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 .
Applicant’s amendments, filed 5/20/2026, is acknowledged.
Claims 1-84, 92, 93, and 97-99 are cancelled.
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Claims 90, 91, 96, 103, and 104 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions and/or Species.
Claims 85-89, 94, 95, and 100-102 are under examination as reading on a knottin-microtubule inhibitor conjugate.
Application 18/018,238 has been abandoned. The double patenting rejection for this reference has been withdrawn.
In view of the amendments and remarks filed on 5/20/2026, the following rejections remain.
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 stand 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 1/22/2026) 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 1/22/2026), 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, cited in Office Action mailed 1/22/2026).
The invention is a prima facie obvious variant of the invention taught by the combined references of Cox et al. in view of Currier et al., as evidenced by Beck et al. for the same reasons discussed in the Office Action mailed 1/22/2026.
Applicant’s arguments, filed on 5/20/2026, have been fully considered, but have been found to be not convincing.
Applicant first argues that the reference Currier et al. teaches away from using knottin-MMAF conjugates. Applicant argues (remarks pg. 5): “…Currier teaches a small knottin peptide that is fused to a human Fc region, with the tubulin inhibitor, MMAF, conjugated to the Fc region, not the knottin peptide, via a non-natural amino acid in the Fc region and a DBCO-PEG linker. As stated in Applicant's previous response, Currier emphasizes the importance of this approach for in vivo efficacy: "Compared with a small peptide, 2.5F-Fc 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"…Applicant therefore respectfully asserts that, in view of Currier, and the knowledge in the art of antibody drug conjugates, including the disclosure of Beck, one of ordinary skill in the art would be motivated to utilize an Fc region or another half-life extending moiety for in vivo delivery of a knottin targeted anti-microtubule agent conjugate, and would lack motivation to conjugate an anti-microtubule agent directly to a small knottin peptide that does not comprise an Fc region as claimed.”
Additionally, the Miller Declaration remarks (pg. 2): “…Currier emphasizes the importance of the Fc region for in vivo delivery of knottin conjugates. At the time of this application filing, the state of the art for targeted drug conjugates was to use full length antibodies for in vivo delivery, as further exemplified by the Examiner's citation of Beck et al. as an overview of antibody drug conjugates (MAbs. 2011 ). I therefore agree that one of ordinary skill in the art, without the knowledge of the unexpected results from the present application, would have sought to develop a drug conjugate comprising either a full length antibody or at least an Fc region as described in Currier.”
This has been found to be not convincing. In contrast to applicant’s assertions; disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. See In re Susi USPQ 423 (CCPA 1971). A known or obvious composition does not patentable simply because it has been described as somewhat inferior to some other product for the same use. See In re Gurley 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). See MPEP 2123.
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.
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." See In re Gurley , 31 USPQ2d 1130, 1131 (Fed. Cir. 1994).
Also see MPEP § 2145(X)(D)(1): “A prior art reference that "teaches away" from the claimed invention is a significant factor to be considered in determining obviousness. However, "the nature of the teaching is highly relevant and must be weighed in substance. A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 553, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (Claims were directed to an epoxy resin based printed circuit material. A prior art reference disclosed a polyester-imide resin based printed circuit material, and taught that although epoxy resin based materials have acceptable stability and some degree of flexibility, they are inferior to polyester-imide resin based materials. The court held the claims would have been obvious over the prior art because the reference taught epoxy resin based material was useful for the inventor’s purpose, applicant did not distinguish the claimed epoxy from the prior art epoxy, and applicant asserted no discovery beyond what was known to the art.).
Furthermore, "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) ("a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.") (internal quotations omitted) (quoting DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009)); and Schwendimann v. Neenah, Inc., 82 F.4th 1371, 1381, 2023 USPQ2d 1173 (Fed. Cir. 2023) ("Although Oez [the prior art] used a white pigment with a cross-linking polymer, it does not discourage a skilled artisan from using the white pigment without a cross-linking polymer or lead the skilled artisan in a direction divergent from the path taken in the Appealed Patents. Thus, Oez's disclosure is substantial evidence that supports the Board's finding that Oez does not teach away from the proposed combination.").”
