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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 1/12/2026 has been entered.
Applicant’s amendments, filed 1/12/2026, is acknowledged.
Claims 85-91, 94-96, and 100-104 are currently pending.
Claims 90, 91, 96, 103, and 104 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions and/or species.
Claims 85-89, 94, 95, and 100-102 are under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 1/12/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner in its entirety.
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 85-87 and 100 are rejected under 35 U.S.C. 103 as being unpatentable over Cox et al. (Angew Chem Int Ed Engl. 2016 Aug 16;55(34):9894-7. doi: 10.1002/anie.201603488. Epub 2016 Jun 15, on IDS submitted 11/5/2021, cited in Office Action mailed 10/10/2025) in view of Currier et al. (Mol Cancer Ther. 2016 Jun;15(6):1291-300. doi: 10.1158/1535-7163.MCT-15-0881. Epub 2016 Mar 29, cited in Office Action mailed 10/10/2025), as evidenced by Beck et al. (MAbs. 2011 Sep-Oct;3(5):415-6. doi: 10.4161/mabs.3.5.17334. Epub 2011 Sep 1).
Cox et al. teaches the EETI-2.5F knottin peptide comprising an RGD sequences and binding to the αvβ3, αvβ5, and α5β1 integrins that are expressed on the cell surface of many types of cancer (Introduction and Fig. 2, cropped below):
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Cox et al. further teaches that these knottin-drug conjugates with a Val-Ala-PAB linker successfully inhibited growth of glioblastoma, breast cancer, ovarian cancer, and pancreatic cancer cell lines (Table 1 and 2, pg. 9896; 5d is the KDC with the Val-Ala-PAB linker): “As shown in Table 2 (entries 2–5), 5d is also a highly potent inhibitor of D270 glioblastoma, MDA-MB-468 breast cancer, A2780 ovarian cancer, and BxPC3 pancreatic cancer cell lines…”
Cox et al. does not teach a knottin peptide conjugated to an anti-microtubule agent via a linker (instant claim 85), an auristatin inhibitor (instant claims 86 and 87), or pharmaceutical compositions comprising the knottin conjugate (instant claim 100).
Currier et al., in the same field of endeavor, teaches the EETI-2.5F knottin peptide conjugated to the microtubule inhibitor MMAF via a linker (i.e., the limitations of instant claims 86 and 87; Abstract). Currier et al. additionally teaches that a pharmaceutical composition comprising the 2.5F-MMAF conjugate in PBS (i.e., “a pharmaceutically acceptable carrier”) significantly reduced tumor growth in a mouse orthotopic tumor model (“Animal Experiments“ section and Figure 5). Currier teaches “[t]he resulting knottin–Fc–drug conjugate (KFDC), termed 2.5F-Fc-MMAF, had approximately 2 drugs attached per KFDC. 2.5F–Fc–MMAF inhibited proliferation in human glioblastoma (U87MG), ovarian (A2780), and breast (MB-468) cancer cells to a greater extent than 2.5F–Fc or MMAF alone or added in combination” (Abstract).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the invention, to have modified the EETI-2.5F conjugate taught by Cox et al. in view of Currier et al. to conjugate a MMAF to the knottin peptide via a linker with a reasonable expectation of success, as Currier et al. teaches methods to complete this. One would have been motivated to make this change for the purposes of delivering MMAF to target tumor cells expressing integrins that the EETI-2.5F knottin peptide binds to, leading to targeted delivery of the MMAF inhibitor to tumor cells and improved therapeutic efficacy of the conjugate when compared to either MMAF or EETI-2.5F alone or in combination as two separate therapeutics.
Applicant’s arguments, filed 1/12/2026, have been fully considered, but have been found to be not convincing.
Applicant argues that Currier et al. teaches away from conjugating a MMAF to a knottin peptide, as Currier teaches knottin-Fc-MMAF conjugates and (Remarks filed 1/12/2026 pg. 5):
“Currier teaches away from the claimed molecules. As stated in Applicant's previous response, Currier specifically discourages the use of small peptides. See e.g., Currier at pages 1291-1292: "Compared with a small peptide, 2.5FFc offers the potential benefits of bivalent antigen binding, extended serum half-life due to larger size and FcRn-mediated recycling, and the ability to leverage conjugation strategies developed for ADCs." The skilled artisan would assume, from this teaching of Currier, that removing the Fc of Currier would have a negative impact on the in vivo efficacy of the conjugates. Because Currier employs an Fc to accomplish its in vivo goals, "if a proposed modification would render the prior art invention being modified unsatisfactory for its intended purpose, there may be no suggestion or motivation to make the proposed modification. In re Gordon, 733 F.2d 900, 221 USPQ 1125 (Fed. Cir. 1984)" See e.g., MPEP 2143.01 V. (Emphasis added).”
