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 .
Claims 2, 8, 9, 11, 13, 17, 18, 22-24, 26, 28, 30, 32, 34-36, 38, 40-42, 45-47, 49-53, 55 and 57-69 have been canceled. Claims 1, 3, 4, 6, 7, 10, 12, 14-16, 19, 20, 25, 27, 29, 31, 33, 37, 39, 44, 48, 54 and 56 have been amended. Claims 1, 3-7, 10, 12, 14-16, 19-21, 25, 27, 29, 31, 33, 37, 39, 43, 44, 48, 54, and 56 are pending and under consideration.
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, 3-7, 10, 12, 14-16, 19, 20, 25, 27, 29, 31, 33, 37, 39, 44, 48, 54 and 56 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.
The recitation of one or more methylene groups in claims 4, 16 and 56 is vague and indefinite because it is unclear where the methylene groups originate from.
The recitation of “the anti-B7H3 single domain antibody” and “the anti-MSLN single domain antibody in claims 27 and 37 lacks specific antecedent basis in claim 25.
The recitation of “n in an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8” in claim 56 lacks specific antecedent basis within the claim because there is no other reference to the index umber “n” within the claim.
Claims 1 and 56 are vague and indefinite because it is unclear why the alternatives for R1, R2, R3a, Ra, Rb, Rc, RdRe, Rf and Rg are also grouped separately in groups (i) , (ii) and (iii). It is unclear why the alternatives of Qa are grouped separately in groups (a), (b), (c).
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-7, 10, 12, 14-16, 19-21, 25, , 27, 29, 31, 33, 37, 39, 43, 44, 48, 54, 56 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re wands, 858 F.2d 731, 737.8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
(A) As drawn to the compound of Formula I in the form of a pharmaceutically acceptable salt, solvate or hydrate.
Clams 1, 3-7, 10, 12, 14-16, 19-21, 25, , 27, 29, 31, 33, 37, 39, 43, 44, 48, and 54 are drawn in part to a pharmaceutically acceptable salt, solvate or hydrate of the conjugates of formulas II, III or IV, and the compounds of ADC1, ADC2 and ADC3 in claims 21 and 43.
The specification defines the terms “solvate” and “hydrate” as
0076] a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which are present in stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form (emphasis added). In another embodiment, the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.
Thus, the claims encompass solid crystalline form or semi-solid crystalline form of the antibody-drug conjugates.
The specification fails to provide any teachings for how to make the solid forms of salts, solvates or the solvates of “the salt” of the instant antibody conjugates. Matheus et al (US 7,960,516) teach the unexpected result that stable pharmaceuticals can be prepared with solid forms of cetuximab and Mab h425 (column 4, lines 56-59) and that the antibodies are biologically active after re-dissolution (column 10, lines 51-59). Matheus et al teach that the crystallization of intact glycosylated antibodies is extremely difficult due to the size of the protein, the different glycosylation patterns of the individual molecules and associated micro-heterogeneities as well as the structural flexibility of the immunoglobulin make an ordered incorporation into a crystal lattice more difficult or even impossible (column 2, lines 50-56) and that there is a risk of denaturing antibodies during the crystallization process (column 2, lines 63-66). It is noted that the number of drugs attached to a single antibody varies between 1-16 (subscript “n”) in claim 1. .
The cumulative number of drug moieties plus linker required in the antibody-conjugate would vastly increase the size of the molecule, and alter flexibility and the micro-heterogeneity, especially since the number of attachments to a single antibody vary from 1-16. These factors are in opposition to the formation of an ordered crystal lattice necessary for solid phase salt formation. Antibodies have aqueous solubility of over 200 mg/ml in histidine buffer at pH 6 (Ke et al, International Journal of Pharmaceutics, 2015, Vol. 548, pp. 682-688, see page 684, first column, lines 6-7, page 683, lines 3-4 under section 2.2.2, lines 2-3 under section 2.2.3). The influence of a group that is much less hydrophilic than the antibody, such as the instant camptothecin derivatives, on the ability of the antibody to go into a crystal lattice of a salt is unknown.
