MULTIFUNCTIONAL PROTEIN MOLECULES COMPRISING DECORIN AND USE THEREOF

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 . Continued Examination Under 37 CFR 1.114 A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on May 11, 2026 has been entered. DETAILED ACTION Applicant’s submission filed on May 11, 2026 in response to the Office Action of February 11, 2026 is acknowledged and has been entered. Claims 2, 4-9, 11 and 13-17 are pending. Claims 16 and 17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim. Claims 2, 4-9, 11 and 13-15 are currently under consideration as drawn to the elected invention. Since no new claim amendment has been made, the 103 rejection set forth in the previous Office Action is maintained. Information Disclosure Statement The Information Disclosure Statement (IDS) filed 08/19/2026 has been considered and entered. MAINTAINED/MODIFIED REJECTIONS 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. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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 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. Claims 2, 4-9, 11, and 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Hubbell (Hubbell et al., WO 2018/195386, Filing Date: 04/20/2018, of record) in view of Jarvinen (Jarvinen et al., BioMed Research International, Vol 2015, Article ID 654765, Publication Year: 2015, of record), Bleck (Bleck et al., US 2012/0238727 A1, Appl. No.: 13/419,045, Publication Date: 09/20/2012, of record) and Kontermann (Kontermann et al., Archives of Biochemistry and Biophysics, 526 (2012), 194-205, Publication Date: 03/16/2012, of record). Hubbell teaches extracellular matrix (ECM)-affinity peptide ([0005]). In some embodiments, the ECM-affinity peptide comprises a decorin peptide, such as SEQ ID NO: 16 ([0006], [0095]). As shown below, SEQ ID NO: 16 comprises a sequence which is 99.8% identical to SEQ ID NO: 7 of the instant application and comprises amino acids Asp45-Lys359 or Leu155-Val260 of full length decorin: RESULT 13 BFT48908 DE Decorin peptide (17-359), SEQ ID 16. Query Match 99.8%; Score 1712; Length 343; Best Local Similarity 99.7%; Matches 328; Conservative 1; Mismatches 0; Indels 0; Gaps 0; Qy 1 DEAAGIGPEVPDDRDFEPSLGPVCPFRCQCHLRVVQCSDLGLDKVPKDLPPDTTLLDLQN 60 |||:|||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 15 DEASGIGPEVPDDRDFEPSLGPVCPFRCQCHLRVVQCSDLGLDKVPKDLPPDTTLLDLQN 74 Qy 61 NKITEIKDGDFKNLKNLHALILVNNKISKVSPGAFTPLVKLERLYLSKNQLKELPEKMPK 120 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 75 NKITEIKDGDFKNLKNLHALILVNNKISKVSPGAFTPLVKLERLYLSKNQLKELPEKMPK 134 Qy 121 TLQELRAHENEITKVRKVTFNGLNQMIVIELGTNPLKSSGIENGAFQGMKKLSYIRIADT 180 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 135 TLQELRAHENEITKVRKVTFNGLNQMIVIELGTNPLKSSGIENGAFQGMKKLSYIRIADT 194 Qy 181 NITSIPQGLPPSLTELHLDGNKISRVDAASLKGLNNLAKLGLSFNSISAVDNGSLANTPH 240 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 195 NITSIPQGLPPSLTELHLDGNKISRVDAASLKGLNNLAKLGLSFNSISAVDNGSLANTPH 254 Qy 241 LRELHLDNNKLTRVPGGLAEHKYIQVVYLHNNNISVVGSSDFCPPGHNTKKASYSGVSLF 300 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 255 LRELHLDNNKLTRVPGGLAEHKYIQVVYLHNNNISVVGSSDFCPPGHNTKKASYSGVSLF 314 Qy 301 SNPVQYWEIQPSTFRCVYVRSAIQLGNYK 329 ||||||||||||||||||||||||||||| Db 315 SNPVQYWEIQPSTFRCVYVRSAIQLGNYK 343 Thus, the decorin peptide taught by Hubbell comprises the TGF-β domain of claims 7 and 8. Hubbell teaches an ECM-affinity peptide operatively linked to a CTLA4 antibody, or to a PD-L1 antibody, or a PD-1 antibody ([15], claims 1, 50, 51). Hubbell teaches various antibodies that can be linked to an ECM-affinity peptide, including Bevacizumab ([0089]), a VEGF antibody as evidenced by paragraph [0100] of the instant publication (US2024/0150452 A1). Hubbell teaches the method making decorin anti-PD-L1 and decorin-anti-CTLA conjugates ([0238] and [0239]), which have enhanced anti-tumor activity ([0073], Fig. 44). As evidenced by [0032], αPD-L1 and αCTLA4 refer to antibodies. Regarding linked to the c-terminal end of a heavy chain of the antibody, Hubbell further teaches that the peptide is covalently linked to the antibody. Linkers such as amino acid sequences may be inserted between the peptide and antibody sequence. In some embodiment, the linker can be joined to a heavy chain immediately after the last amino acid at the C-terminus of the Heavy chain. The length of the linker sequence may vary without significantly affecting the function or activity of the fusion protein ([0007]). Hubbell teaches that the peptide can be linked to anti-PD-L1 or anti-CTLA4 antibody close to heavy chain C-terminal end (Fig. 28A). Hubbell’s teachings are set forth above. However, Hubbell does not teach decorin comprises a mutation such