In contrast to Applicant’s assertations of teaching away by the prior art because Currier et al. indicates a knottin-Fc-MMAF conjugate that is successful in treating U87MG tumors in vivo; there is no discouragement not skepticism in the prior art for also using a knottin-MMAF conjugate to treat tumors as well, particular in light of the teachings of Cox et al. showing knottin-drug conjugates have activity against many different tumor cell types (see Table 2). Additionally, regarding the Miller Declaration, this demonstrates that even before the effective filing date of the instant application, other strategies to target drugs to specific sites such as tumor cells existed, including knottin-drug conjugates.
Additionally, the prior art teaches that an Fc region is not required for functional delivery of drugs via integrin targeting agents to tumors. Liu et al. (Mol Pharm. 2012 Jan 1;9(1):168-75. doi: 10.1021/mp200434n. Epub 2011 Nov 22, in Office Action mailed on 1/22/0206) teaches that small integrin targeting agents conjugated to MMAE via a cleavable linker without Fc region to be efficacious (Abstract). In light of this, one with ordinary skill in the art would appreciate that the delivery of MMAE to integrin expressing cancers.
Furthermore, Applicant argues (Remarks pg. 7): “…[a]s a first matter, Currier does not teach conjugation of an Fe to a knottin peptide, Currier teaches a knottin peptide Fc fusion protein that is conjugated to a tubulin inhibitor via a non-natural amino acid conjugation site in the Fc region. As a second matter, Applicant respectfully disagrees with the Examiner's reasoning that there were finite number of options for one of ordinary skill in the art to test. Without any in vivo data from Cox, one of ordinary skill would not have been motivated to test a knottin peptide conjugated to a tubulin inhibitor without an Fc region. Instead, one of ordinary skill in the art may have been motivated by the teachings of Currier to test other formats that utilize an Fc region, such as other knottin-Fc drug conjugates, as the Examiner suggests. The Examiner has so far provided motivation to use an Fc region (e.g., in Currier and Beck), and no motivation to remove the Fc region or rationale for why one of ordinary skill in the art would have a reasonable expectation of success for doing so…”
This has been found to be not convincing. Cox et al. teaches (pg. 9897): “…these results motivate further development and testing of KDCs for applications in cancer therapy. In addition, this work supports strategies relying upon tumor-associated integrins as targets for drug delivery, and validates antibody-alternatives as scaffolds for drug conjugation.” One with ordinary skill in the art would find this teaching from Cox et al. sufficient motivation to try additional therapeutic conjugates for the knottin peptides taught in the reference. As for the first matter, arguments made over semantic differences that can be attributed to typographical errors do not address the prima facie case of obviousness.
Applicant further argues (Remarks pg. 7): “…Declaration under 37 C.F.R. §1.132 from inventor Caitlyn Miller, PhD, hereinafter "the Miller Declaration." The Miller Declaration describes why one of ordinary skill in the art would not have a reasonable expectation of success from the disclosures of Currier and Cox and also provides in vivo evidence that the knottin-gemcitabine conjugates described by Cox are not functional in vivo. See Figure 1 of the Miller Declaration. This knottin gemcitabine conjugate in vivo result directly contrasts to the present application, which demonstrates surprising in vivo efficacy of the knottin and anti-microtubule agent conjugates, labeled "KDC" that do not comprise an Fc region, in the same U87MG tumor model tested in the Miller Declaration. See e.g., the Miller Declaration at FIG. 2, which is a reproduction of FIG. 23B from the instant application. Thus, it was surprising that the knottin-anti-microtubule agent conjugates of the present invention worked in vivo while the knottin-gemcitabine conjugates of Cox were shown as no better than a negative control. The results presented in the Miller Declaration further emphasize the unexpected nature of the results demonstrated by the inventors of the instant application, that conjugates comprising a knottin and an anti-microtubule agent, and lacking an Fc region, are highly efficacious in vivo at low doses.”
