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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/07/2026 has been entered.
Claim Status
Claims 2-5, 9, 12, 17-20, 28, and 30-34 have been cancelled and claims 1, 13, 24, 27, and 29 have been amended, as requested in the amendment filed on 01/07/2026. 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.
Claim Rejections - 35 USC § 112 - Withdrawn
Claims 32-34 were rejected under 35 USC § 112(b) as being indefinite. Claims 32-34 have been cancelled, rendering the rejection moot. As such, the rejection of claims 32-34 under 35 USC § 112(b) as being indefinite is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 1, 6-8, 10-11, 14-16, and 21-23 were rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0076727 A1 (previously cited on PTO-892; herein after referred to as “McBride”) in view of non-patent literature published by Kai et. al. (Developmental Cell, 2019, 49, 332-346; previously cited on PTO-892; herein after referred to as “Kai”) and non-patent literature published by Lee et. al. (ACS Appl. Mater. Interfaces, 2017, 9, 23389-23399; previously cited on PTO-892; herein after referred to as “Lee”).
Claims 13 and 24-27 were rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0076727 A1 (previously cited on PTO-892; herein after referred to as “McBride”) in view of non-patent literature published by Kai et. al. (Developmental Cell, 2019, 49, 332-346; previously cited on PTO-892; herein after referred to as “Kai”) and non-patent literature published by Lee et. al. (ACS Appl. Mater. Interfaces, 2017, 9, 23389-23399; previously cited on PTO-892; herein after referred to as “Lee”), as applied to claims 1, 6-8, 10-11, 14-16, and 21-23 above, and further in view of US 2016/0106856 A1 (previously cited on PTO-892; herein after referred to as “Castaigne”) and US 2016/0220686 A1 (previously cited on PTO-892; herein after referred to as “Brundo”).
Claim 29 was rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0076727 A1 (previously cited on PTO-892; herein after referred to as “McBride”), non-patent literature published by Kai et. al. (Developmental Cell, 2019, 49, 332-346; previously cited on PTO-892; herein after referred to as “Kai”) and non-patent literature published by Lee et. al. (ACS Appl. Mater. Interfaces, 2017, 9, 23389-23399; previously cited on PTO-892; herein after referred to as “Lee”), US 2016/0106856 A1 (previously cited on PTO-892; herein after referred to as “Castaigne”), and US 2016/0220686 A1 (previously cited on PTO-892; herein after referred to as “Brundo”), as applied to claims 1, 6-8, 10-11, 13-16, and 21-27 above, and further in view of WO 2018/045058 A1 (previously cited on PTO-892; herein after referred to as “Goldberg”).
Claim 32 was rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0076727 A1 (previously cited on PTO-892; herein after referred to as “McBride”), non-patent literature published by Kai et. al. (Developmental Cell, 2019, 49, 332-346; previously cited on PTO-892; herein after referred to as “Kai”) and non-patent literature published by Lee et. al. (ACS Appl. Mater. Interfaces, 2017, 9, 23389-23399; previously cited on PTO-892; herein after referred to as “Lee”), as applied to claims 1, 6-8, 10-11, 14-16, and 21-23 above, and in further view of non-patent literature published by Hussain et. al. (Scientific Reports, 2014, 4(5232), 1-7; previously cited on PTO-892; herein after referred to as “Hussain”).
Claim 33 was rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0076727 A1 (previously cited on PTO-892; herein after referred to as “McBride”), non-patent literature published by Kai et. al. (Developmental Cell, 2019, 49, 332-346; previously cited on PTO-892; herein after referred to as “Kai”) and non-patent literature published by Lee et. al. (ACS Appl. Mater. Interfaces, 2017, 9, 23389-23399; previously cited on PTO-892; herein after referred to as “Lee”), US 2016/0106856 A1 (previously cited on PTO-892; herein after referred to as “Castaigne”), and US 2016/0220686 A1 (previously cited on PTO-892; herein after referred to as “Brundo”), as applied to claims 1, 6-8, 10-11, 13-16, and 21-27 above, and in further view of non-patent literature by Hussain et. al. (Scientific Reports, 2014, 4(5232), 1-7; previously cited on PTO-892; herein after referred to as “Hussain”).
Claim 34 was rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0076727 A1 (previously cited on PTO-892; herein after referred to as “McBride”), non-patent literature published by Kai et. al. (Developmental Cell, 2019, 49, 332-346; previously cited on PTO-892; herein after referred to as “Kai”) and non-patent literature published by Lee et. al. (ACS Appl. Mater. Interfaces, 2017, 9, 23389-23399; previously cited on PTO-892; herein after referred to as “Lee”), US 2016/0106856 A1 (previously cited on PTO-892; herein after referred to as “Castaigne”), US 2016/0220686 A1 (previously cited on PTO-892; herein after referred to as “Brundo”), and WO 2018/045058 A1 (previously cited on PTO-892; herein after referred to as “Goldberg”), as applied to claims 1, 6-8, 10-11, 13-16, 21-27, and 29 above, and further in view of non-patent literature by Hussain et. al. (Scientific Reports, 2014, 4(5232), 1-7; previously cited on PTO-892; herein after referred to as “Hussain”).
With regard to the above-listed claim rejections under 35 USC § 103, it is noted that claims 32-34 have been cancelled, rendering their rejections moot. Applicant further argues the following on Pages 8-12 of Remarks (07/07/2026):
Independent claims 1, 27, and 29 have been amended to require that both the Click Target and the Click Prodrug now require linker components L1 and L2, respectively.
The disclosure of McBride does not teach the now required linker components of the claimed Click Target and Click Prodrug nor does McBride disclose a tissue binding moiety that reacts with an amine group in the target tissue to form a covalent bond with the target tissue; the targeting moieties of McBride rely solely on non-covalent interactions with the target tissue.
Kai does not teach or suggest targeting ECM proteins for any purpose, but rather is generally drawn to how the ECM is impacted during metastasis. Kai, at best, suggests therapies that modulate the structure, function, and biophysical properties of the ECM and regulate adhesion signaling in order to reduce tumor aggression, limit metastasis, and optimize treatment responses.
The approaches of Lee are used exclusively in in vitro settings, and only notes that potential in vivo applications are “promising”. The methods of Lee are also limited to modifying a surface, not a tissue. Additionally, the EGF tethered to collagen as used by Lee should have bioactivity, whereas the instantly claimed Click Target is not designed to have any bioactivity.