This has been found to be not convincing. Applicant is relying on known and expected functions of Fc peptide conjugates, namely extensions in half-life due to larger size and Fc/FcRn interactions.
Beck et al. is provided as an evidentiary reference as to the known and expected effects of Fc fusion proteins. Beck et al. teaches (pg. 415): “…proteins or peptides fused with an Fc is following the success of classical antibodies…The primary reason for fusion of a binding moiety with Fc is half-life exten-sion. Many biologically active proteins and peptides have very short serum half-lives due to fast renal clearance, which limits their exposure in the target tissue and, consequently, their pharmacologi-cal effects. The Fc domain prolongs the serum half-life of antibodies and Fc-fusion proteins due to pH-dependent binding to the neonatal Fc receptor (FcRn), which salvages the protein from being degraded in endosomes…”
A prior art reference may be considered to teach away when "a person of ordinary skill, upon reading the reference, would be discouraged from following the path set out in the reference, or would be led in a direction divergent from the path that was taken by the applicant." In re Gurley, 27 F.3d 551, 553, 31 USPQ2d 1130, 1131 (Fed. Cir. 1994). General skepticism of those in the art -- not amounting to teaching away -- is also "relevant and persuasive evidence" of nonobviousness. Gillette Co. v. S.C. Johnson & Son, Inc., 919 F.2d 720, 726, 16 USPQ2d 1923, 1929 (Fed. Cir. 1990). In effect, "teaching away" is a more pointed and probative form of skepticism expressed in the prior art. In any case, the presence of either of these indicia gives insight into the question of obviousness.
Here, in contrast to applicant’s assertions of teaching away by the prior art because Currier et al. teaches a successful method of immunotherapy using a knottin-Fc-MMAF conjugate there is no discouragement nor skepticism in the prior art for use of a knottin-MMAF conjugate. There is no teaching in Currier et al. that a knottin-MMAF conjugate would not be successful in treating tumors, which would demonstrate “removing the Fc of Currier would have a negative impact on the in vivo efficacy of the conjugates”. Currier et al. teaches that knottin-Fc-MMAF conjugates have a greater effect in reducing U87MG cell tumor growth than the following peptide conjugates: (nonbinding knottin)-Fc-MMAF, knottin-Fc, and MMAF alone (Fig. 5 below):
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Currier et al. merely teaches that conjugating an Fc to knottin peptides has the expected result of increasing serum half-life via increase in size and FcRn binding. Additionally, Cox et al. teaches that knottin-drug conjugates without a Fc region can successfully treat cancer cells, including U87MG cancer cells (i.e., the same cancer cell line used in Currier et al.; Cox et al. Tables 1 and 2, Table 2 below):
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Cox et al. teaches knottin-drug conjugates that successfully treat cancer such as U87MG glioblastoma, and currier teaches knottin-Fc-drug conjugates that successfully treat cancer such as U87MG glioblastoma.
The rationale to support a conclusion that the claim would have been obvious is that “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.”KSR, 550 U.S. at 421, 82 USPQ2d at 1397. If any of these findings cannot be made, then this rationale cannot be used to support a conclusion that the claim would have been obvious to one of ordinary skill in the art. See MPEP § 2143(E).
In KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421, 82 USPQ2d at 1397 ("The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103."). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process. Also see MPEP § 2144.05(II).
In the instant case, Cox et al. teaches a knottin-drug conjugate that successfully treats integrin-expressing cancer such as U87MG glioblastoma. Currier et al. teaches knottin-Fc-drug conjugates that successfully treat integrin-expressing cancer such as U87MG glioblastoma. Cox et al. and Currier et al. additionally teach that knottins conjugated to either gemcitabine or MMAF, respectively, can treat cancer such as U87MG glioblastoma.
