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 .
Claim Status
Claims 2-5, 9, 12, 17-20, 28 and 30-34 have been cancelled as requested in the amendment filed on 06/10/2026. Following the amendment, claims 1, 6-8, 10-11, 13-16, 21-27, and 29 are pending in the instant application.
Claims 1, 6-8, 10-11, 13-16, 21-27, and 29 are under examination in the instant office action.
Double Patenting - Withdrawn
Claims 1, 6-8, 10, 11, 13-16, and 21-27 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 10, and 12-22 of co-pending Application No. 18/032,149 (herein after referred to as “reference application”) in view of US 2012/0076727 (previously cited on PTO-892; herein after referred to as "McBride"), US 2016/0106856 (previously cited on PTO-892; herein after referred to as "Castaigne"), and US 2016/0220686 (previously cited on PTO-892; herein after referred to as "Brudno").
Claim 29 was rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 10, and 12-22 of co-pending Application No. 18/032,149 (herein after referred to as “reference application”), McBride, Castaigne, and Brudno, as applied to claim 1, 6-8, 10, 11, 13-16, and 21-27 above, and in further view of WO 2018/045058 (previously cited on PTO-892; herein after referred to as "Goldberg").
With regard to the above-listed claim rejections on the grounds of nonstatutory double patenting, Applicant argues the following on Pages 15-16 of Remarks (06/10/2026):
The claims of the reference application recite a single compound in which tissue binding and drug delivery occur through one molecule in a single step. The instant claims require a fundamentally different two-component architecture with four critical distinctions: First, structural separation: The Click Target carries no active agent; the Click Prodrug carries no tissue-binding moiety. The active agent is never in the same molecule as X. Second, multi-dose and multi-agent capability: Claims 27, 24, and 26 enable repeat dosing and multiple different Click Prodrugs with different active agents against the same anchored Click Target. Structurally impossible under the reference application's single-compound format. Third, independent pharmacokinetic optimization: The Click Target and Click Prodrug can be independently formulated, dosed, and timed. Fourth, in vivo bioorthogonal click-triggered drug release: Active agent release occurs specifically at the ECM immobilized click motif through the CM1/CM2 bioorthogonal reaction, not through diffusion from a tethered molecule.
Applicant’s arguments have been fully considered and are deemed persuasive. As such, the above-listed claim rejections under nonstatutory double patenting over copending Application No. 18/032,149 are withdrawn.
Claim Rejections - 35 USC § 103 - Maintained
Claims 1, 6-8, 10, 11, 13-16, and 21-27 stand as rejected under 35 U.S.C. § 103 as being unpatentable over US 2012/0076727 (previously cited on PTO-892; herein after referred to as "McBride") in view of non-patent literature by Raave et al., J Controlled Release, 2018, 274, 1-8; previously cited on PTO-892; herein after referred to as "Raave"), US 10,730,976 (previously cited on PTO-892; herein after referred to as "Klein"), US 2016/0106856 (previously cited on PTO-892; herein after referred to as "Castaigne"), and US 2016/0220686 (previously cited on PTO-892; herein after referred to as "Brudno").
Claim 29 stands as rejected under 35 U.S.C. § 103 as being unpatentable over US 2012/0076727 (previously cited on PTO-892; herein after referred to as "McBride"), non-patent literature by Raave et al., J Controlled Release, 2018, 274, 1-8; previously cited on PTO-892; herein after referred to as "Raave"), US 10,730,976 (previously cited on PTO-892; herein after referred to as "Klein"), US 2016/0106856 (previously cited on PTO-892; herein after referred to as "Castaigne"), and US 2016/0220686 (previously cited on PTO-892; herein after referred to as "Brudno"), as applied to claims 1, 6-8, 10, 11, 13-16, and 21-27 above, and in further in view of WO 2018/045058 (hereinafter "Goldberg").
