DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-31, 33-34, 37-39, 42-45, and 47-52 have been cancelled and claims 35 and 57-58 have been amended, as requested in the amendment filed on 12/04/2025. Following the amendment, claims 32, 35-36, 40-41, 46, and 53-66 are pending in the instant application.
Claim 46 stands as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, and claims 40, 53-54, and 63 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species of invention, in the Response filed 06/03/2025, there being no allowable generic or linking claim.
Claims 32, 35-36, 41, 55-62, and 64-66 are under examination in the instant office action.
Specification - Objection Withdrawn
Applicant has amended Page 110 of the specification to delete the embedded hyperlink and/or other form(s) of browser executable code and has limited the reference to the website to the top-level domain. As such, the objection to the specification is withdrawn.
Claim Objections - Withdrawn
Claim 35 was objected to for a minor informality regarding the recitation of “Formula II”. Applicant has amended claim 35 to remove the reference to “Formula II”, rendering the objection moot. As such, the objection to claim 35 is withdrawn.
Claim Rejections - 35 USC § 112 - Withdrawn
Claims 35-36, 41, and 65-66 were 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.
Applicant has amended the claims as follows:
Claim 35 has been amended to remove reference to "1 to 20 of the remaining portion of the compound of Formula II" for further clarity and has removed reference to R15 and R16 to recite that R11 is an antibody and R12 is a drug for further clarity.
Claims 57 and 58 have been amended to depend from claim 56 to remedy the lack of antecedent basis for groups Ra, Rb, Z, and/or Za.
In view of the above amendments, claims 35-36, 41, and 65-66 are now considered to be definite. As such, the rejection of claims 35-36, 41, and 65-66 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 32, 35-36, 41, 55-62, and 64-66 were rejected under 35 U.S.C. 103 as being unpatentable over US 11,576,981 B2 (previously cited on PTO-892; herein after referred to as "Al-awar") in view of WO 2018/200812 A1 (previously cited on PTO-892; herein after referred to as "Bruml") and non-patent literature by Verma and Singh (Drug Discovery and Development, 2014, 1(2), 64-88; previously cited on PTO-892; herein after referred to as “Verma”), non-patent literature by Shen et. al. (Bioorganic & Medicinal Chemistry Letters, 2017, 27, 4871-4875; previously cited on PTO-892; herein after referred to as “Shen”), non-patent literature by Raghav and Singh (European Journal of Medicinal Chemistry, 2014, 77, 231-242; previously cited on PTO-892; herein after referred to as “Raghav”), and non-patent literature by Valverde et. al. (Angew. Chem. Int. Ed., 2013, 52, 8957-8960; previously cited on PTO-892; herein after referred to as “Valverde”).
With regard to the above-listed claim rejection, it is noted that Applicants have provided the following statement pursuant to 35 U.S.C. § 102(b)(2)(C): U.S. Patent Application No. 17/618,248 (the present application) and Al-awar were, not later than the effective filing date of the claimed invention in U.S. Patent Application No. 17/618,248 subject to an obligation of assignment to or owned by Ontario Institute for Cancer (OICR), Toronto, Canada. Accordingly, the Applicant respectfully submits that Al-awar is also not an eligible reference under
35 U.S.C. § 102(a)(2).
In view of the above, the above-listed rejection under 35 U.S.C. 103 in view of Al-awar has been withdrawn.
Claim Rejections - 35 USC § 103 - Maintained
Claims 32, 35-36, 41, 55-62, and 64-66 stand as rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/200812 A1 (previously cited on PTO-892; herein after referred to as "Bruml") in view of non-patent literature by Verma and Singh (Drug Discovery and Development, 2014, 1(2), 64-88; previously cited on PTO-892; herein after referred to as “Verma”), Shen et. al. (Bioorganic & Medicinal Chemistry Letters, 2017, 27, 4871-4875; previously cited on PTO-892; herein after referred to as “Shen”), non-patent literature by Raghav and Singh (European Journal of Medicinal Chemistry, 2014, 77, 231-242; previously cited on PTO-892; herein after referred to as “Raghav”), and non-patent literature by Valverde et. al. (Angew. Chem. Int. Ed., 2013, 52, 8957-8960; previously cited on PTO-892; herein after referred to as “Valverde”), and non-patent literature by English et. al. (Cancer Medicine, 2014, 3(5), 1256-1265; previously cited on PTO-892; herein after referred to as “English”), as evidenced by non-patent literature by Ducry and Stump (Bioconjugate Chem., 2010, 21, 5-13; previously cited on PTO-892; herein after referred to as “Ducry”).
