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 .
Election/Restrictions
Applicant’s election with traverse of Group I (claims 1, 4-6, 9, 18-19, 22-24, 34, 36, 47, 77-78, 85, 171-173, 175-177, 181-182, 228-229, 259-260, and 262) and the below-listed species in the reply filed on 04/07/2026 is acknowledged.
Elected Species:
Formula XI of claim 1;
Formula VI of claim 173;
A targeting moiety that is an antibody;
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The full drug-conjugate structure of compound T-117 (reproduced below).
With regard to Applicant’s traversal of the Restriction/Election requirement, Applicant argues on Pages 30-31 of Remarks (04/07/2026) that the method of Group II specifically claims treating cancer, autoimmune disease, or inflammatory disease using the conjugate of Group I, and that examining both Groups together would not impose a serious search or examination burden.
Applicant’s arguments have been fully considered, but are deemed not persuasive.
With regard to Applicant’s arguments, it is specifically noted that restriction under 35 U.S.C. 121 requires independent and distinct analysis. As indicated in the previous Office Action (01/12/2026), Inventions I and II were identified as being related as product and process of use; the inventions are distinct if either or both of the following can be shown: (1) the process for using the product as claimed can be practiced with another materially different product or (2) the product as claimed can be used in a materially different process of using that product. See MPEP § 806.05(h). As previously presented, cancers, autoimmune diseases, and inflammatory disease can be treated with materially different products such as small molecules, fusion proteins, chemotherapy, radiation, surgery, etc. Thus, the process for using the product as claimed can be practiced with another materially different product, which meets the requirement for the inventions being independent and distinct. Furthermore, regarding search/examination burden, it was identified that the groups of invention have different classifications, acquiring separate status in the art due to recognized divergent subject matter and requiring a different field of search, and each group of invention is likely to raise different issues under 35 USC 101 and 112, first paragraph.
It is noted that no specific arguments regarding the species election requirement were presented.
In view of the above, the Restriction/Election requirement is deemed proper and is therefore made FINAL.
Claim Status
Claims 2-4, 7-22, 24-35, 37-76, 79-84, 86-170, 174, 178-180, 183-227, 230-258, 261, 263-264, and 266-268 have been cancelled; claims 1, 23, 36, 85, 176, and 229 have been amended; and claims 269-272 have been newly added, as requested in the amendment filed on 04/07/2026. Following the amendment, claims 1, 5-6, 23, 36, 77-78, 85, 171-173, 175-176, 181-182, 228-229, 259-260, 262, 265, and 269-272 are pending in the instant application.
Claim 265 stands as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, and claims 5-6, 36, 171, 175-176, 269, and 270-271 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species invention, in the Response filed 04/07/2026, there being no allowable generic or linking claim.
Claims 1, 23, 77-78, 85, 172-173, 181-182, 228-229, 259-260, 262, and 272 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1, 23, 77-78, 85, 172-173, 181-182, 228-229, 259-260, 262, 270, and 272 have an effective filing date of December 21, 2021 corresponding to PRO 63/292,101.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/15/2023, 05/31/2023, 06/14/2023, 06/23/2023, and 04/15/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings are objected to because Figure 1B contains text that is illegible. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because it contains the legal phraseology "said drugs or toxins". A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 23, 77-78, 172, 228-229, 259, 262, and 272 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "promotes the release of Q" and "displace Q-(L’)w" (see Page 4 of claims). There is insufficient antecedent basis for the reference to “Q” in these limitations of the claim; Q is not in any of Formulas (IX), (X), or (XI), and Q is only identified as Formula (IV) at the end of claim 1. The lack of clarity arises because the claim refers to “Q”, but the claim contains no earlier recitation or limitation of “Q” and thus it is unclear as to what element the limitation(s) is/are making reference to. Thus, as claim 1 currently reads there is a lack of antecedent basis with reference to limitations reciting “Q”.
With regard to claim 77, the claim recites “[a] targeted drug conjugate comprising the drug conjugate of claim 1 and a targeting moiety”; it is unclear as to how and where the recited targeting moiety is incorporated into the structure(s) of claim 1. It is unclear as to which functional group(s) are capable of conjugating a targeting moiety to the drug-conjugate, and one of ordinary skill in the art therefor could not reasonably ascertain the metes and bounds of the claim.
With regard to claim 228, the claim recites “[a] drug conjugate comprising the compound of claim 182 and a linker group”; it is unclear as to how and where the recited linker group is incorporated into the structure(s) of claim 182. It is unclear as to which functional group(s) are capable of conjugating a linking group to the compound, and one of ordinary skill in the art therefor could not reasonably ascertain the metes and bounds of the claim.
Claim 229 recites the limitation "displace Q-(L’)w" (see Page 25 of claims). There is insufficient antecedent basis for the reference to “Q” in this limitation of the claim; Q is not in any of Formulas (IX), (X), or (XI), and Q is only identified as Formula (IV) at the end of claim 229. The lack of clarity arises because the claim refers to “Q”, but the claim contains no earlier recitation or limitation of “Q” and thus it is unclear as to what element the limitation is making reference to. Thus, as claim 229 currently reads there is a lack of antecedent basis with reference to limitations reciting “Q”.
With regard to claim 259, the claim recites “[a] targeted drug conjugate comprising the drug conjugate of claim 228 and a targeting moiety”; it is unclear as to how and where the recited targeting moiety is incorporated into the structure(s) of claim 228; it is noted that the linker group of claim 228 renders claim 228 itself ambiguous, and the recitation of the targeting moiety of claim 259 adds additional ambiguity. It is unclear as to which functional group(s) are capable of conjugating a targeting moiety to the drug conjugate; for example, the targeting moiety, as the claim is currently written, could be conjugated directly to the compound(s) of independent claim 85 or could be conjugated to the recited linker of claim 228, wherein the linker attachment/position is also ambiguous. Thus, one of ordinary skill in the art therefor could not reasonably ascertain the metes and bounds of the claim.
Claims 23, 78, 172, and 272 are included in this rejection as they depend from and/or incorporate claim 1. Claim 262 is included in this rejection as it depends from and/or incorporates claims 228 and 259.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 23, 77-78, 85, 172-173, 181-182, 228-229, 259-260, 262, and 272 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO 2021/260438 A1 (herein after referred to as “Park”).
Park teaches antibody-drug conjugates (ADCs) wherein one or more active agents are conjugated to an anti-B7-H3 antibody through a linker; the linker may comprise a unit that covalently links active agents to the antibody (Abstract). The ADCs of the invention are represented by Formula I or a pharmaceutically acceptable salt or solvate thereof, wherein Formula I corresponds to Ab-(G)n wherein: (i) Ab is, generally, an anti-B7-H3 antibody, (ii) G is, independently, a chemical moiety comprising one or more active agent and a linker, wherein the linker covalently links Ab to the active agent(s), and (iii) n is an integer between 1 and 20 (Page 7). Each G, independently, is a group having the structure of Formula II as reproduced below (see Pages 9-10):
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669
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Notably, linking group Z’ is selected from the structures at Pages 16-18, wherein one of said structures is:
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104
408
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108
290
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wherein a” is the bond between Z’ and Ar of Formula II, b” is the bond between Z’ and Ab, Rza is H or methyl, and Z” is selected from:
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414
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which may be positioned in any direction. The Examples of Park disclose the full structures of various ADC species meeting general Formula I, wherein G comprises Formula II, as defined above; notably Table 15 lists the monomer derivatives that were synthesized via a similar synthetic route as explicitly described in Example 4.11.6, wherein on such derivative is that of compound T-217, reproduced below (see Pages 234-236):
Notably, conjugation of an antibody to yield an ADC comprising T-217 above is described in Example 6.2 at Pages 237-238, wherein conjugation of an antibody occurs via the maleimide group. Thus, Park explicitly discloses a drug conjugate as described by instant claim 1, wherein
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T-217 of Park corresponds to a drug conjugate is represented by instant Formula (XI):
wherein Ar is an aryl, Y’ is -(CRb2)yO- wherein y = 0, TG is a monosaccharide, X is -O-, (L’)w is not present as w = 0, Cy is an aryl (i.e., an anisole), Ra” is an alkoxy (i.e., methoxy) group and
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p = 1, Rb” is not present as d is 0, X’ is Cl, L”’ is a bond, X” is -O-, Gly is a monosaccharide, and the structures of DNA binding domain DBD and coupling group Z’ are as shown below, wherein Rza of Z’ is a methyl group:
As such, Park anticipates the instantly elected species corresponding to instant drug conjugate compound T-117. Park further anticipates drug conjugates comprising a targeting moiety (TM as designated in instant claim 78; see Formula (XIV)) that is an antibody (i.e., an anti-B7-H3 antibody). It is further noted that compound T-217 of Park comprises a group corresponding to instantly recited group Q corresponding to instant Formula (IV) (see claim 1) wherein, as provided above, Cy is an aryl (i.e., an anisole), Ra” is an alkoxy (i.e., methoxy) group, X’ is Cl, L”’ is a bond, X” is -O-, Gly is a monosaccharide, and the structures of DNA binding domain DBD has a structure as provided above. Thus, Park discloses the structural element of instant
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DBD-(L”’)r-X”-Gly of the structure:
wherein Y” is N, q = 0, L”’ is a bond, X” is -O-, and Gly is a monosaccharide. Park further discloses a composition (e.g., a pharmaceutical composition) comprising an antibody-drug conjugate of the invention; the compositions and methods of the disclosure may be utilized to treat an individual in need thereof, wherein the individual may be a mammal such as a human, or a non-human mammal wherein, when administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier, which can include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters (Page 96). Thus, Park anticipates instant claims 1, 23, 77-78, 85, 172-173, 181-182, 228-229, 259-260, 262, and 272.