Modifying the method of McBride such that the tissue binding moiety binds an ECM protein as described in Lee would (i) render Lee inoperative for its intended purpose because bioactivity would be masked and/or (ii) McBride would be inoperable for its intended purpose because the requirement of bioactivity in Lee would preclude the addition of a reactive moiety to bind EGF and thus there would not be any delivery of active agent.
The above-presented arguments in view of the instantly amended claims are deemed persuasive. As such, the above-listed claim rejections under 35 USC § 103 are withdrawn.
Claim Rejections - 35 USC § 103 - New
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 1, 6-8, 10-11, 13-16, and 21-27 rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0076727 A1 (previously cited on PTO-892; herein after referred to as “McBride”) in view of non-patent literature by Raave et. al. (Journal of Controlled Release, 2018, 274, 1-8; herein after referred to as “Raave”), US 10,730,976 B2 (herein after referred to as “Klein”), US 2016/0106856 A1 (previously cited on PTO-892; herein after referred to as “Castaigne”), and US 2016/0220686 A1 (previously cited on PTO-892; herein after referred to as “Brundo”).
With regard to claim 1, McBride compositions and 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 (Abstract). The click chemistry involves the reaction of a targeting molecule (i.e., Click Target), such as an antibody or antigen-binding antibody fragment, comprising an activating moiety such as a cyclooctyne, a nitrone or an azide group, with a targetable construct (i.e., Click Prodrug) comprising a corresponding reactive moiety, such as an azide, nitrone or cyclooctyne; where the targeting molecule comprises a cyclooctyne, the targetable construct will comprise an azide or nitrone or similar reactive moiety and where the targeting molecule comprises an azide or nitrone, the targetable construct will comprise a cyclooctyne, alkyne or similar reactive moiety (Paragraph 0016). The click chemistry reaction allows formation of a very stable covalent bond between the targeting molecule and targetable construct (Id.). The click chemistry reaction may occur in vitro to form a highly stable, labeled targeting molecule that is then administered to a subject or, in preferred alternative embodiments,
the click chemistry reaction may occur in vivo (Paragraph 0017). Initially, an antibody or other targeting molecule comprising an activating moiety is administered to a subject and allowed to localize to a target cell, tissue, pathogenic organism or other target (i.e., contact target tissue) and subsequently a targetable construct comprising an appropriate reactive moiety is administered to the subject wherein the reaction between the activating moiety and reactive moiety is sufficiently specific that the targetable construct does not bind to other, non-activated molecules within the subject and the targetable construct irreversibly binds to the targeting molecule localized in the target tissue (Id.). McBride discloses that targetable constructs can be of diverse structure and are selected not only for the availability of an antibody or fragment that binds with high affinity to the targetable construct, but also for rapid in vivo clearance when used within the pre-targeting method and bispecific antibodies (bsAb) or multispecific antibodies and that subunits of the targetable construct may be chosen which have opposite solution properties, for example, peptides, which contain amino acids, some of which are hydrophobic and some of which are hydrophilic; peptides having as few as two amino acid residues, preferably two to ten residues, may be used and may also be coupled to other moieties, such as chelating agents, wherein the linker should be a low molecular weight conjugate, preferably having a molecular weight of less than 50,000 daltons, and advantageously less than about 20,000 daltons, 10,000 daltons or 5,000 daltons (Paragraphs 0062-0063). McBride also discloses that targeting moieties are not limited to antibodies or antibody fragments, but can be any molecules that binds specifically or selectively to a cellular target associated with or diagnostic of a disease state or other condition (Paragraph 0293). Example 17 explicitly discloses the use of a somatostatin analogue peptide for direct targeting od somatostatin receptor expressing tumors (Paragraph 0307). Thus, McBride teaches: (i) a Click Target, wherein the tissue binding moiety is an antibody or any other molecule that can specifically target a disease or diagnostic state/condition, wherein no linker is present, and the click motif can be cyclooctyne, nitrone or azide; (ii) the Click Prodrug, wherein the active agent is a therapeutic or diagnostic agent, a linker may be a peptide, and the second click motif is cyclooctyne, nitrone or azide and is complementary to the click motif of the Click Target; and (iii) that the two click motifs react to form a covalent bond and the Click Target and Click Prodrug may be administered separately such that the Click Target localizes to the tissue/target then the Click Prodrug is administered and the click reaction occurs in vivo at the target tissue. However, while McBride suggests that a skilled artisan will realize that although the majority of targetable constructs disclosed in the Examples of the invention are peptides, other types of molecules may be used as targetable constructs (Paragraph 0068).
It is noted that McBride does not explicitly disclose/suggest that (i) the tissue binding moiety of the Click Target is configured to chemically react with an amine in an ECM protein to form a direct bond with the target tissue nor (ii) both the Click Target and Click Prodrug comprise a linking group. These deficiencies are remedied by (i) the combination of Raave, and Klein and (ii) the combination of Castaigne and Brundo, respectively.
Raave discusses an alternative targeting strategy aimed at delivery of anti-tumor drugs to the tumoral extracellular matrix with the potential to eliminate all cell types; the extracellular matrix of tumors is vastly different from that of healthy tissue and offers hooks for targeted drug delivery wherein it is concluded that matrix targeting is promising (Abstract). Targeting chemotherapeutics to the extracellular matrix (ECM) of tumors may be a promising alternative strategy that can offer advantages over conventional targeting. The strategy is not aimed to target membrane bound receptors on specific tumor cells, but is aimed to target the unique tumoral ECM wherein, upon binding, depots of chemotherapeutic carriers in the tumor ECM are formed; when chemotherapeutics are released in the ECM, they are able to diffuse to and affect all surrounding tumor cells including the heterogeneous tumor cell subsets, tumor supportive cells and tumor stem cells (Page 2, Column 2, Paragraph 3). Various targeting strategies specific for the ECM in tumors are provided by Raave in Table 1 (see Pages 3-6). Raave also highlights that an important characteristic of drug delivery systems for tumoral ECM drug delivery is the
drug release mechanism; upon release, most drug molecules will retain in the tumor area because of the enhanced retention effect and will pass cell membranes due to the hydrophobic properties of the majority of chemotherapeutics, but if not rapidly taken up by tumor or tumor supportive cells, there is a risk of diffusion back into the circulation, which may result in off-target effects (Page 6, Column 1, Last Paragraph). For sufficient release of chemotherapeutics after the drug delivery system is bound to the target, sufficient release is necessary, and Raave discloses approaches including release triggered by enzymes, pH, magnetism, heat, light, and ultrasound (Page 6, Column 2, First Partial Paragraph). Thus, Raave indicates that ECM targeting (including ECM protein targeting via, for example, antibody) is an attractive method for drug delivery to tumors and the subsequent killing of tumor cells. However, Raave does not disclose a tissue targeting moiety configured to chemically react with an amine group in an ECM protein in the target tissue. This deficiency is remedied by Klein.