The instant claims also require a solvate and a hydrate of the antibody conjugate. Matheus et al (U.S. 7,960,516) teach that solvates are a solid form having adductions of inert solvent molecules, and that solvates include hydrates such as monohydrates, dihydrates or alcoholates (column 10, lines 37-43). These solid forms have the same issues as set forth for the “salts” as a crystalline form, above.
The specification has not provided the reagents or conditions for the formation of a single salt, solvate or hydrate for the conjugates encompassed by the claims. It would not be expected that the conditions disclosed for the formation of hydrates of unconjugated cetuximab or Mab h425 would be the same reagents or conditions for the formation of salts, hydrates or solvates for any antibody of the instant conjugates. Thus, one of skill in the art would be subject to undue experimentation in order to make the salts, solvates or hydrates of the conjugates.
(B)As drawn to tautomers of the compounds of Formula I, III, IV or A-I. One of skill in the art woud assume that the ring opened form of the camptothecin derivatives is encompassed within the tautomers. .
The specification has not provided a structure of a tautomer of the compound of formula II, III, IV or A-I. Assuming that the ring-opened form of the molecule is the tautomer, the art teaches that the E-ring open form is far less active than the closed ring E form, in part because >99% of it is bound by HAS. One of skill in the art would conclude that the presence of the antibody linked to the E-ring opened form would not impede the reaction with HAS in plasma. The specification has not addressed this issue, or provided any teachings or guidance, or provided any alternative uses for the antibody-liner-drug of claims 1, 3-7, 10, 12, 14-16, 19-21, 25, 27, 29, 31, 33, 37, 39, 43, 44, 48, 54or linker-drug of claim 56. Thus, one of skill in the art would be subject to undue experimentation in order to use the ring-opened form of Formulas I, III, IV or A-I.
(C)AS drawn to a method of preventing one or more symptoms of a proliferative disease in a subject.
Claim 48 is drawn in part to a method of preventing one or more symptoms of a proliferative disease in a subject comprising the administration to the subject in need thereof a therapeutically effective amount of a compound of claim 1. When given the broadest reasonable interpretation, the subject is a human or non-experimental animal and the symptoms of a proliferative disease are indicative of the subject having the disease. Thus, in order to prevent the symptoms it would be necessary to administer the compound of claim 1 prior to the onset of the symptoms. It is noted that the antibody-drug conjugates of the invention would have a finite lifetime once administered to the patient. It also would be necessary that the antibody-drug conjugates would be circulating in the patient at a therapeutically effective amount prior to the onset of the disease in order to prevent symptoms. Because there is no way of knowing when the disease will occur, there is no way of knowing when to administer the antibody drug conjugate. Further, it would be necessary to know the target antigen of the disease in order that the proper antibody drug conjugate will be administered. The specification fails to address these issues. One of skill in the art would be subject to undue experimentation without reasonable expectation of success in order to practice prevention of the symptoms of a proliferative disease in a subject.
Claims 1, 3-7, 10, 12, 14-16, 19-21, 25, 27, 29, 31, 33, 37, 39, 43, 44, 48, 54, and 56 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
(A)As drawn to the genus of linker-drugs.
Section 2163 of the M.P.E.P. states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a “representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
Claims 1, 3-7, 10, 12, 14-16, 19-21, 25, 27, 29, 31, 33, 37, 39, 43, 44, 48, and 54 are reliant on a genus of antibody-linker-drug conjugates. Claim 56 is reliant on the genus of linker-drug conjugates of said antibody-linker-drug conjugates.
Applicant has reduced to practice the drug-linkers of A1, A2 and A3 and the formation of the antibody conjugates ADC-A1, ADC-A2 and ADC-A3:
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177
480
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212
498
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200
537
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These three linker-drug compounds differ only with respect to small alterations in “L”:
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40
85
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vs
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57
73
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vs
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46
98
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.