Claims 1, 23, 77-78, 85, 172-173, 181-182, 228-229, 259-260, 262, and 272 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 12,168,060 B2 (herein after referred to as “Kim”).
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Kim teaches antibody-drug conjugates (ADCs) wherein one or more active agents are conjugated to an anti-B7-H3 antibody through a linker; the linker may comprise a unit that covalently links active agents to the antibody (Abstract). The ADCs of the invention are represented by Formula I or a pharmaceutically acceptable salt or solvate thereof, wherein Formula I corresponds to Ab-(G)n wherein: (i) Ab is, generally, an anti-B7-H3 antibody, (ii) G is, independently, a chemical moiety comprising one or more active agent and a linker, wherein the linker covalently links Ab to the active agent(s), and (iii) n is an integer between 1 and 20 (Column 6). Each G, independently, is a group having the structure of Formula II as reproduced below (see Column 10):
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Notably, linking group Z’ is selected from the structures at Columns 15-20, wherein one of said structures is:
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wherein a” is the bond between Z’ and Ar of Formula II, b” is the bond between Z’ and Ab, Rza is H or methyl, and Z” is selected from:
which may be positioned in any direction. The Examples of Kim disclose the full structures of various ADC species meeting general Formula I, wherein G comprises Formula II, as defined above; notably Table 15 lists the monomer derivatives that were synthesized via a similar synthetic route as explicitly described in Example 4.11.6, wherein on such derivative is that of compound T-217, reproduced below (see Columns 461-466):
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Notably, conjugation of an antibody to yield an ADC comprising T-217 above is described in Example 6.2 at Columns 468-469, wherein conjugation of an antibody occurs via the maleimide group. Thus, Kim explicitly discloses a drug conjugate as described by instant claim 1, wherein T-217 of Kim corresponds to a drug conjugate is represented by instant Formula (XI):
wherein Ar is an aryl, Y’ is -(CRb2)yO- wherein y = 0, TG is a monosaccharide, X is -O-, (L’)w is not present as w = 0, Cy is an aryl (i.e., an anisole), Ra” is an alkoxy (i.e., methoxy) group, X’ is Cl, L”’ is a bond, X” is -O-, Gly is a monosaccharide, and the structures of DNA binding domain
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DBD and coupling group Z’ are as shown below, wherein Rza of Z’ is a methyl group:
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As such, Kim anticipates the instantly elected species corresponding to instant drug conjugate compound T-117. Kim further anticipates drug conjugates comprising a targeting moiety (TM as designated in instant claim 78; see Formula (XIV)) that is an antibody (i.e., an anti-B7-H3 antibody). It is further noted that compound T-217 of Kim comprises a group corresponding to instantly recited group Q corresponding to instant Formula (IV) (see claim 1) wherein, as provided above, Cy is an aryl (i.e., an anisole), Ra” is an alkoxy (i.e., methoxy) group and p = 1, Rb” is not present as d is 0, X’ is Cl, L”’ is a bond, X” is -O-, Gly is a monosaccharide, and the structures of DNA binding domain DBD has a structure as provided above. Thus, Kim discloses the structural element of instant DBD-(L”’)r-X”-Gly of the structure:
wherein Y” is N, q = 0, L”’ is a bond, X” is -O-, and Gly is a monosaccharide. Kim further discloses a composition (e.g., a pharmaceutical composition) comprising an antibody-drug conjugate of the invention; the compositions and methods of the disclosure may be utilized to treat an individual in need thereof, wherein the individual may be a mammal such as a human, or a non-human mammal wherein, when administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier, which can include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters (Columns 103-104). Thus, Kim anticipates instant claims 1, 23, 77-78, 85, 172-173, 181-182, 228-229, 259-260, 262, and 272.
Claims 1, 23, 77-78, 85, 172-173, 181-182, 228-229, 259-260, 262, and 272 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2025/0121087 A1 (herein after referred to as "Seo").
It is noted that Seo is a divisional of the above-listed Kim patent. As such, the disclosure of Seo is the same as that of the Kim patent and therefore anticipates instant claims 1, 23, 77-78, 85, 172-173, 181-182, 228-229, 259-260, 262, and 272 for the same reasons of record detailed in the rejection above.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 23, 77-78, 85, 172-173, 181-182, 228-229, 259-260, 262, and 272 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/008441 A1 (herein after referred to as "Woo") in view of non-patent literature by Boger et. al. (J. Org. Chem., 1996, 61, 1710-1729; herein after referred to as "Boger") and non-patent literature by Tranoy-Opalinski et. al. (European Journal of Medicinal Chemistry, 2014, 74, 302-313; herein after referred to as "Tranoy-Opalinski").