Therefore, it would have been obvious to one of ordinary skill in the art to try the two different knottin-MMAF conjugate variants taught by the combined references of Cox et al. in view of Currier et al., which are: 1) a knottin-MMAF conjugate; and 2) a knottin-Fc-MMAF conjugate, with a reasonable expectation of success, as Cox et al. teaches the efficacy of a knottin-drug conjugate and Currier et al. teaches the efficacy of a knottin-Fc-drug conjugate. The design need is the need to develop knottin/drug conjugates for the targeted delivery of drugs to tumor cells to treat cancer. The combination of Cox et al in view of Currier et al. teach two finite numbers of predictable solutions of knottin/drug conjugates, a knottin-drug conjugate and a knottin-Fc-drug conjugate. Therefore, it would be obvious to try each of these formats with the MMAF drug through routine optimization, leading to a EETI-2.5F-MMAF conjugate (i.e., the limitations of instant claim 85).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 88, 89, 94, 95, 101, and 102 are rejected under 35 U.S.C. 103 as being unpatentable over Cox et al. (supra) in view of Currier et al. (supra) as applied to claims 85-87 and 100 above, and further in view of Gong et al. (Mol Cancer Ther. 2016 Jul;15(7):1580-90. doi: 10.1158/1535-7163.MCT-16-0114. Epub 2016 May 20, in Office Action mailed 10/10/2025).
The teachings of Cox et al. in view of Currier et al. have been discussed supra. The combined teachings of Cox et al. in view of Currier et al. do not teach a knottin-MMAE conjugate (instant claims 88, 89, 101, and 102) linked via a Val-Cit-PAB linker (instant claims 94 and 95).
Gong et al., in the same field of endeavor, teaches conjugation of MMAE to a polypeptide (in this case, an anti-LGR5 antibody) via the Val-Cit-PAB linker (“Anti-LGR5 mAb production and ADC generation” section). Gong et al. additionally teaches “cleavable linkers release drug through enzymatic cleavage (e.g., cathepsins) following internalization, whereas noncleavable linkers must under lysosomal degradation” (¶2 of Introduction). The linking of MMAE via the cleavable Val-Cit-PAB linker led to increased efficacy of reducing tumor growth in a mouse model of gastrointestinal cancer (“Anti-LGR5 ADC with the cleavable linker is more effective at inducing gastrointestinal cancer cell cytotoxicity” section and Figure 5).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the invention, to have modified to combined teachings of Cox et al. in view of Currier et al. further in view of Gong et al. to conjugate MMAE to a knottin via a Val-Cit-PAB linker with a reasonable expectation of success, as Gong et al. teaches a method of conjugating the MMAE that one with ordinary skill in the art would be able to apply not only to antibodies, but also to other polypeptides such as the knottin peptide conjugates taught by Cox et al. in view of Currier et al. One would have been motivated to make this change for the purposes of conjugating the MMAE drug to the knottin peptide via a cleavable linker that releases the MMAE into the cell upon internalization, leading to increased efficacy of the knottin-drug conjugate in reducing tumor growth.
Applicant’s arguments, filed 1/12/2026, have been fully considered, but have been found to be not convincing.
Applicant argues that Gong teaches linkers between antibodies and MMAE, and therefore a skilled artisan would have no motivation to use this linker in a knottin drug conjugate.
This has been found to be not persuasive. Gong et al. teaches that the Val-Cit-PAB linker is a functional linker for release of MMAE into a cell, and Cox et al. teaches the Val-Ala-PAB linker is a functional cleavable linker for the same purpose (i.e., release of MMAE into a target cell). Therefore, one with ordinary skill in the art would appreciate that either of these linker could be used in peptide-drug conjugates such as knottin-drug conjugates or antibody drug conjugates.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 85-89 and 100-102 are rejected under 35 U.S.C. 103 as being unpatentable over Cox et al. (supra) in view of Liu et al. (Mol Pharm. 2012 Jan 1;9(1):168-75. doi: 10.1021/mp200434n. Epub 2011 Nov 22).
Cox et al. teaches the EETI-2.5F knottin peptide comprising an RGD sequences and binding to the αvβ3, αvβ5, and α5β1 integrins that are expressed on the cell surface of many types of cancer (Introduction and Fig. 2).
Cox et al. further teaches that these knottin-drug conjugates with a Val-Ala-PAB linker successfully inhibited growth of glioblastoma, breast cancer, ovarian cancer, and pancreatic cancer cell lines, all of which express αvβ3, αvβ5, and α5β1 integrins (Table 1 and 2, pg. 9896; 5d is the KDC with the Val-Ala-PAB linker): “As shown in Table 2 (entries 2–5), 5d is also a highly potent inhibitor of D270 glioblastoma, MDA-MB-468 breast cancer, A2780 ovarian cancer, and BxPC3 pancreatic cancer cell lines…”
Cox et al. teaches the Val-Ala-PAB linker is a protease-cleavable linker (pg. 9895): “…given the extensive use of dipeptide-based cleavable linkers in ADCs, we prepared a Val-Ala-PAB (valyl-alanyl-para-aminobenzyloxy) derivative…”
Cox et al. does not teach a knottin peptide conjugated to an anti-microtubule agent (instant claim 85), an auristatin inhibitor (instant claims 86 and 87), or MMAE (instant claims 88 and 89).