as serine to alanine at position 4, or decorin lacks modification by glycosaminoglycans molecules at position 4, or explicitly teach that the decorin molecule is linked to the c-terminal end of a heavy chain of the antibody. Jarvinen teaches that decorin (DCN) is the best characterized member of the small leucine-rich proteoglycan (SLRP) family of extracellular matrix (ECM) proteins (introduction). Jarvinen teaches that DCN influences various cellular functions such as proliferation, spreading, migration, and differentiation, and inflammation (Introduction). Jarvinen teaches that mammalian DCN contains a 42 kDa protein core and a single glycosaminoglycan (GAG) chain, attached to a serine residue near the N terminus (Introduction). Jarvinen teaches that DCN has an antiangiogenic effect on tumor angiogenesis (page 4 § 7. DCN in angiogenesis). Jarvinen teaches that administration of DCN can inhibit tumor growth and progression in vivo, including lung, colon, squamous cell carcinomas, prostate and pancreatic cancer (pages 4-5 § 8 DCN as a Therapeutic anticancer drug in vivo). Jarvinen teaches that most of the anticancer effects of DCN have been generated with recombinant DCN with no GAG attached to it, and most of the interactions DCN has with growth factors or their receptors are through direct binding to the DCN core protein (page 5 § 10 Limitations of DCN). Jarvinen teaches that the GAGs attached to a serine residue at position 4 of DCN, and it is possible to produce recombinant DCN without GAG attached to it by simply mutating the serine residue critical for the GAG attachment, which can simplify production process for recombinant DCN protein (pages 6-7 bridging paragraph). Jarvinen teaches that DCN fusion protein can be produced through recombinant technology (page 7, § 11 Recombinant DCN variant with enhanced biological activity). Bleck teaches decorin protein comprises a mutation at position 4 of the mature decorin core protein (claim 5), wherein the mutation is a serine to alanine mutation (claim 6). Bleck teaches that a serine to alanine modification was made at amino acid 4 of mature decorin. The mutation prevents a GAG from being attached to the decorin molecule (Example 1, [0048]). Kontermann teaches various formats to link a peptide (various cytokines) to antibody, including linked to C-terminal of heavy chains (see Fig. 2(b) and Fig. 3). And the technology is widely used in the art (see Conclusions). It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make a protein molecule comprising at least one decorin molecule having at least 95% sequence identity to SEQ ID NO: 7 linked to an anti-anti-PD-L1 antibody as taught by Hubbell, and to link to the c-terminal end of a heavy chain of an antibody through a linker because it is a well-known and easily-implemented strategy to link a peptide to antibody as taught by Hubbell and Kontermann, because this configuration is less likely to impact antibody binding or ADCC activity, and to substitute wild-type decorin with a decorin variant with a mutation at position 4 and lacking modification by GAG at position 4 as taught by Jarvinen, and to further pick a mutation as a serine to alanine mutation as taught by Bleck, because Jarvinen teaches most of the anticancer effects of DCN have been generated with recombinant DCN with no GAG attached to it, and the GAGs attached to a serine residue at position 4 of DCN, and it is possible to produce recombinant DCN without GAG attached to it by simply mutating the serine residue critical for the GAG attachment, which can simplify production process for recombinant DCN protein, and Bleck teaches decorin with the mutation (S4A) prevents modification by glycosaminoglycans molecules at position 4 of the mature decorin core protein. One of ordinary skill in the art would have reasonable expectation of success to reach the claimed invention, given that all components and methods of heavy chain C-terminal fusion are well known and widely used in the art as evidenced by Hubbell, Kontermann and Jarvinen. The motivation is to make more potent and effective anti-cancer agent with a well-tested strategy. Regarding claims 6 and 9, the format (Fig. 2(b) taught by Kontermann would comprise two copies of the decorin molecules. Regarding claim 11, Hubbell teaches recombinant fusion of decorin with the antibodies ([0224], [0229]). In some embodiments, nucleotides encoding for an ECM-affinity polypeptide and/or an ECM-affinity polypeptide fused to antibody heavy or light chain ([0102]). Regarding claim 13-15, Hubbell teaches a nucleotide encoding the ECM-affinity polypeptide fused to the antibody ([0102]); vector comprises the nucleotide ([0110]); and host cells and expression