Woo teaches a compound including a cleavable linker, a use thereof, and an intermediate compound for preparing the same, and more particularly, the compound including a cleavable linker of the present invention may include an active agent (for example, a drug, a toxin, a ligand, a probe for detection, etc.) having a specific function or activity, a SO2 functional group which is capable of selectively releasing the active agent, and a functional group which triggers a chemical reaction, a physicochemical reaction and/or a biological reaction by external stimulation, and may further include a ligand (for example, oligopeptide, polypeptide, antibody, etc.) having binding specificity for a desired target receptor (Abstract). The invention provides conjugates of Formula (I’) corresponding to (D-L)n-(CB)cb, or a pharmaceutically acceptable salt thereof, wherein CB is a targeting moiety, cb and n are each integers having a value of 1 to 20, and wherein each D-L, independently, is a group having the structure of Formula (I”):
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wherein each Q, independently, is an active agent linked to L’ via a heteroatom (i.e., O or N), Z’ is a linking group; L’ is a spacer moiety attached to SO2 via a heteroatom selected from O, S, and N and is selected such that the cleavage of the bond between L’ and SO2 promotes cleavage of the bond between L’ and Q to release the active agent; X is -O-, -C(Rb)2-, or -N(Rc)-; Ar is a ring; Y’ is -CRb2N(Ra)-, -(CRb2)yO-, or -(CRb2)yS- positioned such that the N, O, or S atom is attached to TG if y is 1; X and Y’ are positioned on adjacent atoms of Ar; TG is a triggering group that, when activated, generates an N, O, or S atom capable of reacting with the SO2 to displace (Q)q-(L’)w and from a 5-6 membered ring including X-SO2 and the intervening atoms of Ar; q is an integer from 1 to 20; w/x/y are each independently an integer of 0 or 1; each Ra/Rc is independently hydrogen or a lower alkyl (i.e., C1-6 alkyl); and each Rb is independently hydrogen or a lower alkyl (i.e., C1-6 alkyl) or two Rb together with the atom to which they are attached form a 3-5 membered ring provided that when w = 0, q = 1 (Page 4). It is noted that Woo identifies a variety of possible triggering groups which are capable of being selectively cleaved, and may comprise a peptide, reactive moiety, and/or functional group that can be (i) hydrolyzed by an enzyme, (ii) cleaved under nucleophilic reagent conditions, (iii) cleaved under basic reagent conditions, (iv) cleaved by photo-irradiation, (v) cleaved by reducing agent conditions, (vi) cleaved using acidic conditions, and/or (vii) cleaved under oxidative conditions (see Paragraphs 0262-0271). A preferred embodiment comprises a triggering group that is a saccharide that can be cleaved under acidic or enzymatic conditions (Paragraph 0271); it is specifically noted that Woo identifies various groups capable of being hydrolyzed by an enzyme, including a moiety selected from a phosphodiester, a phospholipid, an ester, a β-galactose, a β-glucose, a fucose, an oligosugar, and the like which are capable of being hydrolyzed by an oxidoreductase, a transferase, a hydrolase, a lyase, an isomerase, a ligase, etc. (Paragraph 0264). More specifically, Woo indicates that (L’)w-(Q)q may have a structure selected from those on Pages 21-25, wherein one such structure comprises that reproduced below (see Page 23):
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wherein the * designates the position of the SO2 group. In some embodiments, the linker group connecting each CB and Ar (i.e., linking group Z’ as defined above) comprises:
wherein V may be a single bond, -O-, -S-, -NR21-, -C(O)NR22-, -NR23C(O)-, -NR24SO2-, or
-SO2NR25-; R21 to R25 may be each independently hydrogen, (C1-6) alkyl, (C1-6)alkyl(C6-20)aryl, or (C1-6)alkyl(C3-20) heteroaryl; r may be an integer having a value of 1 to about 10; p may be an integer having a value of 0 to about 10; q may be an integer having a value of 1 to about 10’ and L” may be a single bond (Pages 35-36). Additionally, with regard to linking group Z’, it is noted that typically, the linking group should be sufficiently hydrophilic to promote water-solubility
and discourage aggregation of the conjugate, such as by including moieties such as polyethylene glycol moieties, peptide sequences, charge-bearing moieties, etc. to balance the hydrophobic character of any alkyl chains that may be included; because it is often advantageous to prepare conjugates in a modular fashion, Z' may contain a linking unit, a functional group that results from the conjugation of one reactive moiety to another (Paragraph 0083). A full structure of compound D10 of the invention is provided at Page 186, and is reproduced below:
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wherein it is specifically noted that TG is a monosaccharide, the structure corresponding to (L’)w-(Q)q is indicated within the circle, and the structure corresponding to linking group Z’ is indicated within the rectangle. Thus, one of ordinary skill in the art would recognize that replacing the MMAF-containing (L’)w-(Q)q unit with the DNA alkylating agent below (as is within the scope of the invention; see Pages 21-25):
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then the resulting structure would be as shown below:
Thus, the scope of Woo encompasses the structure above, which reads on instant Formula (XI) wherein: wherein Ar is an aryl, Y’ is -(CRb2)yO- wherein y = 0, TG is a monosaccharide, X is
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-O-, (L’)w is not present as w = 0, Cy is an aryl, Ra”/ Rb” are not present as p and d are both 0, X’ is Cl, L”’ is a bond, X” is -O-, Gly is a monosaccharide, and the structures of DNA binding domain DBD and coupling group Z’ are as shown below, wherein Rza of Z’ is a hydrogen:
It is further noted that the ligand or targeting moiety (CB) as disclosed by Woo would be conjugated via the reactive maleimide group. Notably, the ligand or targeting moiety is
any molecular recognition element, which can undergo a specific interaction with at least one other molecular through, e.g., noncovalent bonding such as hydrogen bonding, metal coordination, hydrophobic forces, van der Waals forces, π-π interactions, halogen bonding, electrostatic, and/ or electromagnetic effects; in certain embodiments, CB is selected from a nanoparticle, an immunoglobulin, a nucleic acid, a protein, an oligopeptide, a polypeptide, an antibody, a fragment of an antigenic polypeptide, a repebody, and the like (Paragraph 0427). Additionally, Woo teaches that the compounds and conjugates of the invention may be utilized to treat an individual in need thereof; in certain embodiments, the individual is a mammal such as a human, or a non-human mammal wherein, when administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a disclosed compound and a pharmaceutically acceptable carrier (Paragraph 0758). It is noted that the above compound of Woo comprises a group structurally similar to instantly recited group Q corresponding to instant Formula (IV) (see claim 1) wherein, as provided above, Cy is an aryl, Ra”/ Rb” are not present as p and d are both 0, X’ is Cl, L”’ is a bond, X” is -O-, TG is a monosaccharide, and the structures of DNA binding domain DBD has a structure as provided above. While it is acknowledged that Woo does not explicitly disclose an Rza of instantly claimed coupling group Z’ that is a methyl group as required by the instantly elected species, it is noted that the substitution of methyl for hydrogen on a known compound is not a patentable modification absent unexpected or unobvious results. In re Lincoln, 126 U.S.P.Q. 477, 53 U.S. P.Q. 40 (C.C.P.A. 1942); In re Druey, 319 F.2d 237, 138 U.S.P.Q. 39 (C.C. P.A. 1963); In re Lohr, 317 F.2d 388, 137 U.S.P.Q. 548 (C.C.P.A. 1963); In re Hoehsema, 399 F.2d 269, 158 U.S.P.Q. 598 (C.C.P.A. 1968); In re Wood, 582 F.2d 638, 199 U.S. P.Q. 137 (C.C.P.A. 1978); In re Hoke, 560 F.2d 436, 195 U.S.P.Q. 148 (C.C.PA.A. 1977); Ex parte Fauque, 121 U.S.P.Q. 425 (P.O.B.A. 1954); Ex parte Henkel, 130 U.S.P.Q. 474, (P.O.B.A. 1960). Given that applicant did not provide unexpected or unobvious results of the invention, it is concluded that the normal desire of scientists or artisans to improve upon what is already generally known would provide the motivation to substitute the H group of Woo corresponding to the Rza group of instant coupling group Z’ to a methyl group as required by the instantly elected species, such that the structure of Woo would be as shown below:
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However, it is noted that Woo does not teach or suggest (i) a structural element of instant DBD-(L”’)r-X”-Gly according to the instant claims having the structure:
wherein Y” is N, q = 0, L”’ is a bond, X” is -O-, and Gly is a monosaccharide; nor (ii) Ra” in instant Formula (IX) that is a methoxy group wherein p = 1. These deficiencies are remedied by Boger and Tranoy-Opalinski.