Liu et al., in the same field of endeavor, teaches a MMAE drug conjugate that binds to αvβ3 integrin (Abstract). Liu teaches prodrug 8 (Figure 1):
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Liu et al. teaches prodrug 8 is a small molecule targeting αvβ3 integrin conjugated to MMAE via a Ala-Ala-Asn-PAB protease cleavable linker, which was effective in targeting and killing breast cancer cells expressing αvβ3 integrin both in vitro and in vivo (pg. 171-172 and Figs. 3, 4, and 6). Liu et al. further teaches (pg. 174): “[i]n summary, novel dual-targeted MMAE prodrug 8 designed to bind cell surface glycoprotein integrin αvβ3 and activate using legumain protease as the catalyst was prepared and evaluated both in vitro and in vivo. The antitumor efficacy of prodrug 8 was critically evaluated by using mouse models of three different cancers, which demonstrated that prodrug activation took place in tumor tissues that effectively decreased
tumor growth and metastasis. This strategy greatly reduces toxicity to healthy body cells by synergism of integrin binding αvβ3 and legumain activation function, indicating that this antitumor strategy could be widely applicable and relevant for possible cancer therapy.”
Liu et al. teaches that MMAE is an applicable drug to be conjugated to integrin-targeting agents via protease cleavable linkers.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant application, to have modified Cox et al. in view of Liu et al. to have used MMAE in the knottin-Val-Ala-PAB-drug conjugate taught by Cox et al. with a reasonable expectation of success because Liu et al. teaches MMAE is suitable drug to be used in integrin-targeting conjugates, and can be successfully conjugated to an integrin targeting agent via a protease cleavable linker (such as Ala-Ala-Asn-PAB or Val-Ala-PAB. One would have been motivated to make this change for the purposes of developing knottin-Val-Ala-PAB-MMAE conjugates to treat integrin-expressing cancers.
Regarding “wherein the conjugate does not comprise an Fc region” recited in claim 85, neither Cox et al. nor Liu et al. teach conjugates comprising an Fc region.
Regarding claims 100-102, Liu et al. teaches pharmaceutical compositions comprising integrin-targeting drug-MMAE conjugates and saline (i.e., “acceptable carrier”, the limitations of instant claim 100-102; Liu et al. “Mouse Tumor Models” section).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 94 and 95 are rejected under 35 U.S.C. 103 as being unpatentable over Cox et al. (supra) in view of Liu et al. (supra) as applied to claims 85-87 and 100 above, and further in view of Doronina et al. (Nat Biotechnol. 2003 Jul;21(7):778-84. doi: 10.1038/nbt832. Epub 2003 Jun 1).
The combined teachings of Cox et al. and Liu et al. are discussed supra. The combined teachings do not teach a knottin-MMAE conjugate with a Val-Cit-PAB linker.
Doronina et al., in the same field of endeavor, teaches the Val-Ala-PAB peptide linker (Abstract and Fig. 1, cropped and annotated below to show location of PAB):
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Doronina et al. teaches that conjugates comprising an antigen targeting peptide (in this case, a monoclonal antibody) conjugated to MMAE via a Val-Cit-PAB linker led to protease-mediated release of MMAE (pg. 779): “[b] ecause AE and MMAE are totally synthetic, it was possible to incorporate functional groups for mAb attachment through a variety of linkage strategies. We focused on acid-labile and proteolytically cleavable linkers… Protease-cleavable dipeptide linkers were attached to the N-terminal position of MMAE through a self-immolative p-aminobenzylcarbamate spacer. Consistent with previous findings with peptide derivatives of doxorubicin, Phe-Lys-MMAE and Val-Cit-MMAE were quite stable under physiological conditions but underwent rapid hydrolysis, leading to the release of MMAE in the presence of lysosomal extracts and purified human cathepsin B, a tumor-associated lysosomal enzyme…”