Additionally, the Miller Declaration remarks (pg. 3): “…it is not reasonable to argue that the knottin-gemcitabine construct suggests preparing a knottin-drug conjugate without any other elements because the knottin-gemcitabine construct did not, in face, work in vivo.” Also see Fig.1 of the Miller Declaration:
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The Miller Declaration also remarks (pg. 4): “[i] other words, the knottin-gemcitabine conjugates of Cox were not effective in vivo even at roughly 20 times the molar dose of the knottin-MMAF (KDC) conjugates of the present application”. Also see Fig. 2 of the Miller Declaration:
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This has been found to be not convincing. In response to applicant’s arguments against the references individually, one cannot show non-obviousness by attacking references individually where the rejections are based on combination of references. See MPEP 2145.
Contrary to applicant’s arguments against the references individually, note that One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. Where an applicant’s reply establishes that each of the applied references fails to teach a limitation and addresses the combined teachings and/or suggestions of the applied prior art, the reply as a whole does not attack the references individually as the phrase is used in Keller and reliance on Keller would not be appropriate. This is because "[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA]." In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012). See MPEP 2145 IV.
Additionally, it is noted that in considering the disclosure of a reference, it is proper to take into account not only specific teaching of the reference but also the inferences which one skilled in the art would be reasonably be expected to draw therefrom In re Preda, 401 F.2d 825, 159 USPQ 342, 344 (CCPA 1968). See MPEP 2144.01.
Furthermore, specific statements in the references themselves which would spell out the claimed invention are not necessary to show obviousness, since questions of obviousness involves not only what references expressly teach, but what they would collectively suggest to one of ordinary skill in the art. See CTS Corp. v. Electro Materials Corp. of America 202 USPQ 22 (DC SNY ); and In re Burckel 201 USPQ 67 (CCPA). In re Burckel is cited in MPEP 716.02.
Here, given the teachings of Cox et al. regarding the function of knottin peptides can function to target therapeutic drugs to cancer cells, and Currier et al. regarding the function of MMAF as an anti-cancer therapeutic, the ordinary artisan at the time the invention was made would have had a reasonable expectation of success of making a knottin peptide with an engineered loop containing RGD conjugated to MMAF via a protease cleavable linker.
The motivation to combine can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combine for their commonly known purpose.
Furthermore Applicant’s assertation that the evidence provided in the Miller Declaration describes why one with ordinary skill in the art would not have a reasonable expectation of success has been found to be not convincing. Applicant remarks (pg. 7): “[t]his knottin gemcitabine conjugate in vivo result directly contrasts to the present application, which demonstrates surprising in vivo efficacy of the knottin and anti-microtubule agent conjugates, labeled "KDC" that do not comprise an Fc region, in the same U87MG tumor model tested in the Miller Declaration”. However, this does not provide evidence against the prima facie obvious combination of Cox et al. in view of Currier et al. Cox et al. provides motivation for one with ordinary skill to try other knottin-drug conjugates (see supra), and Currier et al. teaches that MMAE is one of these potential therapeutics to try (see supra).