Boger teaches the synthesis of 7-methoxy-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (MCBI), a substituted CBI derivative bearing a C7 methoxy group para to the C4 carbonyl, which is described in efforts that establish the magnitude of potential electronic effects on the chemical and functional reactivity of the agents (Abstract). The natural enantiomers of the CBI-based analogs have been shown to alkylate DNA with an unaltered sequence selectivity at an enhanced rate and with a greater efficiency than the corresponding CPI analogs, indicating that the simplified CBI alkylation subunit offers important advantages over the natural
alkylation subunit of CC-1065 (Page 1711, Second Paragraph). The diastereomeric adducts derived from the unnatural enantiomers suffer a significant destabilizing steric interaction between the CPI C7 center (CH3) or the CBI C8 center with the base adjacent to the alkylated adenine which is not present with the natural enantiomer adducts; consistent with this observation, the distinguishing features between the natural and unnatural enantiomers diminish or disappear as the inherent steric bulk surrounding this center is reduced or removed, and because of the unnatural enantiomer sensitivity to destabilizing steric interactions surrounding the CPI C7 or CBI C8 center, the unnatural enantiomers of the CBI-based analogs are more effective than the corresponding CPI analogs displaying an even more enhanced relative rate and efficiency of DNA alkylation (Id.). These studies yielded the observation that there is a direct relationship between functional stability and cytotoxic potency; in efforts to verify these observations and further quantitate the magnitude of substituent electronic effects on functional reactivity, the authors report the extension of the studies to the preparation of the first substituted CBI derivative, 7-methoxy-1,2,9,9a-tetrahydrocyclopropa-[c]benz[e]indol-4-one (MCBI), bearing a C7 methoxy substituent para to the C4 carbonyl; the direct comparison of MCBI with CBI was anticipated to permit an assessment of the magnitude of the electronic effects of a C7 substituent on chemical reactivity and, ultimately, the relationship of this functional reactivity with the biological properties of the agents (Page 1712, First and Second Paragraphs). The core structures of the derivatives of the study are provided below (see Page 1712):
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A study of the solvolysis reactivity of N-BOC-MCBI indicated that the introduction of the strong electron-donating C7 methoxy group accelerates the rate of solvolysis by only 1.2-1.06x; this remarkably small effect indicates that protonation of the C4 carbonyl is not the rate-determining step of solvolysis or acid-catalyzed nucleophilic addition and further supports the proposal that the cyclopropane ring-opening reaction requires the presence and assistance of a nucleophile (SN2 mechanism), and the authors conclude that there is no doubt that this contributes to the DNA alkylation selectivity and suggests that the positioning of an accessible nucleophile (adenine N3) and not C4 carbonyl protonation or Lewis acid complexation is the rate-determining step controlling the sequence selectivity of DNA alkylation (Page 1723, Conclusions). This exceptionally small electronic effect on the solvolysis rate had no impact on the solvolysis regioselectivity, and stereoelectronically-controlled nucleophilic addition to the least-substituted carbon of the activated cyclopropane was observed exclusively (Id.). For the natural enantiomers, this very small electronic effect on functional reactivity had little or no perceptible effect on their DNA alkylation selectivity, efficiency, and relative rates or on their biological properties when compared to the corresponding CBI-based agent, while perceptible effects of the C7 methoxy group on the unnatural enantiomers were detected, and they proved to be 4-40x more effective than the corresponding CBI-based unnatural enantiomers and comparable in cytotoxic potency with the corresponding MCBI natural enantiomer; this effect on the unnatural enantiomers is most consistently rationalized not by a C7 methoxy substituent effect on functional reactivity but rather through introduction of additional stabilizing noncovalent interactions which increase DNA alkylation efficiency and further stabilize an inherently reversible DNA alkylation reaction (Id.). Thus, Boger explicitly suggests that modification of the core structure of DNA alkylating agents at position C7 via substitution with a methoxy group improves efficacy/efficiency of the DNA alkylating agent by stabilizing the DNA alkylation reaction.
Tranoy-Opalinski teaches that the design of novel antitumor agents allowing the destruction of malignant cells while sparing healthy tissues is one of the major challenges in medicinal chemistry; in this context, the use of non-toxic prodrugs programmed to be selectively activated by beta-glucuronidase present at high concentration in the microenvironment of most solid tumors has attracted considerable attention (Abstract). Tranoy-Opalinski reviews new prodrugs that have been designed to target a wide variety of anticancer drugs, the prodrugs
employed in the course of a combined therapy, the dendritic glucuronide prodrugs and the concept of β-glucuronidase-responsive albumin binding prodrugs (Id.). Since high level of β-glucuronidase can be found in most solid tumors, this strategy was applied for the targeting of various classes of cytotoxics such as anthracyclines, taxanes, camptothecin derivatives, nitrogen mustards, histone deacetylase inhibitors, hedgehog inhibitors, auristatins and duocarmycins; with a few exceptions, these prodrugs include a self-immolative linker between the carbohydrate trigger and the drug such that the glucuronide moiety is thereby sufficiently far away from
the antitumor agent to allow an easy recognition of the enzymatic substrate by β-glucuronidase (Page 303, Column 1, Second Paragraph). The release of the drug proceeds then via a two steps process including (1) the enzymatic hydrolysis of the glycosidic bound and (2) the spontaneous decomposition of the linker leading to the expulsion of the active compound (Fig. 1) (Id.). Notably, one area of glucuronide prodrugs discussed incudes a glucuronide prodrug of duocarmycin derivatives; the duocarmycins are a family of antineoplastic agents with low picomolar potency against a wide range of cancer cell lines and the cytotoxic activity is believed to derive from their ability to bind and alkylate DNA in AT-rich region of the minor groove, although other modes of action have been suggested (Page 307, Section (6), First Paragraph). However, the duocarmycins display side effects in vivo including hepatotoxicity and myelosuppression which represent a major limitation for their clinical use; thus, Tietze and coworkers have proposed to study the glucuronide prodrug of a seco-analog of duocarmycin (15)
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with the aim to develop more selective therapeutic agents (Id.; Figure 8 reproduced below).
Phenyl β-glucuronides are known to be excellent substrates for β-glucuronidase, the presence of a linker was not necessary and the seco-drug was directly attached to the carbohydrate trigger; in this approach, enzymatic cleavage of the glycosidic bond releases first the seco-drug which is rapidly transformed in situ into the corresponding duocarmycin derivative that is responsible for the biological activity (Id.). In vitro cytotoxicity of prodrug (15) was evaluated on several human cancer cell lines with IC50 values ranging from 10 to 82 nM indicating that (15) was thousand-fold less toxic than the drug; in contrast, addition of b-glucuronidase in the culture mediums produced a dramatic increase of toxicity leading to IC50 values comparable to that of the free drug (from 12 to 46 pM) (Id.). The antitumor activity of prodrug (15) was then tested in mice for the treatment of a CL1-5 human lung cancer xenograft and compared to the efficacy of carboplatin, a commonly used antineoplastic agent wherein glucuronide (15), administered at 2.5 mg/kg, induced better tumor suppression with less toxicity than carboplatin injected at 50 mg/kg; although significant, the antitumor activity remained modest probably due to insufficient level of β-glucuronidase in the tumor microenvironment and the authors hypothesized that increasing the extracellular concentration of this enzyme should further enhance the therapeutic effect of prodrug (15) and for this purpose, prior to the administration of (15), the mice received intratumoral injections of an adenoviral vector expressing membrane-anchored β-glucuronidase (Pages 307-308, Section (6), Second Paragraph). In this experiment, complete tumor remission was observed in seven of nine mice treated with this combined protocol; as expected, pretreatment of cancer tissues by the adenoviral vector strongly potentiated the antitumor activity of prodrug (15) (Id.). Tranoy-Opalinski further notes that other approaches aimed to increase the concentration of β-glucuronidase in the tumor microenvironment have been developed and these strategies could represent valuable alternatives to PMT in order to enhance the therapeutic index of glucuronide prodrugs, especially for the treatment of tumors expressing insufficient levels of β-glucuronidase as well as metastatic tumors. (Page 308, Section (6), Last Paragraph). Thus, Tranoy-Opalinski suggests the use of non-toxic prodrugs programmed to be selectively activated by beta-glucuronidase (i.e., prodrugs comprising β-glucuronides), wherein beta-glucuronidase present at high concentration in the microenvironment of most solid tumors; such an approach can limit side effects and off-target toxicities by promoting tumor-specific cytotoxic activity after cleavage of the β-glucuronides.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the compounds/conjugates of Woo such that in conjugates comprising a DNA-binding/DNA-alkylating agent the C7 position of the core structure is substituted with a methoxy group, as suggested by Boger, and the drug is conjugated to β-glucuronide, as suggested by Tranoy-Opalinski. One would have been motivated to make such modifications because (i) Boger teaches that modification of the core C7 position of DNA-alkylating agents stabilizes the DNA alkylation reaction and improves efficacy/efficiency and (ii) Tranoy-Opalinski teaches that the use of prodrugs comprising β-glucuronide allows for solid-tumor specific release of the active agent to reduce side effects and off-target toxicity; thus, one of ordinary skill in the art would have been motivated to make such modifications in order to improve conjugate targeting, improve drug activity, and reduce side effects and off-target toxicity. One of ordinary skill in the art would have a reasonable expectation of success because the effects of such modifications are taught by Boger and Tranoy-Opalinsky, and as such it would be reasonably expected that the incorporation of such modifications into the compounds/conjugates of Woo would yield similar effects.
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: (i) Woo discloses compounds/conjugates including a cleavable linker, uses thereof, and an intermediate compound for preparing the same, and more particularly, the compound/conjugate including a cleavable linker of the present invention may further include an active agent (e.g., DNA alkylating agents) and a targeting moiety (e.g., an antibody) for therapeutic applications; (ii) Boger discloses site-specific modification of the core structure of DNA-alkylating agents (sharing the core structure of active agents disclosed by Woo) wherein addition of a methoxy group at position C7 improves the efficacy/efficiency of the DNA-alkylating agents; and (iii) Tranoy-Opalinsky discloses that conjugation of active agents to β-glucuronide allows for solid-tumor specific release of the active agent to reduce side effects and off-target toxicity.