Response to Arguments - 35 USC § 103
With regard to the above-listed claim rejections under 35 U.S.C. § 103, Applicant argues the following on Pages 7-15 of Remarks (06/10/2026):
The Examiner’s characterization of Klein and Raave is not consistent with the teaching of those references. Klein is directed to polymeric phosphocholine lipid compounds for forming stabilized liposomes used as lubricants. All twenty claims of Klein are directed to: (1) polymeric compounds for liposome formation; (2) lipid bilayers and liposomes; (3) lubricant compositions for reducing friction of physiological surfaces, specifically articular surfaces of synovial joints; (4) reducing friction of contact lens surfaces; and (5) inhibiting biofilm formation. Click chemistry is not mentioned anywhere in Klein. Tumor extracellular matrices are not mentioned anywhere in Klein. Drug delivery for cancer treatment is not mentioned anywhere in Klein. Raave is a comprehensive review of ECM-targeted drug delivery strategies. Every single strategy in Raave's Table 1 uses non-covalent binding mechanisms. There is no example of NHS-amine covalent anchoring to tumor ECM proteins anywhere in Raave. The closest click chemistry system that Raave's own comprehensive survey could identify is a click-to-release antibody-drug conjugate (Rossin et al., Section 4.3), which is antibody-based and non-covalently tumor-bound, not an NHS-covalent ECM anchoring system. Raave' s overall conclusion is that matrix targeting is "promising, but that clinical studies are required to evaluate translation," which Applicant asserts is an affirmative acknowledgment that the field had not achieved reliable success as of 2018.
The “obvious to try” framework is not satisfied: while ECM targeting as a general concept was recognized, the specific problem solved by the instant claims, anchoring a bioorthogonal click motif covalently to tumor ECM via NHS-amine chemistry to serve as a pre-targeted in vivo click reaction depot for a subsequently administered click prodrug, was not an identified need in the art; Raave' s Table 1 identifies eight distinct ECM target molecules and numerous binding and delivery strategies for each, Klein's targeting moiety section lists approximately fifteen categories of reactive groups, and McBride encompasses diverse click reaction pairs which demonstrates that there is no finite, enumerable set of solutions from which the claimed combination was obvious to select; and one of ordinary skill in the art in bioconjugation chemistry and in vivo drug delivery would not only have lacked a reasonable expectation of success, but also would have had affirmative reasons to expect the proposed combination to fail, based on three well-established limitations of NHS ester chemistry in biological environments that Applicant asserts are part of the common general knowledge in this field (hydrolytic instability of NHS esters in aqueous biological environments, pH dependence of NHS-amine coupling and the inability to control pH in vivo, and the presence of overwhelming competition from abundant soluble amines in biological fluids). Applicant argues that the three well-established limitations of NHS ester chemistry in biological environments (i.e., hydrolytic instability, pH sensitivity, and abundance of competing nucleophiles) would have led one of ordinary skill in the art to actively expect that a systemically administered NHS-functionalized Click Target construct would fail to selectively anchor to tumor ECM in sufficient yield to support an effective in vivo click chemistry pre-targeting platform.
The Examiner's assertion of a reasonable expectation of success amounts to little more than the observation that the individual components were known in the prior art, without an articulated basis for concluding that their combination would achieve the claimed invention.
There is no adequate motivation to combine the references, specifically there is no motivation: (i) to import Klein’s NHS chemistry into McBride’s click chemistry framework; (ii) to use covalent NHS-amine ECM anchoring as opposed to the non-covalent binding approaches of Raave; (iii) to use the Castaigne or Brundo linkers in the functional roles of instant L1 and L2.
Klein is non-analogous art and is not reasonably pertinent to the particular problem the inventor faced, wherein Klein addresses the problem of stabilizing liposomes to improve surface lubrication at physiological pressures, whereas the claimed invention is directed to delivering active agents to target tissues with spatial and temporal precision using a two-step in vivo bioorthogonal click chemistry approach.
The proposed combination would require fundamental redesign of the prior art: McBride's Click Target relies on non-covalent receptor/ligand or antibody-antigen interactions for cellular targeting. Modifying this system to employ covalent NHS-amine anchoring to ECM proteins would be inconsistent with, and would materially alter, the operative mechanism of McBride's pre-targeting system. Such a modification would undermine the manner in which McBride achieves targeting, rather than represent a predictable variation. Additionally, the claimed Click Target is not designed to exhibit bioactivity, but instead functions solely to anchor to ECM and present a click-reactive motif.
The multi-reference combination reflects impermissible hindsight reconstruction.
The Goldberg reference does not supply the missing teachings/deficiencies argued above for the underlying combination of references.
Applicant’s arguments have been fully considered but are deemed not persuasive.