Doronina et al. teaches that the Val-Cit-PAB protease-cleavable linker can be used to conjugate MMAE to peptides targeting antigens, such as monoclonal antibodies.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant application, to have modified the combined teachings of Cox et al. and Liu et al. further in view of Doronina et al. to have substituted the Val-Ala-PAB protease-cleavable linker in the knottin-linker-MMAE conjugate taught by Cox et al. in view of Liu et al. with the Val-Cit-PAB protease-cleavable linker taught by Doronina et al. with a reasonable expectation of success because the references teach that both of these linkers are protease-cleavable linkers that lead to intracellular MMAE delivery. One with ordinary skill in the art would be able to substitute these art-recognized equivalent protease-cleavable linker structures. See Smith v. Hayashi, 209 USPQ 754 (Bd. of Pat. Inter. 1980) (The mere fact that phthalocyanine and selenium function as equivalent photoconductors in the claimed environment was not sufficient to establish that one would have been obvious over the other. However, there was evidence that both phthalocyanine and selenium were known photoconductors in the art of electrophotography. "This, in our view, presents strong evidence of obviousness in substituting one for the other in an electrophotographic environment as a photoconductor." 209 USPQ at 759.). Also see MPEP § 2144.06(II)
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
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 85-89 and 100-102 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 10,844,106 (herein Pat '106), claims 1-16 of U.S. Patent No. 10,407,477 (herein Pat ‘477); claims 1-33 of U.S. Patent No. 10,765,625 (herein Pat ‘625); claims 1-22 of U.S. Patent No. 9,587,001 (herein Pat ‘001); claims 1-20 of U.S. Patent No. 11,466,063 (herein Pat ‘063); and claims 1-14 U.S. Patent No 12,240,882 (herein Pat ‘882; all patents also cited in the Office Action mailed 10/10/2025) in view of Currier et al. (Mol Cancer Ther. 2016 Jun;15(6):1291-300. doi: 10.1158/1535-7163.MCT-15-0881. Epub 2016 Mar 29, in Office Action mailed 10/10/2025, supra).
The invention encompassed by the instant claims are a prima facie obvious variant of the invention claimed by Pat ‘106, ‘477, ‘625, ‘001, ‘063, and ‘882, each in view of Currier et al., for the reasons discussed in the Office Actions mailed on 10/10/2025.
Applicant’s remarks, filed 1/12/2026, have been fully considered, but have been found to be not convincing.
Applicant argues that for the same reasons argues for the 35 USC 103 rejection supra (i.e., Cox et al. in view of Currier et al.), one would not be motivated to combine the references to make a knottin-MMAE drug conjugate with a cleavable linker. However, for the reasons discussed for the 35 USC 103 rejection supra, this has been found to be not convincing.
Claims 94 and 95 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 10,844,106 (herein Pat '106), claims 1-16 of U.S. Patent No. 10,407,477 (herein Pat ‘477); claims 1-33 of U.S. Patent No. 10,765,625 (herein Pat ‘625); claims 1-22 of U.S. Patent No. 9,587,001 (herein Pat ‘001); claims 1-20 of U.S. Patent No. 11,466,063 (herein Pat ‘063); and claims 1-14 U.S. Patent No 12,240,882 (herein Pat ‘882; all patents also cited in the Office Action mailed 10/10/2025) in view of Currier et al. (supra), as applied to claims 85-89 and 100-102 above, and further in view of Gong et al. (Mol Cancer Ther. 2016 Jul;15(7):1580-90. doi: 10.1158/1535-7163.MCT-16-0114. Epub 2016 May 20, in Office Action mailed 10/10/2025, supra).
The invention encompassed by the instant claims are a prima facie obvious variant of the invention claimed by Pat ‘106, ‘477, ‘625, ‘001, ‘063, and ‘882, each in view of Currier et al., and further in view of Gong et al., for the same reasons discussed in the 35 USC 103 rejection supra.
Applicant’s arguments, filed 1/12/2026, have been fully considered, but have been found to be not convincing for the same reasons discussed in the 35 USC 103 rejection supra.
Claims 85-89 and 100-102 are provisionally rejection on the grounds of nonstatutory double patenting as being unpatentable over claims 71-83 and 86-90 of copending Application No. 17/762,694 (herein App ‘694, in the Office Action mailed on 10/10/2025); and claims 65-84 of copending Application No. 18/018,238 (herein App ‘238, in the Office Action mailed on 10/10/2025), both in view of Currier et al. (supra).
The invention encompassed by the instant claims are a prima facie obvious variant of the invention claimed by App ‘694 and ‘238, and ‘882, each in view of Currier et al., for the reasons discussed in the Office Actions mailed on 10/10/2025.
Applicant’s remarks, filed 1/12/2026, have been fully considered, but have been found to be not convincing.