Woo discloses conjugates comprising active agents (e.g., DNA-alkylating agents), cleavable linkers that utilize sugar-based trigger groups for release, and targeting agents for targeted therapeutics, Boger suggests chemical modifications to the core structure of DNA-alkylating agents to improve efficiency and effectiveness, and Tranoy-Opalinsky recognizes the need in the art to reduce side effects/off target toxicity for active agents including DNA-alkylating agents and suggests conjugation to β-glucuronide. Given the recognized need to improve active agents and target-specific release and given the known modifications of (i) adding a methoxy group to position C7 to improve DNA-alkylating agents and (ii) conjugation of β-glucuronide to active agents to improve-site specific release, one of skill in the art could have pursued modifying, with a reasonable expectation of success, the structure below
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encompassed by the teachings of Woo:
such that the DNA-alkylating agent is modified at position C7 to add a methoxy group, as suggested by Boger, conjugate β-glucuronide to the terminal -OH group (the only reactive group open to such conjugation) of the active agent as suggested by Tranoy-Opalinski. Furthermore, it is would also be obvious to one of ordinary skill in the art to replace the monosaccharide of the representative structure with a β-glucuronide as such a triggering group would be capable of being hydrolyzed specifically in solid tumors by the enzyme β-glucuronidase, as suggested by Tranoy-Opalinski, in order to arrive at the instant species:
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because Woo teaches that preferred embodiments comprise a triggering group that is a saccharide that can be cleaved under acidic or enzymatic conditions (Paragraph 0271) wherein it is specifically noted that Woo identifies various groups capable of being hydrolyzed by an enzyme, including a moiety selected from a phosphodiester, a phospholipid, an ester, a β-galactose, a β-glucose, a fucose, an oligosugar, and the like which are capable of being hydrolyzed by an oxidoreductase, a transferase, a hydrolase, a lyase, an isomerase, a ligase, etc. (Paragraph 0264). Such a structure reads on the drug conjugate(s) of instant Formula (XI) of the instant claims wherein Ar is an aryl, Y’ is -(CRb2)yO- wherein y = 0, TG is a monosaccharide, X is -O-, (L’)w is not present as w = 0, Cy is an aryl (i.e., an anisole), Ra” is an alkoxy (i.e., methoxy) group and p = 1, Rb” is not present as d is 0, X’ is Cl, L”’ is a bond, X” is -O-, Gly is a monosaccharide, and the structures of DNA binding domain DBD and coupling group Z’ are as shown below, wherein Rza of Z’ is a methyl group:
One of ordinary skill in the art would have a reasonable expectation of success because the effects of such modifications are taught by Boger and Tranoy-Opalinsky, and as such it would be reasonably expected that the incorporation of such modifications into the compounds/conjugates of Woo would yield similar effects.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 23, 77-78, 85, 172-173, 181-182, 228-229, 259-260, 262, and 272 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9-10, 12-17, and 20 of U.S. Patent No. 12,168,060 (herein after referred to as "reference patent"). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 1 of the reference patent is drawn to an antibody conjugate represented by Formula (I), which corresponds to Ab-(G)n wherein: (i) Ab is, generally, an anti-B7-H3 antibody, (ii) G is, independently, a chemical moiety comprising one or more active agent and a linker, wherein the linker covalently links Ab to the active agent(s), and (iii) n is an integer between 1 and 20. Claim 9 of the reference patent is drawn to the antibody conjugate of claim 1, wherein the link between Ab and the active agent is cleavable. Claim 10 of the reference patent is drawn to the antibody
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conjugate of claim 1 wherein G is represented by Formula (II):
wherein each Q′ is independently an active agent linked to L′ by a heteroatom; Z′ is a linking group; L′ is a spacer moiety attached to the SO2 via a heteroatom selected from O, S, and N, and is selected such that cleavage of the bond between L′ and SO2 promotes cleavage of the bond between L′ and Q′ to release the active agent; X is -O-, -C(Rb)2-, or -N(Rc)-; Ar represents a ring, such as aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; Y′ is -(CRb2)yN(Ra)-, -(CRb2)yO-, or
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-(CRb2)yS-, positioned such that the N, O, or S atom is attached to TG if y is 1; X and Y′ are positioned on adjacent atoms of Ar; TG is a triggering group that, when activated, generates an N, O, or S atom capable of reacting with the SO2 to displace (Q′)q-(L′)w and form a 5-6-membered ring including X- SO2 and the intervening atoms of Ar; q is an integer having a value from 1 to about 20; w, x, and y are each independently an integer having a value of 0 or 1; each Ra and Rc is independently hydrogen or lower alkyl; and each Rb is independently hydrogen or lower alkyl; or two Rb, together with the atom to which they are attached, form a 3-5-membered ring; provided that when w is 0, q is 1. Claim 12 is drawn to the antibody conjugate of claim 10, wherein Z’ is selected from a variety of structures, including the structure reproduced below:
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wherein Rza is H or methyl; a″ represents the bond between Z′ and Ar of Formula (II); b″ represents the bond between Z′ and Ab; and Z″ is selected from the structures below, oriented in either direction:
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Claim 13 of the reference patent is drawn to the antibody conjugate of claim 10, wherein G comprises one of various structures, including the structure reproduced below:
Claim 14 of the reference patent is drawn to the antibody conjugate of claim 10, wherein G comprises on of various structures, including the structure reproduced below:
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Claims 15 and 16 of the reference patent are drawn to the antibody conjugate of claim 1, wherein, respectively: (i) the active agent is an immunomodulatory compound, an anticancer agent, an antiviral agent, an antibacterial agent, an antifungal agent, an antiparasitic agent, or a combination thereof; and (ii) the active agent is selected from a variety of agents, and/or combinations thereof, which can include, for example, duocarmycin. Claim 17 of the reference patent is drawn to a pharmaceutical composition comprising the antibody conjugate of claim 1. Claims 20-22 of the reference patent are generally drawn to the antibody conjugate of claim 1, which has one of various structures, including the structure reproduced below:
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Thus, the reference patent claims a drug conjugate as described by instant claim 1, wherein the structures above for reference patent claims 20-22 corresponds to a drug conjugate is represented by instant Formula (XI):
wherein Ar is an aryl, Y’ is -(CRb2)yO- wherein y = 0, TG is a monosaccharide, X is -O-, (L’)w is not present as w = 0, Cy is an aryl (i.e., an anisole), Ra” is an alkoxy (i.e., methoxy) group, X’ is Cl, L”’ is a bond, X” is -O-, Gly is a monosaccharide, and the structures of DNA binding domain
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DBD and coupling group Z’ are as shown below, wherein Rza of Z’ is a methyl group:
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As such, the reference patent claims the instantly elected species corresponding to instant drug conjugate compound T-117. The reference patent further claims drug conjugates comprising a targeting moiety (TM as designated in instant claim 78; see Formula (XIV)) that is an antibody (i.e., an anti-B7-H3 antibody). It is further noted that the antibody conjugates claimed by the reference patent comprise a group corresponding to instantly recited group Q corresponding to instant Formula (IV) (see claim 1) wherein, as provided above, Cy is an aryl (i.e., an anisole), Ra” is an alkoxy (i.e., methoxy) group and p = 1, Rb” is not present as d is 0, X’ is Cl, L”’ is a bond, X” is -O-, Gly is a monosaccharide, and the structures of DNA binding domain DBD has a structure as provided above. Thus, the reference patent claims the structural element of instant DBD-(L”’)r-X”-Gly of the structure:
wherein Y” is N, q = 0, L”’ is a bond, X” is -O-, and Gly is a monosaccharide. The reference patent further claims pharmaceutical compositions comprising the antibody conjugates. Thus, the claims of the reference patent read directly on instant claims 1, 23, 77-78, 85, 172-173, 181-182, 228-229, 259-260, 262, and 272.
Claims 1, 23, 85, 182, and 272 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 27 of copending Application No. 18/827,143 (herein after referred to as “reference application”; divisional application of US 12,168,060). Although the claims at issue are not identical, they are not patentably distinct from each other.