As can be readily seen, these linker drug differ only in (CH2)3 vs (CH2)2 and CH2-CH(CH3)CH2. Further, the remainder of the linker and the core drug molecule is identical for each of A1, A2 and A3. These compounds fail to adequate describe the genus of antibody-linker-drug and linker-drug of the claims because the claimed genus is highly variant,
encompassing any linker in claim 1 without regard to structure,
and X-Y in claims 4 and 56 wherein
each X is independently C.sub.1-40 alkylene, C.sub.1-40 heteroalkylene, C.sub.2-40 alkenylene, C.sub.2-40 heteroalkenylene, C.sub.2-40 alkynylene, or C.sub.2-40 heteroalkynylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent group and each divalent group is independently C.sub.3-10 cycloalkylene, C.sub.6-14 arylene, heteroarylene, or heterocyclylene; and
each Y is independently a bond, C.sub.1-6 alkylene, C.sub.1-6 heteroalkylene, C.sub.2-6 alkenylene, C.sub.2-6 alkynylene, C.sub.3-10 cycloalkylene, C.sub.6-14 arylene, C.sub.7-15 aralkylene, heteroarylene, or heterocyclylene; wherein each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene is optionally substituted with one or more substituents Q.to structure;
linkers L of claim 16, comprising C.sub.1-50 alkylene, C.sub.1-50 heteroalkylene, C.sub.2-50 alkenylene, C.sub.2-50 heteroalkenylene, C.sub.2-50 alkynylene, or C.sub.2-50 heteroalkynylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent group and each divalent group is independently C.sub.3-10 cycloalkylene, C.sub.6-12 arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q.
Claim 19 includes the linkers:
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701
554
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315
558
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.
Claims 1 and 56 also encompass a broad genus of core molecules having a wide array of substitutents at positions R1, R2 and R3a,:
wherein R.sup.1 and R.sup.2 are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R.sup.1a, —C(O)OR.sup.1a, —C(O)NR.sup.1bR.sup.1c, —C(O)SR.sup.1a, —C(NR.sup.1a)NR.sup.1bR.sup.1c, —C(S)R.sup.1a, —C(S)OR.sup.1a, —C(S)NR.sup.1bR.sup.1c, —OR.sup.1a, —OC(O)R.sup.1a, —OC(O)OR.sup.1a, —OC(O)NR.sup.1bR.sup.1c, —OC(O)SR.sup.1a, —OC(NR.sup.1a)NR.sup.1bR.sup.1c, —OC(S)R.sup.1a, —OC(S)OR.sup.1a, —OC(S)NR.sup.1bR.sup.1c, —OS(O)R.sup.1a, —OS(O).sub.2R.sup.1a, —OS(O)NR.sup.1bR.sup.1c, —OS(O).sub.2NR.sup.1bR.sup.1c, —NR.sup.1bR.sup.1c, —NR.sup.1aC(O)R.sup.1d, —NR.sup.1aC(O)OR.sup.1d, —NR.sup.1aC(O)NR.sup.1bR.sup.1c, —NR.sup.1aC(O)SR.sup.1d, —NR.sup.1aC(NR.sup.1d)NR.sup.1bR.sup.1c, —NR.sup.1aC(S)R.sup.1d, —NR.sup.1aC(S)OR.sup.1d, —NR.sup.1aC(S)NR.sup.1bR.sup.1c, —NR.sup.1aS(O)R.sup.1d, —NR.sup.1aS(O).sub.2R.sup.1d, —NR.sup.1aS(O)NR.sup.1bR.sup.1c, —NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, —SR.sup.1a, —S(O)R.sup.1a, —S(O).sub.2R.sup.1a, —S(O)NR.sup.1bR.sup.1c, or —S(O).sub.2NR.sup.1bR.sup.1c;