Applicant argues that for the same reasons argues for the 35 USC 103 rejection supra (i.e., Cox et al. in view of Currier et al.), one would not be motivated to combine the references to make a knottin-MMAE drug conjugate with a cleavable linker. However, for the reasons discussed for the 35 USC 103 rejection supra, this has been found to be not convincing.
Claims 94 and 95 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 71-83 and 86-90 of copending Application No. 17/762,694 (App ‘694, supra); and claims 65-84 of copending Application No. 18/018,238 (App ‘238, supra), both in view of Currier et al. (supra), as applied to claims 85-89 and 100-102 above, and further in view of Gong et al. (supra).
The invention encompassed by the instant claims are a prima facie obvious variant of the invention claimed by App ‘694 and ‘238, each in view of Currier et al., and further in view of Gong et al., for the same reasons discussed in the 35 USC 103 rejection supra.
Applicant’s arguments, filed 1/12/2026, have been fully considered, but have been found to be not convincing for the same reasons discussed in the 35 USC 103 rejection supra.
Claims 85-89 and 100-102 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 10,844,106 (Pat '106, supra) in view of Cox et al. (Angew Chem Int Ed Engl. 2016 Aug 16;55(34):9894-7. doi: 10.1002/anie.201603488. Epub 2016 Jun 15, on IDS submitted 11/5/2021, cited in Office Action mailed 10/10/2025, supra) and Liu et al. (Mol Pharm. 2012 Jan 1;9(1):168-75. doi: 10.1021/mp200434n. Epub 2011 Nov 22, supra).
Pat ‘106 claims EETI-II knottin polypeptides that bind to integrins (claims 1 and 21), further comprising an RGD (claim 22), and pharmaceutical compositions comprising the knottin polypeptides and an acceptable carrier (i.e., the limitations of instant claim 100; Pat ‘106 claims 23 and 24).
Pat ‘106 does not claim conjugates comprising knottin polypeptides comprising conjugated to an anti-microtubule agent such as MMAE via a protease-cleavable linker (instant claims 85-87, 101, and 102).
Cox et al., in the same field of endeavor, teaches the EETI-2.5F knottin peptide comprising an RGD sequence and binding to the αvβ3, αvβ5, and α5β1 integrins that are expressed on the cell surface of many types of cancer (Introduction and Fig. 2).
Cox et al. further teaches that these knottin-drug conjugates with a Val-Ala-PAB linker successfully inhibited growth of glioblastoma, breast cancer, ovarian cancer, and pancreatic cancer cell lines, all of which express αvβ3, αvβ5, and α5β1 integrins (Table 1 and 2, pg. 9896; 5d is the KDC with the Val-Ala-PAB linker): “As shown in Table 2 (entries 2–5), 5d is also a highly potent inhibitor of D270 glioblastoma, MDA-MB-468 breast cancer, A2780 ovarian cancer, and BxPC3 pancreatic cancer cell lines…”
Cox et al. teaches the Val-Ala-PAB linker is a protease-cleavable linker (pg. 9895): “…given the extensive use of dipeptide-based cleavable linkers in ADCs, we prepared a Val-Ala-PAB (valyl-alanyl-para-aminobenzyloxy) derivative…”
Cox et al. does not teach a knottin peptide conjugated to an anti-microtubule agent (instant claim 85), an auristatin inhibitor (instant claims 86 and 87), or MMAE (instant claims 88 and 89).
Liu et al., in the same field of endeavor, teaches a MMAE drug conjugate that binds to αvβ3 integrin (Abstract). Liu teaches prodrug 8 (Figure 1). Liu et al. teaches prodrug 8 is a small molecule targeting αvβ3 integrin conjugated to MMAE via a Ala-Ala-Asn-PAB protease cleavable linker, which was effective in targeting and killing breast cancer cells expressing αvβ3 integrin both in vitro and in vivo (pg. 171-172 and Figs. 3, 4, and 6). Liu et al. further teaches (pg. 174): “[i]n summary, novel dual-targeted MMAE prodrug 8 designed to bind cell surface glycoprotein integrin αvβ3 and activate using legumain protease as the catalyst was prepared and evaluated both in vitro and in vivo. The antitumor efficacy of prodrug 8 was critically evaluated by using mouse models of three different cancers, which demonstrated that prodrug activation took place in tumor tissues that effectively decreased tumor growth and metastasis. This strategy greatly reduces toxicity to healthy body cells by synergism of integrin binding αvβ3 and legumain activation function, indicating that this antitumor strategy could be widely applicable and relevant for possible cancer therapy.”