system (pages 34 and 35). Response to Arguments For the rejection of claims 2, 4-9, 11 and 13-15 under 35 U.S.C. 103, Applicant argues: The cited references, alone or in combination, do not establish the obviousness of independent claim 2 or the claims dependent thereon. a. Hubbell ¶ [0007] does not teach or suggest C-terminal heavy chain attachment of decorin or any other ECM-affinity peptide; the C-terminal language is sentence-bound to fynomer domains. The C-terminal heavy chain attachment language in Hubbell ¶ [0007] appears in a single sentence the grammatical subject of which is "a fynomer domain": "In an embodiment, a fynomer domain is joined to a Heavy (H) chain or Light (L) chain immediately after the last amino acid at the amino(NH2)terminus or the carboxy(C)-terminus of the Heavy (H) chain or the Light (L) chain." (Hubbell ¶ [0007], emphasis added.) The fynomer domain is a small protein scaffold derived from the human Fyn SH3 domain. It is not part of Hubbell's enumerated ECM-affinity peptides, which Hubbell identifies in ¶¶ [0090]-[0095] as PIGF-2, CXCL-12y, vWF, and decorin. Verification by full-text search of the Hubbell specification confirms that the term "fynomer" appears exactly once in the entire reference (i.e., in the sentence quoted above) and is not mentioned in any of Hubbell's claims. Hubbell's only express teaching of attachment at the C-terminus of an antibody heavy chain is therefore directed to a fusion partner (the fynomer domain) that is structurally and functionally distinct from decorin, and that is not within Hubbell's enumerated category of ECM-affinity peptides. The Examiner's paraphrase of Hubbell ¶ [0007] at Office Action page 5 (and again at page 9) substitutes "the linker" for the actual subject of that sentence ("a fynomer domain"): "In some embodiment, the linker can be joined to a heavy chain immediately after the last amino acid at the C-terminus of the Heavy chain." (Office Action, p. 5.) This is not what Hubbell ¶ [0007] says. The sentence in Hubbell that addresses the C-terminus of the heavy chain has "a fynomer domain" as its grammatical subject, not "the linker." The preceding sentence in ¶ [0007] - "Linkers, such as amino acid or peptidimimetic sequences may be inserted between the peptide and/or antibody sequence" - is generic with respect to linker chemistry and does not specify any attachment location (Nor C-terminus, heavy or light chain). The two sentences are not interchangeable in subject matter, and the proposition that "the linker [for any peptide, including decorin] can be joined to a heavy chain ... at the C-terminus" cannot be drawn from Hubbell ¶ [0007] without rewriting what the paragraph actually says. In this regard, the term "peptide linker" in Claim 2 refers to flexible, unstructured spacer sequences (as disclosed throughout the Specification and as understood in the fusion protein art per Kontermann and Jarvinen). A fynomer domain is a structured, folded protein with its own binding properties and does not fall within the scope of 'peptide linker.' Therefore, it is not appropriate to substitute the term "linker" for "fynomer domain" in the quoted passage from Hubbell. The Examiner's own express concession at Office Action page 5 is consistent with the foregoing reading. The Examiner expressly acknowledges that "Hubbell does not ... explicitly teach that the decorin molecule is linked to the c-terminal end of a heavy chain of the antibody." Office Action, p. 5. If Hubbell ¶ [0007] taught- as the Examiner asserts at the same page - that "the linker [for any peptide, including decorin] can be joined to a heavy chain ... at the C-terminus," then the conceded gap would not exist. The internal tension between the Examiner's contrary characterization of,r [0007] (Office Action, p. 5; restated p.9) and the Examiner's express concession at the same page that Hubbell does not teach the C-terminal heavy chain limitation as applied to decorin is reconcilable only by the reading set forth above: Hubbell ¶ [0007]'s C-terminal heavy chain language is sentence-bound to fynomer domains, and Hubbell does not contain any teaching of C-terminal heavy chain attachment of decorin or of any of Hubbell's enumerated ECM-affinity peptides. Applicant first argues that Hubbell only teaches fynomer domain attached at the C-terminus of heavy chain or light chain. Applicant’s arguments have been fully considered but they are not persuasive. Contrary to applicant’s arguments, Hubbell’s teachings are not limited to fynomer which is only a specific embodiment for the fusion construct. Hubbell clearly teaches that the peptide (including decorin) can be covalently linked to the antibody and linkers such as amino acid