each R.sup.3a is independently (i) deuterium, cyano, halo, or nitro; (ii) C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R.sup.1a, —C(O)OR.sup.1a, —C(O)NR.sup.1bR.sup.1c, —C(O)SR.sup.1a, —C(NR.sup.1a)NR.sup.1bR.sup.1c, —C(S)R.sup.1a, —C(S)OR.sup.1a, —C(S)NR.sup.1bR.sup.1c, —OR.sup.1a, —OC(O)R.sup.1a, —OC(O)OR.sup.1a, —OC(O)NR.sup.1bR.sup.1c, —OC(O)SR.sup.1a, —OC(NR.sup.1a)NR.sup.1bR.sup.1c, —OC(S)R.sup.1a, —OC(S)OR.sup.1a, —OC(S)NR.sup.1bR.sup.1c, —OS(O)R.sup.1a, —OS(O).sub.2R.sup.1a, —OS(O)NR.sup.1bR.sup.1c, —OS(O).sub.2NR.sup.1bR.sup.1c, —NR.sup.1bR.sup.1c, —NR.sup.1aC(O)R.sup.1d, —NR.sup.1aC(O)OR.sup.1d, —NR.sup.1aC(O)NR.sup.1bR.sup.1c, —NR.sup.1aC(O)SR.sup.1d, —NR.sup.1aC(NR.sup.1d)NR.sup.1bR.sup.1c, —NR.sup.1aC(S)R.sup.1d, —NR.sup.1aC(S)OR.sup.1d, —NR.sup.1aC(S)NR.sup.1bR.sup.1c, —NR.sup.1aS(O)R.sup.1d, —NR.sup.1aS(O).sub.2R.sup.1d, —NR.sup.1aS(O)NR.sup.1bR.sup.1c, —NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, —SR.sup.1a, —S(O)R.sup.1a, —S(O).sub.2R.sup.1a, —S(O)NR.sup.1bR.sup.1c, or —S(O).sub.2NR.sup.1bR.sup.1c;
each R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is independently hydrogen, deuterium, C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl;
wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, substituents Q.sup.a; and (c) —C(O)R.sup.a, —C(O)OR.sup.a, —C(O)NR.sup.bR.sup.c, —C(O)SR.sup.a, —C(NR.sup.a)NR.sup.bR.sup.c, —C(S)R.sup.a, —C(S)OR.sup.a, —C(S)NR.sup.bR.sup.c, —OR.sup.a, —OC(O)R.sup.a, —OC(O)OR.sup.a, —OC(O)NR.sup.bR.sup.c, —OC(O)SR.sup.a, —OC(NR.sup.a)NR.sup.bR.sup.c, —OC(S)R.sup.a, —OC(S)OR.sup.a, —OC(S)NR.sup.bR.sup.c, —OP(O)(OR.sup.a)OR.sup.d, —OS(O)R.sup.a, —OS(O).sub.2R.sup.a, —OS(O)NR.sup.bR.sup.c, —OS(O).sub.2NR.sup.bR.sup.c, —NR.sup.bR.sup.c, —NR.sup.aC(O)R.sup.d, —NR.sup.aC(O)OR.sup.d, —NR.sup.aC(O)NR.sup.bR.sup.c, —NR.sup.aC(O)SR.sup.d, —NR.sup.aC(NR.sup.d)NR.sup.bR.sup.c, —NR.sup.aC(S)R.sup.d, —NR.sup.aC(S)OR.sup.d, —NR.sup.aC(S)NR.sup.bR.sup.c, —NR.sup.aS(O)R.sup.d, —NR.sup.aS(O).sub.2R.sup.d, —NR.sup.aS(O)NR.sup.bR.sup.c, —NR.sup.aS(O).sub.2NR.sup.bR.sup.c, —SR.sup.a, —S(O)R.sup.a, —S(O).sub.2R.sup.a, —S(O)NR.sup.bR.sup.c, and —S(O).sub.2NR.sup.bR.sup.c, wherein each R.sup.a, R.sup.b, R.sup.c, and R.sup.d is independently (i) hydrogen or deuterium; (ii) C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q.sup.a;
or (iii) R.sup.b and R.sup.c together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q.sup.a;
wherein each Q.sup.a is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R.sup.e, —C(O)OR.sup.e, —C(O)NR.sup.fR.sup.g, —C(O)SR.sup.e, —C(NR.sup.e)NR.sup.fR.sup.g, —C(S)R.sup.e, —C(S)OR.sup.e, —C(S)NR.sup.fR.sup.g, —OR.sup.e, —OC(O)R.sup.e, —OC(O)OR.sup.e, —OC(O)NR.sup.fR.sup.g, —OC(O)SR.sup.e, —OC(NR.sup.e)NR.sup.fR.sup.g, —OC(S)R.sup.e, —OC(S)OR.sup.e, —OC(S)NR.sup.fR.sup.g, —OS(O)R.sup.e, —OS(O).sub.2R.sup.e, —OS(O)NR.sup.fR.sup.g, —OS(O).sub.2NR.sup.fR.sup.g, —NR.sup.fR.sup.g, —NR.sup.eC(O)R.sup.h, —NR.sup.eC(O)OR.sup.f, —NR.sup.e C(O)NR.sup.fR.sup.g, —NR.sup.eC(O)SR.sup.f, —NR.sup.e C(NR.sup.h)NR.sup.fR.sup.g, —NR.sup.eC(S)R.sup.h, —NR.sup.eC(S)OR.sup.f, —NR.sup.eC(S)NR.sup.fR.sup.g, —NR.sup.eS(O)R.sup.h, —NR.sup.eS(O).sub.2R.sup.h, —NR.sup.eS(O)NR.sup.fR.sup.g, —NR.sup.eS(O).sub.2NR.sup.fR.sup.g, —SR.sup.e, —S(O)R.sup.e, —S(O).sub.2R.sup.e, —S(O)NR.sup.fR.sup.g, and —S(O).sub.2NR.sup.fR.sup.g;
wherein each R.sup.e, R.sup.f, R.sup.g, and R.sup.h is independently (i) hydrogen or deuterium; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R.sup.f and R.sup.g together with the N atom to which they are attached form heterocyclyl.
