a binding fragment thereof.
Ref US11274156B2: Claims:
An isolated molecule comprising a targeting moiety fused with an immunomodulatory moiety, wherein: a) the targeting moiety comprises a polypeptide that specifically binds a component of a tumor cell that is a tumor cell surface molecule; and b) the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of Transforming growth factor-beta receptor (TGFbR).
a) the targeting moiety comprises a polypeptide that specifically binds a component of a tumor cell that is a tumor cell surface molecule; and
b) the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of Transforming growth factor-beta receptor (TGFbR).
The molecule of claim 1 wherein the targeting moiety specifically binds a cell surface molecule that is a tumor antigen, tumor growth factor receptor, or cytokine receptor.
The molecule of claim 1 wherein the targeting moiety comprises an antigen-binding domain of an immunoglobulin, antibody, bispecific or multispecific antibody, antibody fragment, single chain variable fragment (scFv), bivalent or multivalent scFv or Fc-containing polypeptide.
The molecule of claim 1 , wherein the immunomodulatory moiety is fused to the C-terminus or N-terminus of said targeting moiety.
The molecule of claim 1 , wherein the targeting moiety is fused to the immunomodulatory moiety via a linker.
The molecule of claim 5 , wherein the linker is (GGGGS)n (SEQ ID NO:123) and wherein n is 1, 2, 3, 4, 5, 6, 7, or 8.
The molecule of claim 5 , wherein the targeting moiety is an Fc-containing polypeptide comprising a linker at the CH3 region of the Fc.
The molecule of claim 1 , wherein the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of Transforming growth factor-beta receptor II (TGFbRII) or a ligand-binding fragment thereof.
The molecule of claim 8 , wherein the immunomodulatory moiety comprises the amino acid sequence corresponding to SEQ ID NO: 87, or a ligand-binding fragment thereof.
The molecule of claim 1 , wherein the targeting moiety specifically binds Herpesvirus entry mediator (HVEM), Carcinoembryonic antigen (CEA), Prostate-specific membrane antigen (PSMA), Programmed death-ligand 1 (PD-L1), or Epidermal growth factor receptor (EGFR).
Ref US9441044: Claims:
1. An isolated molecule comprising a targeting moiety fused with an immunomodulatory moiety, wherein:
(a) the targeting moiety specifically binds Epidermal Growth Factor Receptor (EGFR); and
(b) the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of Transforming growth factor-beta receptor II (TGF-βRII).
2. The molecule of claim 1, wherein the targeting moiety comprises an antibody, antibody fragment, scFv, or Fc-containing polypeptide that specifically binds EGFR or a fragment thereof.
3. The molecule of claim 1, wherein the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of Transforming growth factor-beta receptor selected from the group consisting of SEQ ID NO: 79-91.
4. The molecule of claim 3, wherein the immunomodulatory moiety comprises the amino acid sequence corresponding to SEQ ID NO: 87 or a binding fragment thereof.
5. The molecule of claim 4, wherein the molecule comprises the amino acid sequence corresponding to SEQ ID NO: 2 or a binding fragment thereof.
6. The molecule of claim 5, wherein the molecule comprises the amino acid sequence corresponding to SEQ ID NO: 2 or a binding fragment thereof and the amino acid sequence corresponding to SEQ ID NO: 71 or a binding fragment thereof.
7. The isolated molecule of claim 1, further comprising a linker at the CH3 region of the Fc.
8. The isolated molecule of claim 7, wherein the linker is (GGGGS)n (SEQ ID NO:104)n and wherein n is 1, 2, 3, 4, 5, 6, 7 or 8.
9. The isolated molecule of claim 7, wherein the linker comprises the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO:104).
10. An isolated molecule comprising a targeting moiety fused with an immunomodulatory moiety, wherein:
(a) the targeting moiety specifically binds Epidermal Growth Factor Receptor (EGFR); and
(b) the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of Transforming growth factor-beta receptor (TGF-βR).
Ref APP-18_811627: Claims:
A method of treating a subject having cancer, comprising: administering to the subject therapeutically effective amounts of (a) a fusion protein comprising a targeting moiety fused to an immunomodulatory moiety, wherein: (i) the targeting moiety comprises amino acids 1-119 of SEQ ID NO: 225 and amino acids 1-107 of SEQ ID NO: 226, and (ii) the immunomodulatory moiety comprises a ligand binding fragment of the extracellular domain (ecd) of transforming growth factor β receptor II (TGFβRIIecd) having the amino acid sequence of SEQ ID NO: 6, and (b) pembrolizumab.
administering to the subject therapeutically effective amounts of
(a) a fusion protein comprising a targeting moiety fused to an immunomodulatory moiety, wherein: (i) the targeting moiety comprises amino acids 1-119 of SEQ ID NO: 225 and amino acids 1-107 of SEQ ID NO: 226, and (ii) the immunomodulatory moiety comprises a ligand binding fragment of the extracellular domain (ecd) of transforming growth factor β receptor II (TGFβRIIecd) having the amino acid sequence of SEQ ID NO: 6,
(i) the targeting moiety comprises amino acids 1-119 of SEQ ID NO: 225 and amino acids 1-107 of SEQ ID NO: 226, and
(ii) the immunomodulatory moiety comprises a ligand binding fragment of the extracellular domain (ecd) of transforming growth factor β receptor II (TGFβRIIecd) having the amino acid sequence of SEQ ID NO: 6,
The method of claim 1, wherein the targeting moiety of said fusion protein is an antibody and the immunomodulatory moiety is fused to the C terminus of the heavy chain of the antibody.
The method of claim 1, wherein the targeting moiety of said fusion protein is an antibody and the immunomodulatory moiety is fused to the C terminus of the light chain of the antibody.
The method of claim 3, wherein the fusion protein further comprises a polypeptide linker fused between the targeting moiety and the immunomodulatory moiety.
The method of claim 4, wherein the linker has the amino acid sequence of SEQ ID NO: 4.
The method of claim 5, wherein the fusion protein comprises, from N-terminus to C-terminus, a light chain comprising SEQ ID NO: 75, fused to a linker comprising SEQ ID NO: 4, fused to the TGFβRIIecd comprising SEQ ID NO: 6.
The method of claim 1, wherein the subject is administered said fusion protein prior to, simultaneously with, or following administration of pembrolizumab.
The method of claim 1, wherein said fusion protein is administered by intravenous administration.
The method of claim 1, wherein pembrolizumab is administered by intravenous or subcutaneous administration.
The method of claim 1, wherein the cancer is head and neck cancer (HNSCC).
The method of claim 1, wherein amino acids 1-119 of SEQ ID NO: 225 comprise the VH domain of cetuximab.
The method of claim 1, wherein amino acids 1-107 of SEQ ID NO: 226 comprise the VL domain of cetuximab.