Applicant further assets that Fig. 2 of the Miller Declaration and instant Fig. 23B show unexpected superior results of the knottin-MMAE conjugate, the instant specification discloses that the experiment that resulted in this graph was from an experiment each agent was administered at an equal mass, instead of an equimolar dose of the microtubule inhibitor MMAE (pg. 41): “…comparing drug conjugates using the clinically relevant comparison of mass of drug conjugate per kg mouse body weight, KOC significantly outperformed both KFDC and KADC (FIG 23). To understand the discrepancy between these results and the pilot study, mice were also treated with KADC administered at a much higher dose of 30 mg/kg, 35 closer to an equimolar dose of MMAE. In this experiment, KADC was very effective and induced complete tumor regression in 5 of 5 mice…”
The instant specification further discloses that when the agents are administered in amounts that lead to equimolar amounts of drug to be delivered, the KFDC and KADC had the greatest effect (pg. 40): “[e]ach dose contained the appropriate drug conjugate normalized to 2.38 nmol MMAE (~0.6 mg/kg KOC, ~5 mg/kg KFOC, ~10 mg/kg KAOC). All drug conjugates significantly extended survival over control mice (FIG 19A, 19B). KOC induced complete tumor regression in 1 of 5 mice and maintained a cytostatic effect tin the remaining 4 of 5 mice (FIG 19C). After 3 weeks of treatment, the tumors of these 4 mice returned. Both KFDC and KADC resulted in complete tumor regression in all 5 mice per respective treatment group (FIG 19C).” Also see Fig. 19:
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Therefore, these results displayed in Fig. 23 are considered expected results, as the instant specification discloses that this increase in efficacy is expected, as an equal mass of the small KDC will deliver a larger amount of microtubule inhibitor and lead to greater tumor regression. Normalizing the amount of agent delivered so that each agent delivers equimolar amounts of microtubule inhibitor has the expected results of reversing this effect.
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 stand as rejected under 35 U.S.C. 103 as being unpatentable over Cox et al. (supra) in view of Currier et al. (supra), as evidenced by Beck (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 1/22/2026).
The invention is a prima facie obvious variant of the invention taught by the combined references of Cox et al. in view of Currier et al., as evidenced by Beck et al., and further in view of Gong et al. for the same reasons discussed in the Office Action mailed 1/22/2026.
Applicant’s arguments, filed on 5/20/2026, have been fully considered, but have been found to be not convincing.
Applicant argues (Remarks pg. 8 and 9): “…Gong, in using a full-length antibody provides no teaching or suggestion to use a knottin conjugate lacing an Fc region, irrespective of the linker. Gong does not provide any motivation for one of ordinary skill in the art to arrive at the claimed conjugates…”
This has been found to be not convincing. Contrary to applicant’s arguments against the references individually, note that One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. Where an applicant’s reply establishes that each of the applied references fails to teach a limitation and addresses the combined teachings and/or suggestions of the applied prior art, the reply as a whole does not attack the references individually as the phrase is used in Keller and reliance on Keller would not be appropriate. This is because "[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA]." In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012). See MPEP 2145 IV.
Additionally, it is noted that in considering the disclosure of a reference, it is proper to take into account not only specific teaching of the reference but also the inferences which one skilled in the art would be reasonably be expected to draw therefrom In re Preda, 401 F.2d 825, 159 USPQ 342, 344 (CCPA 1968). See MPEP 2144.01.
Furthermore, specific statements in the references themselves which would spell out the claimed invention are not necessary to show obviousness, since questions of obviousness involves not only what references expressly teach, but what they would collectively suggest to one of ordinary skill in the art. See CTS Corp. v. Electro Materials Corp. of America 202 USPQ 22 (DC SNY ); and In re Burckel 201 USPQ 67 (CCPA). In re Burckel is cited in MPEP 716.02.
Here, given the teachings of Cox et al. regarding the function of knottin peptides can function to target therapeutic drugs to cancer cells, Currier et al. regarding the function of MMAF as an anti-cancer therapeutic, and Gong et al. regarding the function of MMAE as a different anti-cancer therapeutic that can be conjugated to peptides such as antibodies and knottin peptides, the ordinary artisan at the time the invention was made would have had a reasonable expectation of success of making a knottin peptide with an engineered loop containing RGD conjugated to MMAE via a Val-Cit-PAB.
The motivation to combine can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combine for their commonly known purpose.
Claims 85-89 and 100-102 stand as 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, in Office Action mailed on 1/22/0206, supra).