sequences may be inserted between the peptide and antibody sequence (it is noted that the teaching is before introducing the specific embodiment about fynomers, thus it is not limited by fynomer as Applicant argued). In some embodiment, the linker can be joined to a heavy chain immediately after the last amino acid at the C-terminus of the Heavy chain. The length of the linker sequence may vary without significantly affecting the function or activity of the fusion protein ([0005]-[0007]). Fig.28A shows the peptide can be linked to anti-PD-L1 or anti-CTLA4 antibody close to C-terminal end. In addition, Kontermann teaches various formats to linker a peptide (various cytokines) to antibody, including linked to C-terminal of heavy chains (see Fig. 2(b) and Fig. 3). Thus, as set forth above, one of ordinary skill in the art would link a decorin molecule to the c-terminal end of a heavy chain of an antibody through a linker because this configuration would be less likely to impact antibody binding and ADCC activity. In addition, it is a well-known and easily-implemented strategy to link a peptide to antibody as taught by Hubbell and Kontermann. b. Hubbell's actual decorin-antibody examples use sulfo-SMCC chemical conjugation, not C-terminal heavy chain peptide-linker fusion. The decorin-antibody constructs that the Examiner cites for "enhanced anti-tumor activity" (Office Action, p. 5, citing Hubbell ¶ ¶ [0238], [0239], [0073], and FIG. 44) were not produced by C-terminal heavy chain peptide-linker fusion. Hubbell describes the production procedure for those constructs in ¶ [0238]: "Decorin protein and vWF Al domain protein were produced and purified, following the same procedure as with the vWF A3 domain. The vWF Al domain and decorin were conjugated to the CPI antibodies following the same procedure as for conjugation of the vWF A3 domain protein to CPI." (Hubbell ¶ [0238].) The procedure incorporated by reference is set forth in <JI [0226]: "Anti-mouse PD-LI, anti-mouse CTLA4, anti-mouse CD40 or rat IgG2a control antibody will be incubated with sulfo-SMCC. Excess sulfo-SMCC will be removed using a desalting column. Recombinant VWF A3 protein will be then added and be incubated." (Hubbell ¶ [0226].) Sulfo-SMCC is a heterobifunctional chemical crosslinker that reacts nonsite specifically with primary amines on the antibody (predominantly lysine £-amino groups) and with sulfhydryl groups on the partner protein. The resulting decorin-antibody construct is a chemically conjugated, lysine-randomized molecule bearing decorin moieties at undefined sites - fundamentally different in topology, stoichiometry, site-specificity, and manufacturing process from a recombinantly expressed C-terminal heavy chain peptide-linker fusion protein, which is the construct architecture recited in claim 2. Hubbell does not describe any specific decorin-antibody construct produced by C-terminal heavy chain peptide-linker fusion. The Examiner's stated motivation that the proposed combination would yield "more potent and effective anti-cancer agent[s] with a well-tested strategy" (Office Action, p. 8) appears to import the enhanced anti-tumor activity reported in Hubbell ¶ [0073] and FIG. 44. As shown above, however, the enhanced-activity data correspond to sulfo-SMCC chemical conjugates, not to recombinantly expressed C-terminal heavy chain peptide-linker fusion proteins. Efficacy data established for one construct topology and one conjugation chemistry does not, on this record, transfer to a fundamentally different construct topology and chemistry. Hubbell ¶ [0224]'s generic statement that "the inventors hypothesize that chemical conjugation or recombinant fusion of the VWF A3 or Al domain recombinant protein (VWF A3 or Al) or decorin with the immunomodulatory antibodies will improve localization and retention of antibodies within the tumor microenvironment" is a hypothesis statement that does not specify any fusion site (N- or C-terminus, heavy or light chain), does not exemplify any specific decorin-antibody recombinant fusion construct, and is followed in Hubbell's experimental record only by the sulfo-SMCC chemical-conjugate examples discussed above. For completeness, Applicant respectfully notes that it is not attacking the combined references individually. Rather, Applicant respectfully submits that the Examiner has misinterpreted Hubbell and that that misinterpretation undermines the entire obviousness rejection. Applicant further argues that Hubbell only teaches sulfo-SMCC chemical conjugation. However, contrary to Applicant’s argument, as set forth above, Hubbell clearly teaches the peptide (including decorin) can be covalently linked to antibody (e.g. at position close to