With regard to arguments (1) and (5), it is first noted that Klein is considered to be analogous art. MPEP 2141.01(a)(I) states that a reference is analogous art to the claimed invention if: (1) the reference is from the same field of endeavor as the claimed invention (even if it addresses a different problem); or (2) the reference is reasonably pertinent to the problem faced by the inventor (even if it is not in the same field of endeavor as the claimed invention). Note that "same field of endeavor" and "reasonably pertinent" are two separate tests for establishing analogous art; it is not necessary for a reference to fulfill both tests in order to qualify as analogous art. See Bigio, 381 F.3d at 1325, 72 USPQ2d at 1212. The examiner must determine whether a reference is analogous art to the claimed invention when analyzing the obviousness of the subject matter under examination. When more than one prior art reference is used as the basis of an obviousness rejection, it is not required that the references be analogous art to each other. See Sanofi-Aventis Deutschland GMbH v. Mylan Pharms. Inc., 66 F.4th 1373, 1380, 2023 USPQ2d 552 (Fed. Cir. 2023) and Corephotonics, Ltd. v. Apple Inc., 84 F.4th 990, 1007, 2023 USPQ2d 1202 (Fed. Cir. 2023). While it is acknowledged that the Klein reference is drawn to polymeric phosphocholine lipid compounds for forming stabilized liposomes used as lubricants, it is specifically noted that Klein is further drawn to the targeted delivery of said lipid compounds/liposomes to specific cells/tissues using a targeting moiety (e.g., an antibody), wherein said targeting moiety may further comprise a functional group capable of forming a covalent bond with the target cell/tissue to facilitate that targeted delivery of the lipid compounds/liposomes. Such functional groups specifically include NHS (e.g., NHS esters) and sulfo-NHS, which can be used to target and form covalent bonds via available amines. For example, Klein teaches that, in some embodiments, the functional group capable of forming a bond to a target is a functional group capable of forming a covalent bond with an amine group, optionally a primary amine group; in some such embodiments, the target comprises on or more amino acids or amino acid residues, for example, a peptide or polypeptide of any length ( e.g., at least two amino acid residues, for example, proteins), and the amine groups may optionally be lysine side chain amine groups and/or N-terminal amine groups further wherein, in some embodiments, the target comprises an extracellular matrix protein, for example, collagen, and/or comprises cartilage (e.g., articular cartilage) (Column 24, Lines 23-35; emphasis added). Thus, Kelin is directed to the use of NHS (e.g., NHS esters and/or sulfo-NHS) to form covalent bonds with target cells/tissue, wherein in some embodiments that target comprises ECM protein (such as collagen which would have amines capable of reacting with said NHS to form a covalent bond). Raave specifically suggests the targeting of ECM proteins in the context of cancer/tumors. While the methods of targeting ECM proteins disclosed by Raave are all non-covalent (e.g., antibodies to collagen), the targeting approaches of Raave read on tissue binding moieties, and the teachings of Klein read on the functionalization of targeting moieties to comprise reactive groups capable of forming covalent bonds wherein both references detailed targeting approaches for the delivery of therapeutic modalities.