The invention is a prima facie obvious variant of the invention taught by the combined references of Cox et al. in view of Liu et al. for the same reasons discussed in the Office Action mailed 1/22/2026.
Applicant’s arguments, filed on 5/20/2026, have been fully considered, but have been found to be not convincing.
Applicant argues (Remarks pg. 9 and 10): “…Liu teaches that both prodrug 3 and prodrug 8 are "activated extracellularly" by legumain that is colocalized with integrin on the surface of tumor cells. (Liu at Discussion). In contrast, the knottin peptides taught by Cox are demonstrated to be internalized by the target cell, rather than cleaved extracellularly like the conjugates of Liu… Applicant submits that one of ordinary skill in the art would not have been motivated by the limited data presented in Liu et al. to suspect that integrin binding is the key mechanism of action for the conjugates of Liu et al., rather than the legumain-based cleavage (i.e., prodrug extracellular release mechanism), and would therefore not have been motivated to remove the extracellular, legumain based cleavage from the prodrugs taught by Liu and instead conjugate MMAE to a knottin peptide as claimed…”
This has been found to be not convincing. As stated in the Office Action mailed on 1/22/2026, Liu et al. teaches that MMAE is an applicable drug to be conjugated to integrin-targeting agents via protease cleavable linkers, providing prima facie case of obviousness to use MMAE in the knottin-drug conjugate system taught by Cox et al. to make knottin-Val-Cit-PAB-MMAE conjugates. Furthermore, Cox et al. teaches that the EETI-2.5Z conjugated to a drug via a Val-Cit-PAB linker leads to intracellular delivery of the conjugated therapeutic, and one would be motivated to try MMAE in this format for intracellular delivery of MMAE.
In contrast to applicant’s assertions that other drugs, drug conjugates, or activatable MMAE prodrugs taught by Liu et al. have different efficacies; disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. See In re Susi USPQ 423 (CCPA 1971). A known or obvious composition does not patentable simply because it has been described as somewhat inferior to some other product for the same use. See In re Gurley 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). See MPEP 2123.
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 stand as 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, in Office Action mailed 1/22/2026).
The invention is a prima facie obvious variant of the invention taught by the combined references of Cox et al. in view of Liu et al., and further in view of Doronina et al. for the same reasons discussed in the Office Action mailed 1/22/2026.
Applicant’s arguments, filed on 5/20/2026, have been fully considered, but have been found to be not convincing.
Applicant argues that Doronina et al. do not remedy the deficiencies Applicant has raised for Cox et al. in view of Liu et al., however this has been found not convincing for the reasons discussed supra.
Applicant argues that Doronina et al. does not teach or suggest knottin conjugates. However, this argument against an individual reference in a prima facie case of obviousness is found not convincing for the reasons discussed supra.
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 stand as 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), claims 1-16 of U.S. Patent No. 10,407,477 (Pat ‘477); claims 1-33 of U.S. Patent No. 10,765,625 (Pat ‘625); claims 1-22 of U.S. Patent No. 9,587,001 (Pat ‘001); claims 1-20 of U.S. Patent No. 11,466,063 (Pat ‘063); and claims 1-14 U.S. Patent No 12,240,882 (Pat ‘882; all patents also cited in the Office Action mailed 1/22/2026) 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 1/22/2026, 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 1/22/2026.
Applicant’s remarks, filed 5/20/2026, 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 stand as 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), claims 1-16 of U.S. Patent No. 10,407,477 (Pat ‘477); claims 1-33 of U.S. Patent No. 10,765,625 (Pat ‘625); claims 1-22 of U.S. Patent No. 9,587,001 (Pat ‘001); claims 1-20 of U.S. Patent No. 11,466,063 (Pat ‘063); and claims 1-14 U.S. Patent No 12,240,882 (Pat ‘882; all patents also cited in the Office Action mailed 1/22/2026) 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 1/22/2026, 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 5/20/2026, 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 stand as provisionally rejected 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 1/22/2026) 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 in view of Currier et al. for the reasons discussed in the Office Actions mailed on 1/22/2026.