Claims 3 and 4 encompass the same array of substituents at positions R1, and R2, with the exception that R3a is hydrogen.
The description of compounds A1, A2 and A3 fail to describe the claimed genus because the genus is highly variant and the actual reduction to practice of compounds A1, A2 and A3 are not representative of the wide range of molecules encompassed by the claimed genus, having high variability both in terms of the linker and the core molecules. One of skill in the art would not e able to envisage all members of the genus as one could with a week-described genus.
Further, the specification fails to disclose a minimum structural requirement coupled with a desired functional characteristic that would allow one of skill in the art to envisage members of the claimed genus.
(B)As drawn to diastereomers of the compound of formula II, III, IV, A-I and ADC1, ADC2 and ADC3.
The specification has not described any diastereomers of formula II, II, III, IV, A-I, ADC1, ADC2 or ADC3.
. One of skill in the art would envisage formula II with the opposite chirality at the tetrahedral carbon in the lactone ring, or with the presence of a double bond in the Z configuration as opposed to the E configuration for the exocyclic double bond, there are numerous potential for other chiral centers and thus diastereomers, in the R groups of the core structures which cannot be envisaged by one of skill in the art based on the disclosure. Thus, the description of formula II fails to describe the genus of “diastereomers”.
(C)As drawn to isotopic variants of the compound of formulas II, III, IV, A-I and ADC1, ADC2 and ADC3.
When given the broadest reasonable interpretation, “isotopic variant” encompassed by all the instant claims, includes a change in isotope at any atom of formula II. It is noted that claim 1 is drawn in part to deuterium at R1, R2 and/or R3a, but this fails to describe any other isotopic variant, such as 18-O, 15-N and 32-34,36-S at any other position in the molecule, including the many embodiments of R1, R2 and R3a.
(D)As drawn to prodrugs of the compound of formula II, III, IV, and ADC1, ADC2 and ADC3..
The specification fails to describe a single pro-drug of Formula II, although it is noted that the antibody conjugate of formulas II, III, IV, ADC1, ADC2 or ADC3 is in itself a prodrug until the active drug portion is released from the antibody-linker. One of skill in the art would not be able to envisage a prodrug of formulas II , III, IV, ADC1, ADC2 or ADC3 beyond that of formulas II, III, IV, ADC1, ADC2 or ADC3..
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)(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, 3, 4, 5, 7, 15, 16, 19, 25, 29, 33, 48, 54 and 56 are rejected under 35 U.S.C. 102(a)2 as being anticipated by Zhao et al (WO2020/257998) as evidenced by Erez et al (Bioorganic and Medicinal Chemistry, 2009, Vol. 17, pp. 4327-4335), the abstract of Maloney et al (Blood, 1997, Vol. 90, pp. 218-2195) and Klein et al (WO2016/207091).