Klein generally discloses polymeric compounds usable for forming liposomes (Column 1, Lines 27-30) wherein said polymeric compounds may comprise at least one targeting moiety (Column 4, Lines 6-19); said targeting moiety comprises a nucleophilic group and is capable of forming a covalent bond with a target; the functional group(s) are capable of forming a covalent bond with one or more specific functional groups (e.g., hydroxy, amine, thiohydroxy and/or oxo groups) which are present on the target (Columns 22-23). Examples of functional groups (in a targeting moiety) capable of forming a covalent bond with a target and the type of covalent bonds they are capable of forming, include nucleophilic leaving groups such as halo, azide (-N3), sulfate, phosphate, sulfonyl (e.g., mesyl, tosyl), N-hydroxysuccinimide (NHS) (e.g., NHS esters), sulfo-N-hydroxysuccinimide, and anhydride, which may form covalent bonds with, e.g., a nucleophilic group (e.g., an amine) in a target (Column 23, Lines 4-22). A "targeting moiety" refers to a moiety which is capable of bringing a compound (e.g., a compound according to some embodiments of the invention) into proximity with a selected substance and/or material (which is referred to as a "target"); the target is optionally a cell (e.g., a proliferating cell associated with the 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 (Column 20, Lines 41-50). Thus, Klein teaches targeting moieties configured to chemically react with an amine group to form a covalent bond and suggests said targeting moiety may be directed toward cells of a proliferative disease (e.g., cancer). However, none of the above-cited references explicitly disclose methods utilizing Click Targets or Click Prodrugs that each comprise linkers. This deficiency is remedied by Castaigne and Brundo.
Castaigne teaches antibody-polypeptide-cytotoxin conjugates and methods of making, packaging, and using the conjugates (Abstract). More specifically, Castaigne teaches multiple ways in which an antibody may be conjugated to a polypeptide that has, in turn, been conjugated to a cytotoxic agent including: conjugation by click chemistry wherein a cyclooctyne linked to the antibody moiety reacts with an azide group at the N-terminus of the polypeptide wherein the reactive substituents could also be reversed (Paragraph 0021; Figure 2a). Configurations for the conjugates are also disclosed, such that each part of a given conjugate, including the antibody moiety, cytotoxic agent, linker, and polypeptide, can be selected independently; any of the linkers described can be used to conjugate any of the polypeptides and cytotoxic agents described to any of the antibody moieties described provided that the component parts to be linked include compatible reactive substituents (Paragraph 0057). More specifically, a given protein conjugate can include a single antibody moiety, but may include two or more (e.g., 2, 3, or 4) that are identical to one another or different from one another wherein different antibody moieties may specifically bind the same target or different targets (Paragraph 0058). Additionally, component parts of the present conjugates can be configured in a variety of ways, such that the conjugate can assume an essentially linear form with an antibody moiety being linked to at least one polypeptide linked to a cytotoxic agent, or the conjugate can have a branched configuration as seen in dendrimers, with one or more branches extending at some point from the antibody moiety (Paragraph 0058). Castaigne also teaches, with regard to linkers, that a given linker within the invention compositions can provide a cleavable linkage (e.g., a thioester linkage) or a non-cleavable linkage (e.g., a maleimide linkage) and that a cytotoxic protein can be bound to a linker that reacts with modified free amines, which are present at lysine residues within the polypeptide and/or at the amino-terminus of the polypeptide and that useful linkers in the conjugates of the invention can comprise a group that is reactive with a primary amine on the polypeptide or modified polypeptide to which the antibody moiety is conjugated (Paragraph 0068). Thus, Castaigne teaches: (i) the Click Target, wherein the tissue binding moiety is an antibody, a linker may be present, and the click motif is cyclooctyne; (ii) the Click Prodrug, wherein the active agent is a cytotoxic agent, a linker may be present, and the second click motif is an azide; and (iii) that the two click motifs react to form a covalent bond ultimately resulting in the antibody-polypeptide-cytotoxin conjugates of the invention.
Brundo teaches refillable drug delivery systems, as well as methods of refilling the systems, and methods of using them to treat diseases (Abstract). More specifically, Brundo teaches a system comprising a drug delivery device and a drug refill, wherein the drug delivery device comprises a carrier and a target recognition moiety and is suitable for implantation in a desirable location within a subject; wherein the drug refill comprises a pharmaceutical composition and a target; wherein the target and the target recognition moiety form a two-component binding pair; wherein the drug refill is mobile until the target on the drug refill binds to the target recognition moiety on the drug delivery device, and wherein upon binding of the target to the target recognition moiety, the drug refill delivers the pharmaceutical composition directly to the drug delivery device (Paragraph 0006). Brundo further teaches that in some embodiments the target comprises a biorthogonal functional group and the target recognition moiety comprises a complementary functional group, wherein the bioorthogonal functional group is capable of chemically reacting with the complementary functional group to form a covalent bond wherein the biorthogonal functional group is capable of reacting by click chemistry with the complementary functional group (Paragraph 0027). The invention also provides a method of maintaining or reducing the size of a tumor in a subject in need thereof, comprising the steps of: (i) administering the drug delivery device of the present invention to a desired location within the subject, wherein the pharmaceutical composition comprises an anti-cancer drug; (ii) subsequently administering the drug refill of the present invention to the subject; (iii) allowing the target on the drug refill to bind to the target recognition moiety on the drug delivery device, thereby delivering the pharmaceutical composition directly to the drug delivery device; (iv) allowing the pharmaceutical composition to be released from the drug delivery device to the desired location within the subject; and (v) optionally repeating steps (ii)-(iv) thereby maintaining or reducing the size of the tumor in the subject wherein the desired location is a tumor site or site away from the tumor site (Paragraphs 0056-0057) and/or wherein the desired location is a tissue within a subject or a site away from the tissue (Paragraph 0060). Thus, Brundo teaches administering a device to a desired location/tissue and subsequently administering a drug refill capable of reacting with the device via click chemistry to release a pharmaceutical composition to said desired location/tissue (i.e., contacting a tissue with a device then contacting the tissue with a drug refill wherein the device and drug refill chemically react via click chemistry). Brundo teaches that the pharmaceutical composition of the invention is attached to the target of the invention via a cleavable linker wherein examples of cleavable linkers include a hydrolysable linker, a pH cleavage linker, an enzyme cleavable linker, or any cleavable linker as described (Paragraph 0290).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to deliver an active agent to a target tissue in a subject comprising (i) contacting the target tissue with a Click Target consisting of Formula I and (ii) contacting the target tissue with a Click Prodrug defined by Formula II. 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; thus one of ordinary skill in the art would have been motivated to try applying the click-chemistry based drug delivery methods/compositions of McBride wherein said methods utilize targeting agents that can specifically target ECM proteins.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, it is noted that:
(1) 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.