Double Patenting - Maintained
Claims 32, 35-36, 41, 55-62, and 64-66 stand as rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,576,981 (herein after referred to as "first reference patent") in view of WO 2018/200812 A1 (previously cited on PTO-892; herein after referred to as "Bruml") and non-patent literature by Verma and Singh (Drug Discovery and Development, 2014, 1(2), 64-88; previously cited on PTO-892; herein after referred to as “Verma”), non-patent literature by Shen et. al. (Bioorganic & Medicinal Chemistry Letters, 2017, 27, 4871-4875; previously cited on PTO-892; herein after referred to as “Shen”), non-patent literature by Raghav and Singh (European Journal of Medicinal Chemistry, 2014, 77, 231-242; previously cited on PTO-892; herein after referred to as “Raghav”), and non-patent literature by Valverde et. al. (Angew. Chem. Int. Ed., 2013, 52, 8957-8960; previously cited on PTO-892; herein after referred to as “Valverde”).
Claims 32, 35-36, 41, 55-62, and 64-66 stand as rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 14-18 of U.S. Patent No. 11,850,287 (herein after referred to as "second reference patent") in view of WO 2018/200812 A1 (WO 2018/200812 A1 (previously cited on PTO-892; herein after referred to as "Bruml") and non-patent literature by Verma and Singh (Drug Discovery and Development, 2014, 1(2), 64-88; previously cited on PTO-892; herein after referred to as “Verma”), non-patent literature by Shen et. al. (Bioorganic & Medicinal Chemistry Letters, 2017, 27, 4871-4875; previously cited on PTO-892; herein after referred to as “Shen”), non-patent literature by Raghav and Singh (European Journal of Medicinal Chemistry, 2014, 77, 231-242; previously cited on PTO-892; herein after referred to as “Raghav”), and non-patent literature by Valverde et. al. (Angew. Chem. Int. Ed., 2013, 52, 8957-8960; previously cited on PTO-892; herein after referred to as “Valverde”).
Claims 32, 35-36, 41, 55-62, and 64-66 stand as provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the below-listed copending Application Nos. in view of US 2019/0151464 A1 (previously cited on PTO-892; herein after referred to as “Siang-Yo”) and non-patent literature by Verma and Singh (Drug Discovery and Development, 2014, 1(2), 64-88; previously cited on PTO-892; herein after referred to as “Verma”), Shen, Raghav, and Valverde.
Application No.
Brief Description of the Invention
Pertinent Claims
17618298
Compounds Comprising Hydrazone Linkers Heterocycloalkyl or Heteroaromatic Rings, ADCs, and Methods of Preparation Thereof
1, 3, 7-8, 25, 35-39, 41, 55
18014890
Compounds Comprising Hydrazone Linkers Heterocycloalkyl or Heteroaromatic Rings, ADCs, and Methods of Preparation Thereof
1, 3, 7-8, 16, 26, 36-39, 55
Claims 32, 35-36, 41, 55-62, and 64-66 stand as rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the below-listed U.S. Patents in view of WO 2018/200812 A1 (previously cited on PTO-892; herein after referred to as "Bruml") in view of non-patent literature by Verma and Singh (Drug Discovery and Development, 2014, 1(2), 64-88; previously cited on PTO-892; herein after referred to as “Verma”), Shen et. al. (Bioorganic & Medicinal Chemistry Letters, 2017, 27, 4871-4875; previously cited on PTO-892; herein after referred to as “Shen”), non-patent literature by Raghav and Singh (European Journal of Medicinal Chemistry, 2014, 77, 231-242; previously cited on PTO-892; herein after referred to as “Raghav”), and non-patent literature by Valverde et. al. (Angew. Chem. Int. Ed., 2013, 52, 8957-8960; previously cited on PTO-892; herein after referred to as “Valverde”), and non-patent literature by English et. al. (Cancer Medicine, 2014, 3(5), 1256-1265; previously cited on PTO-892; herein after referred to as “English”), as evidenced by non-patent literature by Ducry and Stump (Bioconjugate Chem., 2010, 21, 5-13; previously cited on PTO-892; herein after referred to as “Ducry”).
Patent No.