Zhao et al disclose Conjugate a025 (page 70) and compound b026 (page 385), which meets the limitations of claim 1, and 3 for RA being an antibody, m being 1-30 (claim 1 of ‘998), R1 and R2 being H, n=0, L is a linker, X or Y being C1-C40 heteroalkylene, or X or Y being C1-C6 optionally coupled with one or more substituents Q in claims 3, 4, 5 and 7 and claim 16 wherein comprising C1-50 alkylene or heteralkyene wherein the alkene is optionally substituted with one or more substituents Q, wherein Q is oxo. The linker of the compounds of a025 and b026 are non-cleavable, being -GGG- as evidenced by Erez et al (page 4329, first column, line 6 under the heading “Cell-growth inhibition assays”), thus fulfilling the limitations of claim 15. The linker of the compounds of a025 and b026 comprise the structure
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, thus fulfilling the limitations of instant claim 19.
Zhao et al disclose that the conjugates of the invention have improved pharmacokinetics in the delivery of the cytotoxic agent for the treatment of cancer (abstract) which meets the limitations of claim 54 and claim 48 because improved pharmacokinetics refers to in vivo use and therefore in a subject. Zhao et al disclose that the conjugates of the invention are more stable during the targeted delivery and minimize exposure to non-target cells, tissues or organs in the circulation, resulting in longer half-life in the blood stream, less the off-target toxicity and wider therapeutic windows of the conjugate (page 3, line 34 to page 4, line 3) which meets the limitations of a administering to a subject a therapeutically effective amount of the compound” in instant claim 48. Zhao et al disclose a pharmaceutical composition comprising the conjugates (claim 16 of ‘998) which meets the limitations of instant claim 44.
Zhao et al disclose that preferred antibodies of the inventive conjugates included rituximab (page 174, line 4), Trastuzumab (page 174, lines 16-17), anti-FOLR1 (page 175, line 30), anti-MSLN (page 179, line 8) and anti-TROP2 (page 179, line 34), which meets those limitations of claim 25.
The abstract of Maloney et al provides evidence that the rituximab comprises the CDR sequences as required in claim 29.
Table 1a of Klein et al (page 91) provides evidence that the light chain of trastuzumab (SEQ ID NO: 123) comprises the required light chain CDR sequences in claim 33, and the heavy chain of trastuzumab comprises the required heavy chain CDR sequences in claim 33:
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Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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, 3, 4, 5, 7, 15, 16, 19, 25, 29, 33, 39, 48, 54 and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Tang et al (WO2019029715).
Zhou et al, Erez et al, the abstract of Maloney et al and Klein et al teach the embodiment of claims 1, 3, 4, 5, 7, 15, 16, 19, 25, 29, 33, 48, 54 and 56 for the reasons set forth above. Zhou et al further teach that the antibodies of the conjugates include anti-TROP2 antibodies.
Tang et al teach anti-TROP2 drug conjugates comprising SEQ ID NO: 2 which meets the limitations of the CDR sequences require in claim 39:
.
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It would have been prima facie obvious to use the anti-TROP2 antibody of Tang et al in the conjugates of Zhao et al. One of skill in the art would have been motivated to do so because Zhao et al suggests that anti-ROP2 antibodies be used and Tang et al teaches the use of the specific anti-TROP2 antibody for antibody-drug conjugates.
Claims 1, 3, 4, 5, 7, 15, 16, 19, 25, 29, 33, 37, 48, 54 and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Zhong et al (WO2019246003).
Zhou et al, Erez et al, the abstract of Maloney et al and Klein et al teach the embodiment of claims 1, 3, 4, 5, 7, 15, 16, 19, 25, 29, 33, 48, 54 and 56 for the reasons set forth above. Zhou et al further teach that the antibodies of the conjugates include anti-MSLN antibodies.
Zhong et al teach single domain anti-MSLN antibodies comprising the required CDR sequences of claim 37 (paragraph [0009]).
It would have been prima facie obvious at the time prior to the effective filing date to use the anti-MSLN antibodies of Zhong et al for the anti-MSLN antibody of Zhou et al , because Zhong et al teach that the antibodies are useful for treating cancer in a method that comprises administering anti-mesothelin agent and a cytokine (abstract).
All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAREN A CANELLA whose telephone number is (571)272-0828. The examiner can normally be reached M-F 10-6:30.
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KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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