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Claim 27 of the reference application is drawn to a compound selected from a variety of structures, wherein one of the listed structures is reproduced below:
Thus, the reference application claims a drug conjugate as described by instant claim 1, wherein the structures above for reference application claim 27 corresponds to a drug conjugate is represented by instant Formula (XI):
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wherein Ar is an aryl, Y’ is -(CRb2)yO- wherein y = 0, TG is a monosaccharide, X is -O-, (L’)w is not present as w = 0, Cy is an aryl (i.e., an anisole), Ra” is an alkoxy (i.e., methoxy) group, X’ is Cl, L”’ is a bond, X” is -O-, Gly is a monosaccharide, and the structures of DNA binding domain DBD and coupling group Z’ are as shown below, wherein Rza of Z’ is a methyl group:
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As such, the reference application claims the instantly elected species corresponding to instant drug conjugate compound T-117. It is further noted that the compounds claimed by the reference application comprise a group corresponding to instantly recited group Q corresponding to instant Formula (IV) (see claim 1) wherein, as provided above, Cy is an aryl (i.e., an anisole), Ra” is an alkoxy (i.e., methoxy) group and p = 1, Rb” is not present as d is 0, X’ is Cl, L”’ is a bond, X” is -O-, Gly is a monosaccharide, and the structures of DNA binding domain DBD has a structure as provided above. Thus, the reference application claims the structural element of instant DBD-(L”’)r-X”-Gly of the structure:
wherein Y” is N, q = 0, L”’ is a bond, X” is -O-, and Gly is a monosaccharide. Thus, the claims of the reference application read directly on instant claims 1, 23, 85, 182, and 272.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 77-78, 172-173, 181, 259-260, and 262 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 27 of copending Application No. 18/827,143 (herein after referred to as “reference application”; divisional application of US 12,168,060) in view of WO 2019/008441 A1 (herein after referred to as "Woo").
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Claim 27 of the reference application is drawn to a compound selected from a variety of structures, wherein one of the listed structures is reproduced below:
However, it is noted that the reference application does not claim a pharmaceutical composition comprising the compound above, nor the compound above further comprising a targeting moiety (e.g., an antibody) and a pharmaceutical composition thereof. These deficiencies are remedied by Woo.
Woo teaches compounds and conjugates comprising a cleavable linker and uses thereof; representative compounds and conjugates comprise an active agent (e.g., a chemical factor, a biological factor, a hormone, an oligonucleotide, a drug, a toxin, a ligand, a probe for detection, etc.) having a desired function or activity, a functional group that undergoes a chemical reaction (e.g., a physicochemical reaction and/or a biological reaction) under predetermined conditions to release a nucleophilic heteroatom, and an SO2 functional group positioned proximal to the nucleophilic heteroatom so that it can react with the nucleophilic heteroatom in an intramolecular
cyclization reaction to release the active agent (Paragraph 0041). In some embodiments, the compounds and conjugates of the invention further comprise a targeting moiety (e.g., oligopeptide, polypeptide, antibody, etc.) having binding specificity for a desired target receptor or other molecule associated with a target cell (Id.). Woo teaches conjugates of Formula (I’) corresponding to (D-L)n-(CB)cb, or a pharmaceutically acceptable salt thereof, wherein CB is a targeting moiety, cb and n are each integers having a value of 1 to 20, and wherein each D-L, independently, is a group having the structure of Formula (I”):
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wherein each Q, independently, is an active agent linked to L’ via a heteroatom (i.e., O or N), Z’ is a linking group; L’ is a spacer moiety attached to SO2 via a heteroatom selected from O, S, and N and is selected such that the cleavage of the bond between L’ and SO2 promotes cleavage of the bond between L’ and Q to release the active agent; X is -O-, -C(Rb)2-, or -N(Rc)-; Ar is a ring; Y’ is -CRb2N(Ra)-, -(CRb2)yO-, or -(CRb2)yS- positioned such that the N, O, or S atom is attached to TG if y is 1; X and Y’ are positioned on adjacent atoms of Ar; TG is a triggering group that, when activated, generates an N, O, or S atom capable of reacting with the SO2 to displace (Q)q-(L’)w and from a 5-6 membered ring including X-SO2 and the intervening atoms of Ar; q is an integer from 1 to 20; w/x/y are each independently an integer of 0 or 1; each Ra/Rc is independently hydrogen or a lower alkyl (i.e., C1-6 alkyl); and each Rb is independently hydrogen or a lower alkyl (i.e., C1-6 alkyl) or two Rb together with the atom to which they are attached form a 3-5 membered ring provided that when w = 0, q = 1 (Page 4). A full structure of exemplary compound D10 of the invention is provided at Page 186, and is reproduced below:
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wherein it is specifically noted that TG is a monosaccharide, the structure corresponding to (L’)w-(Q)q is indicated within the circle, and the structure corresponding to linking group Z’ is indicated within the rectangle. It is specifically noted that a targeting moiety would be conjugated to the exemplary structure above via the maleimide group (i.e., via Z’ of Woo Formula I”). Notably, the ligand or targeting moiety is any molecular recognition element, which can undergo a specific interaction with at least one other molecular through, e.g., noncovalent bonding such as hydrogen bonding, metal coordination, hydrophobic forces, van der Waals forces, π-π interactions, halogen bonding, electrostatic, and/ or electromagnetic effects; in certain embodiments, CB is selected from a nanoparticle, an immunoglobulin, a nucleic acid, a protein, an oligopeptide, a polypeptide, an antibody, a fragment of an antigenic polypeptide, a repebody, and the like (Paragraph 0427) Targeting moieties of the invention specifically bind to: (i) targets associated with particular cell types (e.g., endothelial cells, cancer cells, malignant cells, prostate cancer cells, etc.); (ii) a target that is specific for one or more particular disease states (e.g., tumor cells vs. healthy cells); (iii) a target that is specific for one or more particular developmental stages (e.g., stem cells vs. differentiated cells) (Paragraphs 0436-0438). Additionally, Woo teaches that the compounds and conjugates of the invention may be utilized to treat an individual in need thereof; in certain embodiments, the individual is a mammal such as a human, or a non-human mammal wherein, when administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a disclosed compound and a pharmaceutically acceptable carrier (Paragraph 0758).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the compounds claimed by the reference application such that said compounds of the reference application are (i) conjugated to a targeting moiety and/or (ii) comprised within a pharmaceutical composition, because there is a teaching, suggestion, and/or motivation in the prior art that would have lead one of ordinary skill in the art to make such a modification; Woo teaches the conjugation of targeting moieties to compounds that comprise the same core structure and administering pharmaceutical compositions comprising such conjugates for therapeutic applications. One would have been motivated to make such a modification because Woo teaches structurally similar compounds that comprise the same core structure and rely on the same mechanism(s) of release (e.g., a spacer moiety attached to SO2 via a heteroatom selected from O, S, and N and is selected such that the cleavage of the bond between the spacer and SO2 promotes cleavage of the bond between the spacer and active agent to release the active agent, further wherein a triggering group that, when activated, generates an N, O, or S atom capable of reacting with SO2 to displace the active agent bound to the spacer) and Woo identifies that such compounds can further comprise a targeting moiety which is specific for a target that is associated with one or a few cell types, with one or a few diseases, and/or with one or a few developmental stages. Such a modification would allow for the specific targeting of the compounds/conjugates to particular cell types, with one or a few diseases, and/or with one or a few developmental stages. One of ordinary skill in the art would have a reasonable expectation of success because Woo explicitly teaches the conjugation of targeting moieties through reactive linkers, including linkers comprising maleimide groups as present in the compound(s) of reference application claim 27. Thus, one of ordinary skill in the art would reasonably expect that (i) a targeting moiety would be successfully conjugated and (ii) the targeting moiety would reasonably serve to specifically target the conjugate to a specific cell type for a targeted therapeutic approach comprising, for example, the administration of a pharmaceutical composition comprising such conjugates.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 23, 77-78, 85, 172-173, 181-182, 228-229, 259-260, 262, and 272 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 10, and 14-18 of U.S. Patent No. 11,753,431 (herein after referred to as "second reference patent") in view of WO 2019/008441 A1 (herein after referred to as "Woo") in view of non-patent literature by Boger et. al. (J. Org. Chem., 1996, 61, 1710-1729; herein after referred to as "Boger") and non-patent literature by Tranoy-Opalinski et. al. (European Journal of Medicinal Chemistry, 2014, 74, 302-313; herein after referred to as "Tranoy-Opalinski").