Brief Description of the Invention
Pertinent Claims
11576981
Compounds Comprising Hydrazone Linkers Heterocycloalkyl or Heteroaromatic Rings and ADCs Thereof
1-20
11850287
Compounds Comprising Hydrazone Linkers Heterocycloalkyl or Heteroaromatic Rings, ADCs, and Methods of Preparation Thereof
1-12, 14-18
Claims 32, 35-36, 41, 55-62, and 64-66 stand as provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the below-listed copending Application Nos. in view of WO 2018/200812 A1 (previously cited on PTO-892; herein after referred to as "Bruml") in view of non-patent literature by Verma and Singh (Drug Discovery and Development, 2014, 1(2), 64-88; previously cited on PTO-892; herein after referred to as “Verma”), Shen et. al. (Bioorganic & Medicinal Chemistry Letters, 2017, 27, 4871-4875; herein after referred to as “Shen”), non-patent literature by Raghav and Singh (European Journal of Medicinal Chemistry, 2014, 77, 231-242; previously cited on PTO-892; herein after referred to as “Raghav”), and non-patent literature by Valverde et. al. (Angew. Chem. Int. Ed., 2013, 52, 8957-8960; previously cited on PTO-892; herein after referred to as “Valverde”), and non-patent literature by English et. al. (Cancer Medicine, 2014, 3(5), 1256-1265; previously cited on PTO-892; herein after referred to as “English”), as evidenced by non-patent literature by Ducry and Stump (Bioconjugate Chem., 2010, 21, 5-13; previously cited on PTO-892; herein after referred to as “Ducry”).
Application No.
Brief Description of the Invention
Pertinent Claims
17618298
Compounds Comprising Hydrazone Linkers Heterocycloalkyl or Heteroaromatic Rings, ADCs, and Methods of Preparation Thereof
1, 3, 7-8, 25, 35-39, 41, 55
18014890
Compounds Comprising Hydrazone Linkers Heterocycloalkyl or Heteroaromatic Rings, ADCs, and Methods of Preparation Thereof
1, 3, 7-8, 16, 26, 36-39, 55
Response to Arguments
Applicant's arguments filed 12/04/2025 (herein after referred to as "Remarks") and the affidavit under 37 CFR 1.132 filed 12/04/2025 (herein after referred to as "Affidavit") have been fully considered, but are deemed insufficient to overcome the above-listed claim rejections (indicated as “Maintained”) as set forth in the last Office action.
In short, Applicant argues the following with regard to the Affidavit:
Figure 1 in the Mamai declaration is a graph showing the stability of exemplary trastuzumab antibody-drug conjugates of the application (i.e. compounds of Formula IV as claimed in the present application) and a comparative antibody-drug conjugate which comprises a linker with a simple phenyl group as "A" instead of a heterocycloalkyl and heteroaromatic group as defined in the compounds of the present application. Compound T-14869, containing a linker with a simple phenyl group as "A" as defined in the compounds of the present application (for example, as in Ducry), has a high bar and therefore low stability in serum. Conversely, compounds of the present application, such as T-19772 (IVd), T-16418 (IVf) and T-19392 (IVa), which each have a heterocyclic or heteroaryl group as A, have much lower bars which equates to a higher serum stability. It is noted that compound T-16527 (IVi), has a much lower bar than T-14869 at least in the first 12 hours.
Applicant submits that these results clearly demonstrate the unexpected improved stability of the compounds of the application comprising 5 or 6 membered heterocycloalkyl or heteroaromatic acyl hydrazone linkers. Moreover, it is submitted that these results clearly demonstrate that modifications to the linker such as the replacement of a phenyl ring with a 5-6-membered unsaturated heterocyclic or heteroaromatic ring (i.e., the identity of group A) have a significant impact on the stability of the resulting conjugated compounds, and that such modifications to the linker cannot be predicted without undue experimentation, nor with any reasonable expectation of success.
The above have been fully considered, but are deemed not persuasive.
With regard to the Affidavit, it is noted that Affidavit evidence must be statistically significant:
MPEP 716.02b: The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c).