Liu et al. teaches that MMAE is an applicable drug to be conjugated to integrin-targeting agents via protease cleavable linkers.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant application, to have modified the invention claimed by Pat ‘106 in view of Cox et al. and Liu et al. to have used the knottins claimed by Pat ‘106 in knottin-MMAE conjugates, wherein the MMAE is conjugated by a protease-cleavable linker (i.e., the limitations of instant claim 85-89 and 100-102) with a reasonable expectation of success, as Cox et al. teaches that knottins such as the ones claimed by Pat ‘106 can be used in drug conjugates with protease cleavable linkers and Liu et al. teaches MMAE is suitable drug to be used in integrin-targeting conjugates, and can be successfully conjugated to an integrin targeting agent via a protease cleavable linker (such as Ala-Ala-Asn-PAB or Val-Ala-PAB. One would have been motivated to make this change for the purposes of developing knottin-Val-Ala-PAB-MMAE conjugates to treat integrin-expressing cancers.
Regarding “wherein the conjugate does not comprise an Fc region” recited in claim 85, Pat ‘106 claims knottin conjugates, and Cox et al. teaches these knottins can be used in knottin-drug conjugates without an Fc region, meeting these limitations.
Therefore, the invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by Pat ‘106 in view of Cox et al. and Liu et al., especially in absence of evidence to the contrary.
Applicant’s arguments are rendered moot in light of this new rejection.
Claims 94 and 95 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 10,844,106 (Pat '106, supra) in view of Cox et al. (supra) and Liu et al. (supra), as applied to claims 85-89 and 100-102 above, and further in view of Doronina et al. (Nat Biotechnol. 2003 Jul;21(7):778-84. doi: 10.1038/nbt832. Epub 2003 Jun 1, supra).
The invention encompassed by claims 85-89 and 100-102 are a prima facie obvious variant of the invention claimed by Pat ‘106 in view of Cox et al. and Liu et al. for the reasons discussed supra. The combined references do not teach a Val-Cit-PAB protease-cleavable linker (the limitations of instant claims 94 and 95).
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by Pat ‘106 in view of Cox et al. and Liu et al., and further in view of Doronina et al. for the same reasons discussed in the 35 U.S.C. § 103 rejection supra.
Applicant’s arguments are rendered moot in light of this new rejection.
Claims 85-89 and 100-102 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 10,407,477 (Pat ‘477, supra); claims 1-33 of U.S. Patent No. 10,765,625 (Pat ‘625, supra); claims 1-20 of U.S. Patent No. 10,166,273 (Pat ‘273, supra); claims 1-22 of U.S. Patent No. 9,587,001 (Pat ‘001, supra); claims 1-35 of U.S. Patent No. 10,888,603 (Pat ‘603, supra); claims 1-30 of U.S. Patent No. 11,096,989 (Pat ‘989, supra); claims 1-3 of U.S. Patent No. 11,498,952 (Pat ‘952, supra); claims 1-20 of U.S. Patent No. 11,466,063 (Pat ‘063, supra); and claims 1-14 U.S. Patent No 12,240,882 (Pat ‘882, supra; all patents also cited in the Office Action mailed 10/10/2025), all in view of Cox et al. (supra) and Liu et al. (supra).
The following table shows where in each double patenting reference the mentioned limitations are claimed:
Patent No.
Limitations claimed
‘477
Knottin-drug conjugates connected via a linker (claim 1), the knottin comprising an RGD (claim 7), EETI-II knottin (claim 8; SEQ ID NO: 2 is an EETI-2F knottin sequence), pharmaceutical compositions comprising the conjugate (claim 10).
‘625
Knottin-drug conjugates connected via a cleavable linker (claim 1), EETI-II knottins (claim 2), pharmaceutical composition comprising the conjugate (claim 20).
‘273
Knottin peptides used in conjugates (claim 1), comprising an RGD sequence (claim 7), and EETI-II knottins (claim 8).
‘001
EETI-II knottins conjugated via a linker (claims 1 and 2), comprising an RGD sequence (claim 6).
‘603
Knottin peptides used in conjugates (claim 1), comprising an RGD sequences (claim 10), and EETI-II knottins (claim 8).
‘989
Knottin peptides used in conjugates (claim 1), comprising RGD sequences (claim 11), and EETI-II knottins (claims 12 and 13).
‘952
Knottin peptides used in conjugates (claim 1), EETI-II knottins comprising an RGD sequence (claim 2, SEQ ID NO: 33 contains RGD), pharmaceutical compositions comprising the conjugates (claim 2).