(2) 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.
(3) 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 (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).
Thus, 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.
With regard to claim 6, Klein discloses targeting moieties may comprise a nucleophilic group and are capable of forming a covalent bond with a target; the functional group(s) are capable of forming a covalent bond with one or more specific functional groups (e.g., hydroxy, amine, thiohydroxy and/or oxo groups) which are present on the target (Columns 22-23). Examples of functional groups (in a targeting moiety) capable of forming a covalent bond with a target and the type of covalent bonds they are capable of forming, include nucleophilic leaving groups such as halo, azide (-N3), sulfate, phosphate, sulfonyl (e.g., mesyl, tosyl), N-hydroxysuccinimide (NHS) (e.g., NHS esters), sulfo-N-hydroxysuccinimide, and anhydride, which may form covalent bonds with, e.g., a nucleophilic group (e.g., an amine) in a target (Column 23, Lines 4-22). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 7-8 and 10-11, it is noted that McBride teaches that the click chemistry of the invention involves the reaction of a targeting molecule (i.e., Click Target), such as an antibody or antigen-binding antibody fragment, comprising an activating moiety such as a cyclooctyne, a nitrone or an azide group, with a targetable construct (i.e., Click Prodrug) comprising a corresponding reactive moiety, such as an azide, nitrone or cyclooctyne; where the targeting molecule comprises a cyclooctyne, the targetable construct will comprise an azide or nitrone or similar reactive moiety and where the targeting molecule comprises an azide or nitrone, the targetable construct will comprise a cyclooctyne, alkyne or similar reactive moiety (Paragraph 0016; emphasis added). McBride also discloses that the Diels-Alder reaction has also been used for in vivo labeling; for example, a trans-cyclooctene-labeled CC49 antibody was administered to mice bearing colon cancer xenografts, followed 1 day later by injection of 111In-labeled tetrazine probe wherein the reaction of radiolabeled probe with tumor localized antibody resulted in pronounced radioactivity localized in the tumor, as demonstrated by SPECT imaging of live mice three hours after injection of radiolabeled probe, with a tumor-to-muscle ratio of 13:1 and the results confirmed the in vivo chemical reaction of the TCO and tetrazine-labeled molecules (Paragraph 0053). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 13, Raave discloses that triggered-release of active agents (e.g., chemotherapeutic agents) in the ECM is preferable in reducing off-target effects (see Page 6). Brundo further discloses specific types of cleavable linkers used in click chemistry approaches (i.e., specifically for use with a Click Prodrug as instantly claimed); pharmaceutical compositions of the invention are attached to the target of the invention via a cleavable linker wherein examples of cleavable linkers include a hydrolysable linker, a pH cleavage linker, an enzyme cleavable linker, or any cleavable linker as described (Paragraph 0290). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 14-16, McBride teaches compositions and 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 (Abstract). Therapeutic agents are preferably selected from the group consisting of a radionuclide, an immunomodulator, an antiangiogenic agent, a cytokine, a chemokine, a growth factor, a hormone, a drug, a prodrug, an enzyme, an oligonucleotide, a pro-apoptotic agent, an interference RNA, a photoactive therapeutic agent, a cytotoxic agent, which may be a chemotherapeutic agent or a toxin, and a combination thereof; the drugs of use may possess a pharmaceutical property selected from the group consisting of antimitotic, anti-kinase, alkylating, antimetabolite, antibiotic, alkaloid, anti-angiogenic, proapoptotic agents and combinations thereof (Paragraphs 0127). Specific exemplary therapeutic agents are provided in Paragraphs 0128-0136, wherein said exemplary therapeutic agents are known to be the types of drugs/have the functions listed in instant claim 16. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 21, McBride teaches that the methods and compositions described
may be used to detect or treat malignant or premalignant conditions wherein such uses are indicated in conditions known or suspected of preceding progression to neoplasia or cancer, in particular, where non-neoplastic cell growth consisting of hyperplasia, metaplasia, or most particularly, dysplasia has occurred (Paragraph 0154). Such conditions can include, for example, solid tumors (Paragraph 0157). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 22-23, McBride teaches that the preferred route for administration of the compositions described herein is parenteral injection; injection may be subcutaneous, intramuscular, intravenous, intraarterial, intralymphatic, intrathecal, or intracavitary (Paragraph 0141). Various embodiments of the methods and/or compositions of the invention may concern one or more labeled peptides to be administered to a subject wherein administration may occur by any route known in the art, including but not limited to oral, nasal, buccal, inhalational, rectal, vaginal, topical, orthotopic, intradermal, subcutaneous, intramuscular, intraperitoneal, intraarterial, intrathecal or intravenous injection; where, for example, labeled peptides are administered in a pretargeting protocol, the peptides would preferably be administered via IV (Paragraph 0147). Thus, McBride suggests delivery of, for example, the Click Target for contact with the target tissue via injection. Furthermore, one of ordinary skill in the art would recognize that said Click Target, and subsequently the Click Prodrug, could be delivered directly to the target tissue (e.g., solid tumor) via any acceptable route, and/or be administered systemically, such as by IV, as suggested by McBride. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
PNG
media_image1.png
144
406
media_image1.png
Greyscale
With regard to claims 24 and 26, Castaigne teaches dendrimeric conjugates that can be structured as in Formula I (shown below), wherein D is an antibody, Am is a polypeptide of the invention, Xcore and Xbranch join the parts of the conjugate and are linkers, Xnth in one of n surface branches, and D’ is a cytotoxic agent.
Various polypeptides conjugated to cytotoxic agents can be conjugated to/react with a single antibody, such that the dendrimeric conjugate can include multiple surface functionalities to which multiple polypeptides and/or cytotoxins can be conjugated (Paragraph 0061). Thus, one Click Target (i.e., antibody) can be reacted with multiple polypeptides/cytotoxic agents (i.e., Click Prodrugs) that can be different. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 25, Castaigne teaches that single or multiple administrations of the pharmaceutical compositions of the invention can be carried out with dosage levels and the timing or pattern of administration being selected by the treating physician such that the dose and administration schedule can be determined and adjusted based on the severity of the disease or condition in the subject, which may be monitored throughout the course of treatment according
to the methods commonly practiced by clinicians or other skilled healthcare professionals (Paragraph 0108). As evidenced by the references, it is also noted administration doses and administration schedules were recognized as treatment variables which achieve a recognized result and as set forth in MPEP 2144.05: “A particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation. In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977).