C-terminal of antibody heavy chain. In addition, Kontermann teaches various formats to linker a peptide (various cytokines) to antibody, including linked to C-terminal of heavy chains (see Fig. 2(b) and Fig. 3). Thus, based on the combined teaching one of ordinary skill in the art would have a reasonable expectation that fusing decorin to the C-terminal of heavy chain would not impact antibody binding and activity. In addition, making C-terminal fusion protein is well known and widely used method in the art. c. Kontermann does not bridge the gap between Hubbell's teachings and the claimedC-terminal heavy chain peptide-linker fusion of decorin. Kontermann is a review of antibody-cytokine fusion proteins. The fusion partners that Kontermann discusses, depicts, and surveys are uniformly cytokines and TNFsuperfamily death ligands. Figure 3 of Kontermann (page 197) enumerates the cytokine fusion partners as IL-2, IL-6, IL-7, IL-10, IL-12, IL-15, IL-17, IFN-a, IFN-y, GM-CSF, TNF, FasL, and TRAIL. Tables 1 and 2 of Kontermann (pages 195 and 198, respectively) similarly list cytokines and clinical-stage antibody-cytokine fusion proteins. Decorin, biglycan, lumican, asporin, fibromodulin, and other small leucine-rich proteoglycans (SLRPs) are not addressed in Kontermann; nor are proteoglycans or ECM-affinity peptides as a fusion-partner class. The Examiner's reliance on Kontermann to establish that C-terminal heavy chain peptide-linker fusion is "a well-known and easily-implemented strategy to link a peptide to antibody" (Office Action, p. 7) and is "widely used in the art" (Office Action, p. 10) thus depends, as applied to decorin, on a cross-class extrapolation from cytokine fusion partners to a structurally and functionally distinct fusion partner, i.e., decorin, that Kontermann does not address. Decorin is not a cytokine. As Jarvinen describes (Introduction): "Mammalian DCN contains a monomeric protein core of 42 kDa and a single chondroitin/dermatan sulfate glycosaminoglycan (GAG) chain ... DCN exists as a dimer in physiological solutions ... and is the best characterized member of the growing family of SLRPs. Structurally, it has a domain of tandem leucine-rich repeats (LRRs, altogether 12 LRRs), flanked on both sides by two cysteine-rich regions." (Jarvinen, Introduction.) The cytokine fusion partners surveyed by Kontermann are, by contrast, smaller signaling proteins, typically 14-74 kDa monomeric, homodimeric, or homotrimeric moleculeswith single, well-defined receptor-binding interfaces (see Kontermann, Fig. 2(a) and Fig. 3, pp. 196-197). The structural-class differences between decorin and cytokines (including size, oligomeric state, multi-LRR domain architecture, and multi-partner binding mode) are not addressed in Kontermann's review and present folding, oligomerization, and conformational considerations that are not within the scope of Kontermann's cytokine-focused teachings. Jarvinen, the only other reference of record that addresses decorin in fusion-protein form, similarly does not bridge the gap. Jarvinen describes only one worked example of a decorin fusion protein (i.e., fusion of decorin to a 9-amino-acid homing peptide ("CAR," sequence CARSKNKDC)) not to an antibody (Jarvinen § 11, page 7; Figure 3). Jarvinen's worked decorin fusion is therefore a fusion to a small homing tag of a fundamentally different size and class from an antibody, and does not exemplify or validate antibody fusion of decorin in any topology, much less the C-terminal heavy chain peptide-linker fusion topology recited in claim 2. The Examiner's citation to Jarvinen page 7, § 11 for the proposition that "DCN fusion protein can be produced through recombinant technology" (Office Action, p. 6) understates that Jarvinen's only worked DCN fusion is to a small homing peptide, not to an antibody. Applicant’s arguments above have been fully considered but they are not persuasive. Because as set forth above, Hubbell teaches that decorin can be linked through a linker to an anti-PD-L1 antibody or an anti-CTLA4 antibody. Kontermann teaches various formats to linker a peptide (various cytokines) to antibody, including linked to C-terminal of heavy chains (see Fig. 2(b) and Fig. 3). Based on the combined teachings, one of ordinary skill in the art would use the format taught by Kontermann to make the fusion protein, because the format would be less likely to impact the antibody binding and function. And the format is well known and widely-used in the art. d. The Examiner's reasonable-expectation-of-success rationale is in tension with prior art evidence in the references of record that the Examiner has not addressed. The Examiner asserts that "as evidenced by Hubbell and