‘063
Methods of making knottin-drug conjugates (which one with ordinary skill would appreciate would lead to the product itself; claim 1), knottins comprising RGD (claim 4), EETI-II knottins (claim 2).
‘882
Methods of making knottin conjugates (which one with ordinary skill would appreciate would lead to the product itself; claim 1), knottins comprising RGD (claim 1), EETI-II knottins (claim 1).
The invention encompassed by instant claims 85-89 and 100-102 are a prima facie obvious variant of the inventions claimed by Pats ‘477, ‘625, ‘273, ‘001, ‘603, ‘989, ‘952, ‘063, and ‘882, each in view of Cox et al. and Liu et al., for the same reasons discussed for Pat ‘106 supra.
Applicant’s arguments are rendered moot in light of these new rejections.
Claims 94 and 95 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 10,407,477 (Pat ‘477, supra); claims 1-33 of U.S. Patent No. 10,765,625 (Pat ‘625, supra); claims 1-20 of U.S. Patent No. 10,166,273 (Pat ‘273, supra); claims 1-22 of U.S. Patent No. 9,587,001 (Pat ‘001, supra); claims 1-35 of U.S. Patent No. 10,888,603 (Pat ‘603, supra); claims 1-30 of U.S. Patent No. 11,096,989 (Pat ‘989, supra); claims 1-3 of U.S. Patent No. 11,498,952 (Pat ‘952, supra); claims 1-20 of U.S. Patent No. 11,466,063 (Pat ‘063, supra); and claims 1-14 U.S. Patent No 12,240,882 (Pat ‘882, supra) in view of Cox et al. (supra) and Liu et al. (supra), as applied to claims 85-89 and 100-102 above, and further in view of Doronina et al. (supra).
The invention encompassed by the instant claims are a prima facie obvious variant of the inventions claimed by Pats ‘477, ‘625, ‘273, ‘001, ‘603, ‘989, ‘952, ‘063, and ‘882, each in view of Cox et al. and Liu et al., and further in view of Doronina et al. for the same reasons discussed in the 35 U.S.C. § 103 rejection supra.
Applicant’s arguments are rendered moot in light of these new rejections.
Claims 85-89 and 100-102 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 71-83 and 86-90 of copending Application No. 17/762,694 (App ‘694, supra) in view of Cox et al. (supra) and Liu et al. (supra).
App ‘694 claims EETI-II knottin peptide conjugates comprising an RGD sequence (claims 1), and pharmaceutical composition comprising the conjugate and an acceptable carrier (claim 86).
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘694 in view of Cox et al. and Liu et al. for the same reasons discussed for Pat ‘106 supra.
Applicant’s arguments are rendered moot in light of these new rejections. This is a provisional nonstatutory double patenting rejection.
Claims 94 and 95 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 71-83 and 86-90 of copending Application No. 17/762,694 (App ‘694, supra) in view of Cox et al. (supra) and Liu et al. (supra), as applied to claims 85-89 and 100-102 above, and further in view of Doronina et al. (supra).
The invention encompassed by the instant claims are a prima facie obvious variant of the inventions claimed by App ‘694 in view of Cox et al. and Liu et al., and further in view of Doronina et al. for the same reasons discussed in the 35 U.S.C. § 103 rejection supra.
Applicant’s arguments are rendered moot in light of these new rejections. This is a provisional nonstatutory double patenting rejection.
Claims 85-89 and 100-102 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 65-84 of copending Application No. 18/018,238 (App ‘238, supra) in view of Cox et al. (supra) and Liu et al. (supra).
App ‘238 claims EETI-II knottin peptide conjugates comprising an RGD sequence (claims 1), and pharmaceutical composition comprising the conjugate and an acceptable carrier (claim 86).
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘238 in view of Cox et al. and Liu et al. for the same reasons discussed for Pat ‘106 supra.
Applicant’s arguments are rendered moot in light of these new rejections. This is a provisional nonstatutory double patenting rejection.
Claims 94 and 95 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 65-84 of copending Application No. 18/018,238 (App ‘238, supra) in view of Cox et al. (supra) and Liu et al. (supra), as applied to claims 85-89 and 100-102 above, and further in view of Doronina et al. (supra).
The invention encompassed by the instant claims are a prima facie obvious variant of the inventions claimed by App ‘694 in view of Cox et al. and Liu et al., and further in view of Doronina et al. for the same reasons discussed in the 35 U.S.C. § 103 rejection supra.
Applicant’s arguments are rendered moot in light of these new rejections. This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MAHER M HADDAD/Primary Examiner, Art Unit 1641