It is a common objective in the art to optimize result effective variables, so as achieve optimal effect and maximal benefit. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” (citations omitted)). Therefore, any optimization of administration doses and administration schedules would be seen as routine optimization. Therefore, one of ordinary skill is the art could optimize administration of the Click Prodrugs such that the second Click Prodrug is administered at least one week after administration of the first Click Prodrug and thus the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 27, Brundo teaches that invention is directed to method of maintaining or reducing the size of a tumor (i.e., treating a tumor) in a subject in need thereof comprising the steps of: (i) administering the drug delivery device of the present invention to a desired location within the subject, wherein the pharmaceutical composition comprises an anti-cancer drug; (ii) subsequently administering the drug refill of the present invention to the subject; (iii) allowing the target on the drug refill to bind to the target recognition moiety on the drug delivery device, thereby delivering the pharmaceutical composition directly to the drug delivery device; (iv) allowing the pharmaceutical composition to be released from the drug delivery device to the desired location within the subject; (v) optionally, repeating steps (ii)-(iv); thereby maintaining or reducing the size of the tumor in the subject. The limitations regarding the Click Target and Click Prodrug and method of administration are rendered obvious as detailed for claim 1 above. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0076727 A1 (previously cited on PTO-892; herein after referred to as “McBride”), non-patent literature by Raave et. al. (Journal of Controlled Release, 2018, 274, 1-8; herein after referred to as “Raave”), US 10,730,976 B2 (herein after referred to as “Klein”), US 2016/0106856 A1 (previously cited on PTO-892; herein after referred to as “Castaigne”), and US 2016/0220686 A1 (previously cited on PTO-892; herein after referred to as “Brundo”). as applied to claims 1, 6-8, 10-11, 13-16, and 21-27 above, and further in view of WO 2018/045058 A1 (previously cited on PTO-892; herein after referred to as “Goldberg”).
The limitations regarding the Click Target and Click Prodrug, method of administration, the limitation(s) regarding the tissue binding moiety, and the use of the methods for the treatment of a tumor are made obvious by McBride, Raave, Klein, Castaigne, and Brundo as detailed above. However, none of the cited references teach or suggest surgical resection of the tumor or a portion thereof prior to administration of the Click Target and Click Prodrug. This deficiency is remedied by Goldberg.
Goldberg teaches drug delivery compositions and devices useful for the treatment and/or prevention of cancer and metastatic tumors (Abstract). Goldberg further teaches drug delivery compositions and devices comprising a biomaterial (e.g., a hydro gel) and an activator of innate immune response (e.g., a STING agonist) in addition to drug delivery compositions and devices that further comprise one or more additional activators of adaptive immune response wherein the activator of adaptive immune response is an antibody (e.g., anti-PD-1 antibody, anti-PD-LI antibody, anti-CTLA-4 antibody, agonist anti-CD137 antibody), a bispecific antibody (e.g., a bifunctional fusion-protein targeting PD-Ll and TGFβ), an antibody-drug conjugate (e.g., trastuzumab emtansine, inotuzumab ozogamicin), or a small molecule (e.g., celecoxib, bortezomib) (Paragraphs 0006-00011). In certain embodiments, the methods further comprise implanting the drug delivery compositions after surgical resection of a tumor and/or comprise implanting the drug delivery compositions at the site of tumor resection (Paragraph 00017).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to further modify the method(s) rendered obvious above to further include resection of a tumor prior to administering the Click Target and Click Prodrug because Goldberg indicates that after surgical resection of a tumor or portion thereof drug delivery is still desirable and useful in the treatment of cancer and metastatic tumors.
Double Patenting - Withdrawn
Claims 1, 6-8, 10-11, 13-16, 21-23, and 27 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of copending Application No. 18/032,149 (herein after referred to as “’149”) in view of McBride.
Claims 24-26 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of ‘149 and McBride and in further view of Castaigne.
Claim 29 was provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of ‘149, McBride, and Castaigne and in further view of Goldberg.
Claims 32-33 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of ‘149, McBride, and Castaigne and in further view of Hussain.
Claim 34 was provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of ‘149, McBride, Castaigne, and/or Goldberg and in further view of Hussain.
It is noted that independent claims 1, 27, and 29 have been amended to require linking groups in the both the Click Target and the Click Prodrug; as argued by Applicant in Remarks (see Pages 9-10 and 13 and arguments presented in the 103 section above), McBride nor ‘149 disclose linker components in both the Click Target and Click Prodrug. Additionally, claims 32-34 have been cancelled rendering their rejections under nonstatutory double patenting moot. As such, the above-listed claim rejections under nonstatutory double patenting are withdrawn.
Double Patenting - New
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 1, 6-8, 10-11, 13-16, and 21-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 10, and 12-22 of copending Application No. 18/032,149 (herein after referred to as “’149”) in view of US 2012/0076727 A1 (previously cited on PTO-892; herein after referred to as “McBride”), US 2016/0106856 A1 (previously cited on PTO-892; herein after referred to as “Castaigne”), and US 2016/0220686 A1 (previously cited on PTO-892; herein after referred to as “Brundo”).
Claim 1 of ‘149 is drawn to a method for delivering an active agent to a target tissue in a subject, the method comprising contacting the target tissue with a therapeutically effective amount of a compound defined by Formula I (X – L1 – A) wherein X represents a tissue binding moiety, L1 is absent or represents a linking group, and A represents an active agent wherein the tissue binding moiety comprises a functional group capable of chemically reacting with the target tissue to form a covalent bond. Claims 2-5 and 10 are drawn to additional limitations regarding the tissue binding moiety that comprises a functional group (e.g., sulfo-NHS group) that is capable of forming a covalent bond with the target tissue (e.g., through ECM proteins such as collagen). Claim 12 is drawn to L1 representing a cleavable linker selected from the group consisting of a hydrolytically cleavable linker, a photocleavable linker, and an enzymatically cleavable linker. Claims 13-19 are drawn to limitations regarding group A; group A can be a diagnostic or therapeutic agent. Claim 20 is drawn to the target tissue comprising a solid tumor and claim 21 is drawn to the step of contacting the target tissue wherein said contacting comprises injecting the compound of Formula I into the target tissue. Claim 22 is drawn to a method of maintaining or reducing the size of a tumor in a subject, the method comprising injecting into the tumor a therapeutically effective amount of a compound defined by Formula I (X – L1 – A) wherein X represents a tissue binding moiety, L1 is absent or represents a linking group, and A represents an active agent thereby maintaining or reducing the size of the tumor in the subject wherein the tissue binding moiety comprises a functional group capable of chemically reacting with the target tissue to form a covalent bond. It is noted that the claims of ‘149 are drawn exclusively to Formula I (X – L1 – A), and not a Click Target and Click Prodrug as required by the instant claims.