Applicant’s remarks, filed 5/20/2026, 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.
This is a provisional double patenting rejection.
Claims 94 and 95 stand as 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 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 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.
This is a provisional double patenting rejection
Claims 85-89 and 100-102 stand as 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 1/22/2026, supra) and Liu et al. (Mol Pharm. 2012 Jan 1;9(1):168-75. doi: 10.1021/mp200434n. Epub 2011 Nov 22, supra).
The invention encompassed by the instant claims 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 in the Office Actions mailed on 1/22/2026.
Applicant’s arguments, filed 1/12/2026, have been fully considered, but have been found to be not convincing. Applicant argues that for the same reasons discussed in the 35 USC 103 rejection supra, one would not be motivated to combined the references. However, this has been found convincing for the reasons stated in the 35 USC 103 rejection supra.
Claims 94 and 95 stand as 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 the instant claims are 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 reasons discussed in the Office Actions mailed on 1/22/2026.
Applicant’s arguments, filed 1/12/2026, have been fully considered, but have been found to be not convincing. Applicant argues that for the same reasons discussed in the 35 USC 103 rejection supra, one would not be motivated to combined the references. However, this has been found convincing for the reasons stated in the 35 USC 103 rejection supra.
Claims 85-89 and 100-102 stand as 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 1/22/2026), all in view of Cox et al. (supra) and Liu et al. (supra).
The invention encompassed by the instant claims are a prima facie obvious variant of the invention claimed by Pat ‘477, Pat ‘625, Pat ‘273, Pat ‘001, Pat ‘603, Pat ‘989, Pat ‘952, Pat ‘063, and Pat ‘882 in view of Cox et al. and Liu et al. for the reasons discussed in the Office Actions mailed on 1/22/2026.
Applicant’s arguments, filed 1/12/2026, have been fully considered, but have been found to be not convincing. Applicant argues that for the same reasons discussed in the 35 USC 103 rejection supra, one would not be motivated to combined the references. However, this has been found convincing for the reasons stated in the 35 USC 103 rejection supra.
Claims 94 and 95 stand as 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 invention claimed by Pat ‘477, Pat ‘625, Pat ‘273, Pat ‘001, Pat ‘603, Pat ‘989, Pat ‘952, Pat ‘063, and Pat ‘882 in view of Cox et al. and Liu et al., and further in view of Doronina et al. for the reasons discussed in the Office Actions mailed on 1/22/2026.
Applicant’s arguments, filed 1/12/2026, have been fully considered, but have been found to be not convincing. Applicant argues that for the same reasons discussed in the 35 USC 103 rejection supra, one would not be motivated to combined the references. However, this has been found convincing for the reasons stated in the 35 USC 103 rejection supra.
Claims 85-89 and 100-102 stand as 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).
The invention encompassed by the instant claims are a prima facie obvious variant of the invention claimed by App ‘694 in view of Cox et al. and Liu et al. for the reasons discussed in the Office Actions mailed on 1/22/2026.
Applicant’s arguments, filed 1/12/2026, have been fully considered, but have been found to be not convincing. Applicant argues that for the same reasons discussed in the 35 USC 103 rejection supra, one would not be motivated to combined the references. However, this has been found convincing for the reasons stated in the 35 USC 103 rejection supra.
This is a provisional double patenting rejection.
Claims 94 and 95 stand as 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 invention claimed by App ‘694 in view of Cox et al. and Liu et al., and further in view of Doronina et al. for the reasons discussed in the Office Actions mailed on 1/22/2026.
Applicant’s arguments, filed 1/12/2026, have been fully considered, but have been found to be not convincing. Applicant argues that for the same reasons discussed in the 35 USC 103 rejection supra, one would not be motivated to combined the references. However, this has been found convincing for the reasons stated in the 35 USC 103 rejection supra.
This is a provisional double patenting rejection.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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