Kontermann, the antibodypeptide fusion at the C-terminal end of heavy chain of an antibody has been widely used in the art, thus one of skilled in the art would have had a reasonable expectation that a decorin fused to c-terminal of heavy chains of an antibody would generate a protein molecule with better properties." Office Action, p. 10. As shown above (sub-section a), Hubbell does not teach C-terminal heavy chain attachment of decorin or of any other ECM-affinity peptide. As shown above (sub-section c ), Kontermann teaches such a format only for cytokine fusion partners, and the cross-class extrapolation to decorin is not addressed by either reference. In addition, Kontermann itself documents - at the same page on which the Examiner relies for the proposition that the C-terminal heavy chain fusion format is well-known – that fusion arrangement is outcome-determinative: "These studies also revealed that the arrangement of the antibody and cytokine moiety is of importance, with the scFv-IL-2 fusion protein being superior over the IL-2-scFv fusion protein." (Kontermann, p. 197.) For a single antibody-cytokine pairing (anti-EDB scFv L19 + IL-2), Kontermann reports that one fusion arrangement was "superior over" the opposite arrangement. This is direct prior-art evidence, within the very reference the Examiner cites for reasonable expectation of success, that fusion-orientation effects on activity are not predictable a priori, even within a single antibody-partner pairing in the cytokine class. The Examiner has not addressed this passage of Kontermann or its implications for the asserted reasonable expectation of success as applied to a different fusion-partner class (decorin) for which no prior-art validation of any antibody fusion topology is on the record. That arrangement is outcome-determinative within a single antibody-partner pairing means, on this record, that one of ordinary skill in the art would not have had a reasonable expectation that decorin specifically (a fusion partner with which Kontermann is silent and Hubbell never exemplified C-terminal heavy chain peptide-linker fusion) would retain its activities and yield "a protein molecule with better properties" when fused at the C-terminus of an antibody heavy chain through a peptide linker. The Examiner's reasonable-expectation-of-success conclusion is therefore not supported by the record. The Examiner's further statement that "in the field of biological technology, no invention has absolute certainty of success before experimental tests" and that "only a reasonable expectation of success (not absolute) would have motivated an artisan to make the claimed fusion protein" (Office Action, p. 11) is correct as a statement of general law; reasonable expectation of success does not require certainty. But that proposition does not establish that the standard is met on this record. The standard requires that one of ordinary skill, in light of the prior art of record, would have had a reasonable expectation that the proposed modification would have worked as claimed. Where the very reference relied upon for reasonable expectation of success documents that fusion arrangement matters and is outcome-determinative within the very partner class it surveys, and where the claimed fusion partner (decorin) is outside that class and outside any other reference's antibody-fusion teaching of record, that standard is not met. Applicant’s arguments above have been fully considered but they are not persuasive. Because as set forth above, Hubbell teaches that decorin can be linked through a linker to an anti-PD-L1 antibody or an anti-CTLA4 antibody. Kontermann teaches various formats to linker a peptide (various cytokines) to antibody, including linked to C-terminal of heavy chains (see Fig. 2(b) and Fig. 3). Based on the combined teachings, one of ordinary skill in the art would modify the format taught by Hubbell, and to use the format taught by Kontermann to make the fusion protein, because one of ordinary skill in the art would have a reasonable expectation that with this configuration, the relative large decroin protein would be less likely to impact the antibody binding domain or antibody ADCC activity (compared to randomly inserting or connecting a decorin at a random position of antibody), because antibody binding domain is close to the N-terminus of the heavy/light chains, and Fc region is critical for ADCC function. Given the teachings from references, an ordinary skill in the art would have would have had a reasonable expectation of success in producing the claimed invention. Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /CHENG LU/ Examiner, Art Unit 1642 /PETER J REDDIG/ Primary Examiner, Art Unit 1646