With regard to instant claim 1, McBride compositions and 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 (Abstract). The click chemistry involves the reaction of a targeting molecule (i.e., Click Target), such as an antibody or antigen-binding antibody fragment, comprising an activating moiety such as a cyclooctyne, a nitrone or an azide group, with a targetable construct (i.e., Click Prodrug) comprising a corresponding reactive moiety, such as an azide, nitrone or cyclooctyne; where the targeting molecule comprises a cyclooctyne, the targetable construct will comprise an azide or nitrone or similar reactive moiety and where the targeting molecule comprises an azide or nitrone, the targetable construct will comprise a cyclooctyne, alkyne or similar reactive moiety (Paragraph 0016). The click chemistry reaction allows formation of a very stable covalent bond between the targeting molecule and targetable construct (Id.). The click chemistry reaction may occur in vitro to form a highly stable, labeled targeting molecule that is then administered to a subject or, in preferred alternative embodiments,
the click chemistry reaction may occur in vivo (Paragraph 0017). Initially, an antibody or other targeting molecule comprising an activating moiety is administered to a subject and allowed to localize to a target cell, tissue, pathogenic organism or other target (i.e., contact target tissue) and subsequently a targetable construct comprising an appropriate reactive moiety is administered to the subject wherein the reaction between the activating moiety and reactive moiety is sufficiently specific that the targetable construct does not bind to other, non-activated molecules within the subject and the targetable construct irreversibly binds to the targeting molecule localized in the target tissue (Id.). McBride discloses that targetable constructs can be of diverse structure and are selected not only for the availability of an antibody or fragment that binds with high affinity to the targetable construct, but also for rapid in vivo clearance when used within the pre-targeting method and bispecific antibodies (bsAb) or multispecific antibodies and that subunits of the targetable construct may be chosen which have opposite solution properties, for example, peptides, which contain amino acids, some of which are hydrophobic and some of which are hydrophilic; peptides having as few as two amino acid residues, preferably two to ten residues, may be used and may also be coupled to other moieties, such as chelating agents, wherein the linker should be a low molecular weight conjugate, preferably having a molecular weight of less than 50,000 daltons, and advantageously less than about 20,000 daltons, 10,000 daltons or 5,000 daltons (Paragraphs 0062-0063). McBride also discloses that targeting moieties are not limited to antibodies or antibody fragments, but can be any molecules that binds specifically or selectively to a cellular target associated with or diagnostic of a disease state or other condition (Paragraph 0293). Example 17 explicitly discloses the use of a somatostatin analogue peptide for direct targeting od somatostatin receptor expressing tumors (Paragraph 0307). Thus, McBride teaches: (i) a Click Target, wherein the tissue binding moiety is an antibody or any other molecule that can specifically target a disease or diagnostic state/condition, wherein no linker is present, and the click motif can be cyclooctyne, nitrone or azide; (ii) the Click Prodrug, wherein the active agent is a therapeutic or diagnostic agent, a linker may be a peptide, and the second click motif is cyclooctyne, nitrone or azide and is complementary to the click motif of the Click Target; and (iii) that the two click motifs react to form a covalent bond and the Click Target and Click Prodrug may be administered separately such that the Click Target localizes to the tissue/target then the Click Prodrug is administered and the click reaction occurs in vivo at the target tissue. However, McBride does not teach or suggest utilizing Click Targets or Click Prodrugs that each comprise linkers. This deficiency is remedied by Castaigne and Brundo.
Castaigne teaches antibody-polypeptide-cytotoxin conjugates and methods of making, packaging, and using the conjugates (Abstract). More specifically, Castaigne teaches multiple ways in which an antibody may be conjugated to a polypeptide that has, in turn, been conjugated to a cytotoxic agent including: conjugation by click chemistry wherein a cyclooctyne linked to the antibody moiety reacts with an azide group at the N-terminus of the polypeptide wherein the reactive substituents could also be reversed (Paragraph 0021; Figure 2a). Configurations for the conjugates are also disclosed, such that each part of a given conjugate, including the antibody moiety, cytotoxic agent, linker, and polypeptide, can be selected independently; any of the linkers described can be used to conjugate any of the polypeptides and cytotoxic agents described to any of the antibody moieties described provided that the component parts to be linked include compatible reactive substituents (Paragraph 0057). More specifically, a given protein conjugate can include a single antibody moiety, but may include two or more (e.g., 2, 3, or 4) that are identical to one another or different from one another wherein different antibody moieties may specifically bind the same target or different targets (Paragraph 0058). Additionally, component parts of the present conjugates can be configured in a variety of ways, such that the conjugate can assume an essentially linear form with an antibody moiety being linked to at least one polypeptide linked to a cytotoxic agent, or the conjugate can have a branched configuration as seen in dendrimers, with one or more branches extending at some point from the antibody moiety (Paragraph 0058). Castaigne also teaches, with regard to linkers, that a given linker within the invention compositions can provide a cleavable linkage (e.g., a thioester linkage) or a non-cleavable linkage (e.g., a maleimide linkage) and that a cytotoxic protein can be bound to a linker that reacts with modified free amines, which are present at lysine residues within the polypeptide and/or at the amino-terminus of the polypeptide and that useful linkers in the conjugates of the invention can comprise a group that is reactive with a primary amine on the polypeptide or modified polypeptide to which the antibody moiety is conjugated (Paragraph 0068). Thus, Castaigne teaches: (i) the Click Target, wherein the tissue binding moiety is an antibody, a linker may be present, and the click motif is cyclooctyne; (ii) the Click Prodrug, wherein the active agent is a cytotoxic agent, a linker may be present, and the second click motif is an azide; and (iii) that the two click motifs react to form a covalent bond ultimately resulting in the antibody-polypeptide-cytotoxin conjugates of the invention.