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Claim 1 of the second reference patent is drawn to a compound of Formula (I’):
wherein each Q′ is independently an active agent linked to L′ by a heteroatom; Z′ is a linking group; L′ is a spacer moiety attached to the SO2 via a heteroatom selected from O, S, and N, and is selected such that cleavage of the bond between L′ and SO2 promotes cleavage of the bond between L′ and Q′ to release the active agent; X is -O-, -C(Rb)2-, or -N(Rc)-; Ar represents a ring, such as aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; Y′ is -(CRb2)yN(Ra)-, -(CRb2)yO-, or
-(CRb2)yS-, positioned such that the N, O, or S atom is attached to TG if y is 1; X and Y′ are positioned on adjacent atoms of Ar; TG is a triggering group that, when activated, generates an N, O, or S atom capable of reacting with the SO2 to displace (Q′)q-(L′)w and form a 5-6-membered ring including X- SO2 and the intervening atoms of Ar; q is an integer having a value from 1 to about 20; w, x, and y are each independently an integer having a value of 0 or 1; each Ra and Rc is independently hydrogen or lower alkyl; and each Rb is independently hydrogen or lower alkyl; or two Rb, together with the atom to which they are attached, form a 3-5-membered ring; provided that when w is 0, q is 1. Second reference patent claims 2-3 further limit the compound of claim 1 wherein, respectively, X is -O- and Ar is an aryl. Second reference patent claims 4-5 further limit the compound of claim 1, wherein the structural components of Z’ are further specified. Claims 10 and 14 further limit the compound of claim 1, wherein, respectively: (i) TG is a reactive chemical moiety or functional group that can be cleaved by nucleophilic reagent conditions, basic reagent conditions, photo-irradiation, reducing agent conditions, acidic conditions, enzymatic conditions, or oxidative conditions; and (ii) Q is a chemical factor, a biological factor, a hormone, an oligonucleotide, a toxin, an affinity ligand, a probe for detection, a drug selected from a cytokine, an immunomodulatory compound, an anti-cancer agent, an anti-viral agent, an anti-bacterial agent, an anti-fungal agent, an anthelmintic agent, or a combination thereof. Claims 15-16 of the second reference patent further limit the compound of claim 1, wherein the structure of (Q)q-(L’)w is further specified; it is particularly noted that one of the claimed structures is that which is reproduced below, wherein * is the point of connection to the
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SO2:
Second reference patent claim 17 further limits the compound of claim 1 wherein the targeting moiety is a nanoparticle, immunoglobulin, nucleic acid, protein, oligopeptide, polypeptide, antibody, fragment of an antigenic polypeptide, or a repebody. Second reference patent claim 18 is drawn to a pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
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However, it is noted that the second reference patent does not explicitly claim (i) a structural element of instant DBD-(L”’)r-X”-Gly according to Formula (XI) of the instant claims having the structure:
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wherein Y” is N, q = 0, L”’ is a bond, X” is -O-, and Gly is a monosaccharide; (ii) Ra” in instant Formula (IX) that is a methoxy group wherein p = 1, nor (iii) a linking/coupling group Z’ represented by:
wherein Rza is a methyl group and Z” is a triazole. These deficiencies are addressed by the cited references, as provided by the teachings specified in the 103 section above.
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the to modify the compounds/conjugates of the third reference patent, which share common core structures of Woo, such that in conjugates comprising a DNA-binding/DNA-alkylating agent the C7 position of the core structure is substituted with a methoxy group, as suggested by Boger, and the drug is conjugated to β-glucuronide, as suggested by Tranoy-Opalinski. One would have been motivated to make such modifications because (i) Boger teaches that modification of the core C7 position of DNA-alkylating agents stabilizes the DNA alkylation reaction and improves efficacy/efficiency and (ii) Tranoy-Opalinski teaches that the use of prodrugs comprising β-glucuronide allows for solid-tumor specific release of the active agent to reduce side effects and off-target toxicity; thus, one of ordinary skill in the art would have been motivated to make such modifications in order to improve conjugate targeting, improve drug activity, and reduce side effects and off-target toxicity. One of ordinary skill in the art would have a reasonable expectation of success because the effects of such modifications are taught by Boger and Tranoy-Opalinsky, and as such it would be reasonably expected that the incorporation of such modifications into the compounds/conjugates of the second reference patent, based on the teachings of Woo, Boger, and Tranoy-Opalinsky, would yield similar effects.
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: (i) Woo discloses compounds/conjugates including a cleavable linker, uses thereof, and an intermediate compound for preparing the same, and more particularly, the compound/conjugate including a cleavable linker of the present invention may further include an active agent (e.g., DNA alkylating agents) and a targeting moiety (e.g., an antibody) for therapeutic applications; (ii) Boger discloses site-specific modification of the core structure of DNA-alkylating agents (sharing the core structure of active agents disclosed by Woo) wherein addition of a methoxy group at position C7 improves the efficacy/efficiency of the DNA-alkylating agents; and (iii) Tranoy-Opalinsky discloses that conjugation of active agents to β-glucuronide allows for solid-tumor specific release of the active agent to reduce side effects and off-target toxicity.
Woo discloses conjugates comprising that same core structure of the second reference patent, wherein said conjugates comprise active agents (e.g., DNA-alkylating agents), cleavable linkers that utilize sugar-based trigger groups for release, and targeting agents for targeted therapeutics, Boger suggests chemical modifications to the core structure of DNA-alkylating agents to improve efficiency and effectiveness, and Tranoy-Opalinsky recognizes the need in the art to reduce side effects/off target toxicity for active agents including DNA-alkylating agents and suggests conjugation to β-glucuronide. Given the recognized need to improve active agents and target-specific release and given the known modifications of (i) adding a methoxy group to position C7 to improve DNA-alkylating agents and (ii) conjugation of β-glucuronide to active agents to improve-site specific release, one of skill in the art could have pursued modifying, with a reasonable expectation of success, the structure below encompassed by the claims of the
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second reference patent and the teachings of Woo:
such that the DNA-alkylating agent is modified at position C7 to add a methoxy group, as suggested by Boger, conjugate β-glucuronide to the terminal -OH group (the only reactive group open to such conjugation) of the active agent as suggested by Tranoy-Opalinski. Furthermore, it is would also be obvious to one of ordinary skill in the art to replace the monosaccharide of the representative structure with a β-glucuronide as such a triggering group would be capable of being hydrolyzed specifically in solid tumors by the enzyme β-glucuronidase, as suggested by Tranoy-Opalinski, in order to arrive at the instant species:
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because Woo teaches that preferred embodiments comprise a triggering group that is a saccharide that can be cleaved under acidic or enzymatic conditions (Paragraph 0271) wherein it is specifically noted that Woo identifies various groups capable of being hydrolyzed by an enzyme, including a moiety selected from a phosphodiester, a phospholipid, an ester, a β-galactose, a β-glucose, a fucose, an oligosugar, and the like which are capable of being hydrolyzed by an oxidoreductase, a transferase, a hydrolase, a lyase, an isomerase, a ligase, etc. (Paragraph 0264). Such a structure reads on the drug conjugate(s) of instant Formula (XI) of the instant claims wherein Ar is an aryl, Y’ is -(CRb2)yO- wherein y = 0, TG is a monosaccharide, X is -O-, (L’)w is not present as w = 0, Cy is an aryl (i.e., an anisole), Ra” is an alkoxy (i.e., methoxy) group and p = 1, Rb” is not present as d is 0, X’ is Cl, L”’ is a bond, X” is -O-, Gly is a monosaccharide, and the structures of DNA binding domain DBD and coupling group Z’ are as shown below, wherein Rza of Z’ is a methyl group:
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One of ordinary skill in the art would have a reasonable expectation of success because Woo teaches the same core conjugate structure as the second reference patent, and the effects of such modifications are taught by Boger and Tranoy-Opalinsky, and as such it would be reasonably expected that the incorporation of such modifications into the compounds/conjugates of the second reference patent, in view of the teachings of Woo, would yield similar effects.
Claims 1, 23, 77-78, 85, 172-173, 181-182, 228-229, 259-260, 262, and 272 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 10-12, and 15 of U.S. Patent No. 12,479,927 (herein after referred to as "third reference patent") in view of WO 2019/008441 A1 (herein after referred to as "Woo") in view of non-patent literature by Boger et. al. (J. Org. Chem., 1996, 61, 1710-1729; herein after referred to as "Boger") and non-patent literature by Tranoy-Opalinski et. al. (European Journal of Medicinal Chemistry, 2014, 74, 302-313; herein after referred to as "Tranoy-Opalinski").