With regard to arguments (2)-(4) and (6), it is specifically noted that: McBride recognizes methods of synthesis and use involving click chemistry reactions for in vivo or in vitro formation of therapeutic and/or diagnostic complexes wherein a chelating moiety or targetable construct may be conjugated to a targeting molecule, such as an antibody or antibody fragment, using a click chemistry reaction involving cyclooctyne, nitrone or azide reactive moieties which can be used for delivering diagnostic and/or therapeutic agents and Raave discloses that it is attractive to target the ECM of tumors in order to effectively target all tumor-associated cells, including heterogenous tumor cells, wherein it is further desirable to use triggered release mechanisms to reduce off-target effects; Raave and McBride both disclose targeting moieties (e.g., antibodies) that are capable of being tissue and/or ECM protein specific, wherein McBride also suggests the use of bispecific targeting moieties for more specific/effective targeting; Klein teaches a targeting moiety approach wherein a targeting moiety is capable of bringing a compound into proximity with a selected substance and/or material (i.e., a target), which may be a cell/tissue (e.g., a proliferating cell associated with a proliferative disease or disorder), wherein the proximity is such that the targeting moiety facilitates attachment and/or internalization of the compound into a target cell, and such that the compound may exert a therapeutic effect wherein the targeting moiety attaches to the target covalently as the targeting moiety comprises a functional group (e.g., NHS) which is capable of forming a covalent bond with functional groups (e.g., amines) of the target. Castaigne and Brundo disclose click chemistry based conjugation methods of therapeutic/drug delivery applications which utilize linker components and wherein such linker components may be cleavable (i.e., enzyme-triggered cleavage). The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992); see also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP 2144(I). Thus, it is maintained that to one of ordinary skill in the art, it would have been obvious to try the method of drug delivery comprising a Click Target and Click Prodrug disclosed by McBride wherein the tissue-targeting moiety is capable of specifically targeting an ECM protein, as motivated by Raave, wherein the tissue binding moiety is further modified to comprise a functional group that is capable of reacting with a primary amine in an extracellular matrix protein (i.e., NHS capable of reacting with primary amine of a targeted ECM protein) as disclosed by Klein to covalently immobilize the targeting construct (i.e., Click Target) to the target tissue, and to further utilize linkers in said Click Target and/or Click Prodrug, as linkers are commonly used in click chemistry based conjugation approaches as disclosed by Castaigne and Brundo and motivated by Raave. One of ordinary skill in the art would have had a reasonable expectation of success because Click Targets and Click Prodrugs are well established in the art in the delivery of therapeutic drugs for the treatment of, for example, cancer (as disclosed by McBride, Castaigne, and Brundo), the targeting of the ECM for therapeutic applications is disclosed/motivated by Raave, and immobilization of the Click Target to the target tissue via covalent bond with proteins of the ECM is suggested by Klein; all together one of ordinary skill in the art would have a reasonable expectation of (i) delivering the Click Target to a tissue of interest (i.e., cancerous tissue/tumor stroma) and immobilizing the Click Target to the tissue via covalent bond (e.g., NHS functionalization leads to covalent bonds with primary amines of ECM proteins) and (ii) delivering the Click Prodrug wherein the Click Prodrug chemically reacts with the Click Target in the target tissue and wherein the active agent is subsequently released in the target tissue (e.g., triggered release via cleavable linker) to exert localized therapeutic effects. Further, it is specifically noted that while in vivo applications of NHS do not provide optimal conditions for bond formation as indicated by Applicant, it is noted that the methods of Klein are directed to in vivo applications of NHS anchoring to a target via covalent bond, which would provide a reasonable expectation of success for in vivo NHS applications, including that instantly claimed. Furthermore, it is noted that Applicant’s arguments as pertain specifically to (i) NHS and (ii) to systemic administration of the Click Target of instant claim 1 are not fully commensurate in scope with the instant claims. Notably, the instant claims require (i) “contacting the target tissue with a Click Target consisting of Formula (I)”, wherein contacting the target tissue is not limited to systemic administration, but may also include local administration directly to the target tissue (e.g. administration directly into a tumor); and (ii) “a tissue binding moiety configured to chemically react with an amine group in an extracellular matrix protein in the target tissue, thereby forming a direct bind with the target tissue”, wherein it is noted that such a configuration for a chemical reaction is not necessarily limited to an NHS, but any reactive group capable of reacting with an amine. Furthermore, specifically with regard to argument (6), it is noted that the non-covalent targeting interactions are still being utilized (i.e., the non-covalent targeting approaches using, for example, antibodies specific to a target cell/tissue), but that as suggested by Klein a subsequent covalent interaction is being further utilized for anchoring/attachment. Thus, it is not a fundamental redesign of McBride, but modification(s) to McBride based on available teachings in the prior art.
With regard to argument (7), it is specifically noted that “[a]ny judgement on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper.” In re McLaughlin 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). As provided above, the obviousness rejection relies only on knowledge available to and within the level of ordinary skill in the art at the time the instant application was effectively filed.
With regard to argument (8), it is maintained that there are no deficiencies with respect to the primary combination of cited prior art reference, and thus Goldberg is relied upon solely for its teaching regarding surgical resection of tumors prior to using/implanting drug delivery devices.
Thus, the above-listed claim rejections under 35 U.S.C. § 103 are deemed proper and are maintained.
Conclusion
Claims 1, 6-8, 10-11, 13-16, 21-27, and 29 are pending. Claims 1, 6-8, 10-11, 13-16, 21-27, and 29 are rejected. No claims are 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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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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