Brundo teaches refillable drug delivery systems, as well as methods of refilling the systems, and methods of using them to treat diseases (Abstract). More specifically, Brundo teaches a system comprising a drug delivery device and a drug refill, wherein the drug delivery device comprises a carrier and a target recognition moiety and is suitable for implantation in a desirable location within a subject; wherein the drug refill comprises a pharmaceutical composition and a target; wherein the target and the target recognition moiety form a two-component binding pair; wherein the drug refill is mobile until the target on the drug refill binds to the target recognition moiety on the drug delivery device, and wherein upon binding of the target to the target recognition moiety, the drug refill delivers the pharmaceutical composition directly to the drug delivery device (Paragraph 0006). Brundo further teaches that in some embodiments the target comprises a biorthogonal functional group and the target recognition moiety comprises a complementary functional group, wherein the bioorthogonal functional group is capable of chemically reacting with the complementary functional group to form a covalent bond wherein the biorthogonal functional group is capable of reacting by click chemistry with the complementary functional group (Paragraph 0027). The invention also provides a method of maintaining or reducing the size of a tumor in a subject in need thereof, comprising the steps of: (i) administering the drug delivery device of the present invention to a desired location within the subject, wherein the pharmaceutical composition comprises an anti-cancer drug; (ii) subsequently administering the drug refill of the present invention to the subject; (iii) allowing the target on the drug refill to bind to the target recognition moiety on the drug delivery device, thereby delivering the pharmaceutical composition directly to the drug delivery device; (iv) allowing the pharmaceutical composition to be released from the drug delivery device to the desired location within the subject; and (v) optionally repeating steps (ii)-(iv) thereby maintaining or reducing the size of the tumor in the subject wherein the desired location is a tumor site or site away from the tumor site (Paragraphs 0056-0057) and/or wherein the desired location is a tissue within a subject or a site away from the tissue (Paragraph 0060). Thus, Brundo teaches administering a device to a desired location/tissue and subsequently administering a drug refill capable of reacting with the device via click chemistry to release a pharmaceutical composition to said desired location/tissue (i.e., contacting a tissue with a device then contacting the tissue with a drug refill wherein the device and drug refill chemically react via click chemistry). Brundo teaches that the pharmaceutical composition of the invention is attached to the target of the invention via a cleavable linker wherein examples of cleavable linkers include a hydrolysable linker, a pH cleavage linker, an enzyme cleavable linker, or any cleavable linker as described (Paragraph 0290).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to deliver an active agent to a target tissue in a subject comprising (i) contacting the target tissue with a Click Target consisting of Formula I and (ii) contacting the target tissue with a Click Prodrug defined by Formula II. 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; thus one of ordinary skill in the art would have been motivated to try applying the click-chemistry based drug delivery methods/compositions of McBride wherein said methods utilize targeting agents that can specifically target ECM proteins.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, it is noted that:
(1) 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 the claims of ‘149 are drawn to targeting moieties that are configured to chemically react with a functional group in an extracellular matrix protein in the target tissue thereby forming a direct (i.e., covalent) bond with the target tissue.
(2) McBride and the claims of ‘149 are drawn to 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.
(3) The claims of ‘149 are drawn to a targeting moiety that covalently attaches to the target (i.e., an ECM protein). 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).
Thus, 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 claimed in ‘149, wherein the tissue binding moiety is capable of chemically reacting with a primary amine in an extracellular matrix protein, 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. 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 and immobilization of the Click Target to the target tissue via covalent bond with proteins of the ECM is claimed by ‘149; 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.
With regard to instant claim 6, it is noted that claims 2-5 and 10 of ‘149 are drawn to additional limitations regarding the tissue binding moiety that comprises a functional group (e.g., sulfo-NHS group) that is capable of forming a covalent bond with the target tissue (e.g., through ECM proteins such as collagen). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to instant claims 7-8 and 10-11, it is noted that McBride teaches that the click chemistry of the invention involves the reaction of a targeting molecule (i.e., Click Target), such as an antibody or antigen-binding antibody fragment, comprising an activating moiety such as a cyclooctyne, a nitrone or an azide group, with a targetable construct (i.e., Click Prodrug) comprising a corresponding reactive moiety, such as an azide, nitrone or cyclooctyne; where the targeting molecule comprises a cyclooctyne, the targetable construct will comprise an azide or nitrone or similar reactive moiety and where the targeting molecule comprises an azide or nitrone, the targetable construct will comprise a cyclooctyne, alkyne or similar reactive moiety (Paragraph 0016; emphasis added). McBride also discloses that the Diels-Alder reaction has also been used for in vivo labeling; for example, a trans-cyclooctene-labeled CC49 antibody was administered to mice bearing colon cancer xenografts, followed 1 day later by injection of 111In-labeled tetrazine probe wherein the reaction of radiolabeled probe with tumor localized antibody resulted in pronounced radioactivity localized in the tumor, as demonstrated by SPECT imaging of live mice three hours after injection of radiolabeled probe, with a tumor-to-muscle ratio of 13:1 and the results confirmed the in vivo chemical reaction of the TCO and tetrazine-labeled molecules (Paragraph 0053). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to instant claim 13, it is noted that claim 12 of ‘149 is drawn to L1 representing a cleavable linker selected from the group consisting of a hydrolytically cleavable linker, a photocleavable linker, and an enzymatically cleavable linker. Additionally, Brundo suggests the use of cleavable linkers (see Paragraph 0290). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to instant claims 14-16, it is noted that claims 13-19 of ‘149 are drawn to limitations regarding group A; group A can be a diagnostic or therapeutic agent wherein said therapeutic agent may have the functions as required by instant claim 16. Additionally, McBride teaches compositions and 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 (Abstract). Therapeutic agents are preferably selected from the group consisting of a radionuclide, an immunomodulator, an antiangiogenic agent, a cytokine, a chemokine, a growth factor, a hormone, a drug, a prodrug, an enzyme, an oligonucleotide, a pro-apoptotic agent, an interference RNA, a photoactive therapeutic agent, a cytotoxic agent, which may be a chemotherapeutic agent or a toxin, and a combination thereof; the drugs of use may possess a pharmaceutical property selected from the group consisting of antimitotic, anti-kinase, alkylating, antimetabolite, antibiotic, alkaloid, anti-angiogenic, proapoptotic agents and combinations thereof (Paragraphs 0127). Specific exemplary therapeutic agents are provided in Paragraphs 0128-0136, wherein said exemplary therapeutic agents are known to be the types of drugs/have the functions listed in instant claim 16. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to instant claim 21, it is noted that claim 20 of ‘149 is drawn to the target tissue comprising a solid tumor. Additionally, McBride teaches that the methods and compositions described may be used to detect or treat malignant or premalignant conditions wherein such uses are indicated in conditions known or suspected of preceding progression to neoplasia or cancer, in particular, where non-neoplastic cell growth consisting of hyperplasia, metaplasia, or most particularly, dysplasia has occurred (Paragraph 0154). Such conditions can include, for example, solid tumors (Paragraph 0157). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to instant claims 22-23, it is noted that claim 21 of ‘149 is drawn to the step of contacting the target tissue wherein said contacting comprises injecting the compound of Formula I into the target tissue. Additionally, McBride teaches that the preferred route for administration of the compositions described herein is parenteral injection; injection may be subcutaneous, intramuscular, intravenous, intraarterial, intralymphatic, intrathecal, or intracavitary (Paragraph 0141). Various embodiments of the methods and/or compositions of the invention may concern one or more labeled peptides to be administered to a subject wherein administration may occur by any route known in the art, including but not limited to oral, nasal, buccal, inhalational, rectal, vaginal, topical, orthotopic, intradermal, subcutaneous, intramuscular, intraperitoneal, intraarterial, intrathecal or intravenous injection; where, for example, labeled peptides are administered in a pretargeting protocol, the peptides would preferably be administered via IV (Paragraph 0147). Thus, McBride suggests delivery of, for example, the Click Target for contact with the target tissue via injection. Furthermore, one of ordinary skill in the art would recognize that said Click Target, and subsequently the Click Prodrug, could be delivered directly to the target tissue (e.g., solid tumor) via any acceptable route, and/or be administered systemically, such as by IV, as suggested by McBride. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
PNG
media_image1.png
144
406
media_image1.png
Greyscale
With regard to instant claims 24 and 26, Castaigne teaches dendrimeric conjugates that can be structured as in Formula I (shown below), wherein D is an antibody, Am is a polypeptide of the invention, Xcore and Xbranch join the parts of the conjugate and are linkers, Xnth in one of n surface branches, and D’ is a cytotoxic agent.