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Claim 1 of the third reference patent is drawn to a compound of Formula (Ia):
wherein each Q′ is independently an active agent linked to L′ by a heteroatom; Z′ is a linking group; L′ is a spacer moiety attached to the SO2 via a heteroatom selected from O, S, and N, and is selected such that cleavage of the bond between L′ and SO2 promotes cleavage of the bond between L′ and Q′ to release the active agent; X is -O-, -C(Rb)2-, or -N(Rc)-; Ar represents a ring, such as aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; Y′ is -(CRb2)yN(Ra)-, -(CRb2)yO-, or
-(CRb2)yS-, positioned such that the N, O, or S atom is attached to TG if y is 1; X and Y′ are positioned on adjacent atoms of Ar; TG is a triggering group that, when activated, generates an N, O, or S atom capable of reacting with the SO2 to displace (Q′)q-(L′)w and form a 5-6-membered ring including X- SO2 and the intervening atoms of Ar; q is an integer having a value from 1 to about 20; w, x, and y are each independently an integer having a value of 0 or 1; each Ra and Rc is independently hydrogen or lower alkyl; and each Rb is independently hydrogen or lower alkyl; or two Rb, together with the atom to which they are attached, form a 3-5-membered ring; provided that when w is 0, q is 1. Third reference patent claims 2-3 further limit the compound of claim 1 wherein, respectively, X is -O- and Ar is an aryl. Third reference patent claims 4-5 further limit the compound of claim 1, wherein the structural components of Z’ are further specified. Claims 6 and 10 further limit the compound of claim 1, wherein, respectively: (i) TG is a reactive chemical moiety or functional group that can be cleaved by nucleophilic reagent conditions, basic reagent conditions, photo-irradiation, reducing agent conditions, acidic conditions, enzymatic conditions, or oxidative conditions; and (ii) Q is a chemical factor, a biological factor, a hormone, an oligonucleotide, a toxin, an affinity ligand, a probe for detection, a drug selected from a cytokine, an immunomodulatory compound, an anti-cancer agent, an anti-viral agent, an anti-bacterial agent, an anti-fungal agent, an anthelmintic agent, or a combination thereof. Claims 11-12 of the third reference patent further limit the compound of claim 1, wherein the structure of (Q)q-(L’)w is further specified; it is particularly noted that one of the claimed structures is that which is reproduced below, wherein * is the point of connection to the
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SO2:
Third reference patent claim 15 further limits the compound of claim 1 wherein Ar represents an aryl or heteroaryl.
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However, it is noted that the third reference patent does not explicitly claim (i) a structural element of instant DBD-(L”’)r-X”-Gly according to Formula (XI) of the instant claims having the structure:
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wherein Y” is N, q = 0, L”’ is a bond, X” is -O-, and Gly is a monosaccharide; (ii) Ra” in instant Formula (IX) that is a methoxy group wherein p = 1, (iii) a linking/coupling group Z’ represented by:
wherein Rza is a methyl group and Z” is a triazole, nor (iv) pharmaceutical compositions. These deficiencies are addressed by the cited references, as provided by the teachings specified in the 103 section above.
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the to modify the compounds/conjugates of the third reference patent, which share common core structures of Woo, such that in conjugates comprising a DNA-binding/DNA-alkylating agent the C7 position of the core structure is substituted with a methoxy group, as suggested by Boger, and the drug is conjugated to β-glucuronide, as suggested by Tranoy-Opalinski. One would have been motivated to make such modifications because (i) Boger teaches that modification of the core C7 position of DNA-alkylating agents stabilizes the DNA alkylation reaction and improves efficacy/efficiency and (ii) Tranoy-Opalinski teaches that the use of prodrugs comprising β-glucuronide allows for solid-tumor specific release of the active agent to reduce side effects and off-target toxicity; thus, one of ordinary skill in the art would have been motivated to make such modifications in order to improve conjugate targeting, improve drug activity, and reduce side effects and off-target toxicity. One of ordinary skill in the art would have a reasonable expectation of success because the effects of such modifications are taught by Boger and Tranoy-Opalinsky, and as such it would be reasonably expected that the incorporation of such modifications into the compounds/conjugates of the second reference patent, based on the teachings of Woo, Boger, and Tranoy-Opalinsky, would yield similar effects.
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: (i) Woo discloses compounds/conjugates including a cleavable linker, uses thereof, and an intermediate compound for preparing the same, and more particularly, the compound/conjugate including a cleavable linker of the present invention may further include an active agent (e.g., DNA alkylating agents) and a targeting moiety (e.g., an antibody) for therapeutic applications; (ii) Boger discloses site-specific modification of the core structure of DNA-alkylating agents (sharing the core structure of active agents disclosed by Woo) wherein addition of a methoxy group at position C7 improves the efficacy/efficiency of the DNA-alkylating agents; and (iii) Tranoy-Opalinsky discloses that conjugation of active agents to β-glucuronide allows for solid-tumor specific release of the active agent to reduce side effects and off-target toxicity.
Woo discloses conjugates comprising that same core structure of the third reference patent, wherein said conjugates comprise active agents (e.g., DNA-alkylating agents), cleavable linkers that utilize sugar-based trigger groups for release, and targeting agents for targeted therapeutics, Boger suggests chemical modifications to the core structure of DNA-alkylating agents to improve efficiency and effectiveness, and Tranoy-Opalinsky recognizes the need in the art to reduce side effects/off target toxicity for active agents including DNA-alkylating agents and suggests conjugation to β-glucuronide. Given the recognized need to improve active agents and target-specific release and given the known modifications of (i) adding a methoxy group to position C7 to improve DNA-alkylating agents and (ii) conjugation of β-glucuronide to active agents to improve-site specific release, one of skill in the art could have pursued modifying, with a reasonable expectation of success, the structure below encompassed by the claims of the third
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reference patent and the teachings of Woo:
such that the DNA-alkylating agent is modified at position C7 to add a methoxy group, as suggested by Boger, conjugate β-glucuronide to the terminal -OH group (the only reactive group open to such conjugation) of the active agent as suggested by Tranoy-Opalinski. Furthermore, it is would also be obvious to one of ordinary skill in the art to replace the monosaccharide of the representative structure with a β-glucuronide as such a triggering group would be capable of being hydrolyzed specifically in solid tumors by the enzyme β-glucuronidase, as suggested by Tranoy-Opalinski, in order to arrive at the instant species:
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because Woo teaches that preferred embodiments comprise a triggering group that is a saccharide that can be cleaved under acidic or enzymatic conditions (Paragraph 0271) wherein it is specifically noted that Woo identifies various groups capable of being hydrolyzed by an enzyme, including a moiety selected from a phosphodiester, a phospholipid, an ester, a β-galactose, a β-glucose, a fucose, an oligosugar, and the like which are capable of being hydrolyzed by an oxidoreductase, a transferase, a hydrolase, a lyase, an isomerase, a ligase, etc. (Paragraph 0264). Such a structure reads on the drug conjugate(s) of instant Formula (XI) of the instant claims wherein Ar is an aryl, Y’ is -(CRb2)yO- wherein y = 0, TG is a monosaccharide, X is -O-, (L’)w is not present as w = 0, Cy is an aryl (i.e., an anisole), Ra” is an alkoxy (i.e., methoxy) group and p = 1, Rb” is not present as d is 0, X’ is Cl, L”’ is a bond, X” is -O-, Gly is a monosaccharide, and the structures of DNA binding domain DBD and coupling group Z’ are as shown below, wherein Rza of Z’ is a methyl group:
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One of ordinary skill in the art would have a reasonable expectation of success because Woo teaches the same core conjugate structure as the third reference patent, and the effects of such modifications are taught by Boger and Tranoy-Opalinsky, and as such it would be reasonably expected that the incorporation of such modifications into the compounds/conjugates of the third reference patent, in view of the teachings of Woo, would yield similar effects.
Conclusion
Claims 1, 5-6, 23, 36, 77-78, 85, 171-173, 175-176, 181-182, 228-229, 259-260, 262, 265, and 269-272 are pending. Claims 5-6, 36, 171, 175-176, 265, 269, and 270-271 are withdrawn. Claims 1, 23, 77-78, 85, 172-173, 181-182, 228-229, 259-260, 262, and 272 are rejected. No claims are allowed.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
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