Various polypeptides conjugated to cytotoxic agents can be conjugated to/react with a single antibody, such that the dendrimeric conjugate can include multiple surface functionalities to which multiple polypeptides and/or cytotoxins can be conjugated (Paragraph 0061). Thus, one Click Target (i.e., antibody) can be reacted with multiple polypeptides/cytotoxic agents (i.e., Click Prodrugs) that can be different. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to instant claim 25, Castaigne teaches that single or multiple administrations of the pharmaceutical compositions of the invention can be carried out with dosage levels and the timing or pattern of administration being selected by the treating physician such that the dose and administration schedule can be determined and adjusted based on the severity of the disease or condition in the subject, which may be monitored throughout the course of treatment according to the methods commonly practiced by clinicians or other skilled healthcare professionals (Paragraph 0108). As evidenced by the references, it is also noted administration doses and administration schedules were recognized as treatment variables which achieve a recognized result and as set forth in MPEP 2144.05: “A particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation. In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977). It is a common objective in the art to optimize result effective variables, so as achieve optimal effect and maximal benefit. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” (citations omitted)). Therefore, any optimization of administration doses and administration schedules would be seen as routine optimization. Therefore, one of ordinary skill is the art could optimize administration of the Click Prodrugs such that the second Click Prodrug is administered at least one week after administration of the first Click Prodrug and thus the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to instant claim 27, it is noted that claim 22 of ‘149 is drawn to a method of maintaining or reducing the size of a tumor in a subject, the method comprising injecting into the tumor a therapeutically effective amount of a compound defined by Formula I (X – L1 – A) wherein X represents a tissue binding moiety, L1 is absent or represents a linking group, and A represents an active agent thereby maintaining or reducing the size of the tumor in the subject wherein the tissue binding moiety comprises a functional group capable of chemically reacting with the target tissue to form a covalent bond. Additionally, Brundo teaches that invention is directed to method of maintaining or reducing the size of a tumor (i.e., treating a tumor) in a subject in need thereof comprising the steps of: (i) administering the drug delivery device of the present invention to a desired location within the subject, wherein the pharmaceutical composition comprises an anti-cancer drug; (ii) subsequently administering the drug refill of the present invention to the subject; (iii) allowing the target on the drug refill to bind to the target recognition moiety on the drug delivery device, thereby delivering the pharmaceutical composition directly to the drug delivery device; (iv) allowing the pharmaceutical composition to be released from the drug delivery device to the desired location within the subject; (v) optionally, repeating steps (ii)-(iv); thereby maintaining or reducing the size of the tumor in the subject. The limitations regarding the Click Target and Click Prodrug and method of administration are rendered obvious as detailed for claim 1 above. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Claim 29 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 10, and 12-22 of ‘149, US 2012/0076727 A1 (previously cited on PTO-892; herein after referred to as “McBride”), US 2016/0106856 A1 (previously cited on PTO-892; herein after referred to as “Castaigne”), and US 2016/0220686 A1 (previously cited on PTO-892; herein after referred to as “Brundo”) as applied to claims 1, 6-8, 10-11, 13-16, and 21-27 above, and in further view of WO 2018/045058 A1 (previously cited on PTO-892; herein after referred to as “Goldberg”).
The limitations regarding the Click Target and Click Prodrug, method of administration, the limitation(s) regarding the tissue binding moiety, and the use of the methods for the treatment of a tumor are made obvious by ‘149, McBride, Castaigne, and Brundo as detailed above. However, none of the cited references teach surgical resection of the tumor or a portion thereof prior to administration of the Click Target and Click Prodrug. This deficiency is remedied by Goldberg.
Goldberg teaches drug delivery compositions and devices useful for the treatment and/or prevention of cancer and metastatic tumors (Abstract). Goldberg further teaches drug delivery compositions and devices comprising a biomaterial (e.g., a hydro gel) and an activator of innate immune response (e.g., a STING agonist) in addition to drug delivery compositions and devices that further comprise one or more additional activators of adaptive immune response wherein the activator of adaptive immune response is an antibody (e.g., anti-PD-1 antibody, anti-PD-LI antibody, anti-CTLA-4 antibody, agonist anti-CD137 antibody), a bispecific antibody (e.g., a bifunctional fusion-protein targeting PD-Ll and TGFβ), an antibody-drug conjugate (e.g., trastuzumab emtansine, inotuzumab ozogamicin), or a small molecule (e.g., celecoxib, bortezomib) (Paragraphs 0006-00011). In certain embodiments, the methods further comprise implanting the drug delivery compositions after surgical resection of a tumor and/or comprise implanting the drug delivery compositions at the site of tumor resection (Paragraph 00017).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to further modify the method(s) rendered obvious above to further include resection of a tumor prior to administering the Click Target and Click Prodrug because Goldberg indicates that after surgical resection of a tumor or portion thereof drug delivery is still desirable and useful in the treatment of cancer and metastatic tumors.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642