It is noted that there is no statistical analysis presented with regard to stability studies between the different compounds; as such it is not immediately clear that any of the differences in stability are “real” or “significant” as argued. Furthermore, it is noted that Applicant specifically argues unexpected improved stability of the compounds of the application comprising 5 or 6 membered heterocycloalkyl or heteroaromatic acyl hydrazone linkers, asserting that all linkers of the instant invention have improved stability relative to an exemplary linker of Ducry (i.e., compound T-14869). However, it is noted that the data presented is not commensurate in scope with the instant claims; the data presented is drawn to specific types of compounds with specific moieties whereas independent claim 32 is broader and is drawn to compounds which may comprise a variety of moieties. For example, the data presented is drawn to four different heterocyclic/heteroaromatic groups (i.e., T-19722, T-16418, T-16527, and T-19392), whereas independent claim 32 indicates that the heterocyclic/heteroaromatic group may be a 5-6 membered ring, comprising from 1-4 heteroatoms (wherein the heteroatoms may be selected from O, N, and S) wherein said heterocyclic/heteroaromatic group may optionally be substituted with one or more substituents including CN, NO2, halo, C1-6alkyl, C1-6fluoroalkyl, =O, OR5, SR5, and NR5R6 further wherein R2 and R3 may join together with the atoms therebetween to form a 4-6 membered saturated or unsaturated ring, optionally containing one additional heteroatom selected from O, N and S, and optionally substituted with one or more substituents selected from C1-6alkyl and C1-6fluoroalkyl. No examples of 5-6 membered heterocyclic/heteroaromatic rings with four heteroatoms are presented, nor 5-6 membered rings with O or S as heteroatoms. Additionally, no 5-6 membered heterocyclic/heteroaromatic rings substituted with CN, NO2, halo, C1-6fluoroalkyl, OR5, SR5, nor NR5R6 are presented. Furthermore, no examples wherein R2 and R3 join together with the atoms therebetween to form a 4-6 membered saturated or unsaturated ring are presented that contain (i) an additional heteroatom selected from O, N and S, and/or (ii) are substituted with one or more of C1-6alkyl and C1-6fluoroalkyl. Thus, the data presented is not commensurate in scope with the instant claims. Additionally, based on the data presented, the assertion regarding all linkers of the instant invention having improved stability does not appear to be fully supported as generally as it is argued. In particular, Applicant argues T-16527 (IVi; compound of the instant invention) has a much lower bar than T-14869 at least in the first 12 hours; absent statistical analysis it is unclear that the difference is significant, and more notably compound T-1652 based on bar heights alone becomes the most unstable compound after the 12 hour measurement wherein the bar heights at the later timepoints are even higher than that of T-14869 to which all of the instant compounds are compared to establish their enhanced stability. As such, the data presented in the Affidavit is deemed to be not persuasive. The arguments regarding predictability and reasonable expectations of success are more specifically addressed below.
In short, Applicant argues the following with regard to the prior art references and their subsequent combination (for claim rejections under 35 U.S.C. 103 and nonstatutory double patenting):
A person of skill in the art would have no motivation to modify the structurally different linkers of Bruml, let alone make the number of changes to the linker of Bruml needed to arrive at the compounds of the present application comprising 5 or 6 membered heterocycloalkyl and heteroaromatic acyl hydrazone linkers in light of Ducry, Verma, Shen, Raghav, Valverde, and English alone or in combination.
Given the unpredictability of the effect of any modifications to the linker, it is submitted a person skilled in the art would not have any reasonable expectation that the 5-6-membererd unsaturated heterocyclic or heteroaromatic ring acyl hydrazone linkers would work to provide stable and effective linkers, let alone ones with improved stability, based on the disclosure of the structurally different linkers of Bruml and Ducry and English and/or, the teaching of biologically active heterocycles such as triazolones and triazoles of Verma Shen, Raghav and Valverde.
None of the various exemplified compounds or linkers of Bruml comprise an acyl hydrazone let alone a 5 or 6 membered heterocycloalkyl or heteroaromatic acyl hydrazone in the linker.
Ducry not disclose or suggest linkers comprising 5 or 6 membered heterocycloalkyl or heteroaromatic acyl hydrazones. Ducry further does not teach or suggest improved stability of the 5 or 6 membered heterocycloalkyl or heteroaromatic acyl hydrazone linkers of the present application compared to the structurally different phenyl acyl hydrazone in the compound of Ducry.
None of Verma Shen, Raghav and Valverde relate to antibody-drug conjugates or linker groups for use in linkers of ADC. Moreover, none of Verma Shen, Raghav and Valverde disclose heterocycloalkyl and heteroaromatic acyl hydrazones.
English relates to Trastuzumab emtansine which the Applicant submits is an antibody-drug conjugate comprising a non-cleavable linker linking Trastuzumab and DM1. Therefore, English also does not teach or suggest the acyl hydrazone linker as presently claimed.
There is no reason a person skilled in the art would be motivated to combine Bruml with Ducry, Verma Shen, Raghav, Valverde and English in the way alleged by the Examiner to arrive at the compounds of the present application specifically comprising 5 or 6 membered heterocycloalkyl and heteroaromatic acyl hydrazone linkers. Bruml simply lists a hydrazone as an example of a linker group in a large number of possible linker groups. However, none of the numerous exemplified linkers and exemplified compounds in Bruml comprise an acyl hydrazone group, let alone the combination of heterocycloalkyl and heteroaromatic group with the acyl hydrazone group. Ducry illustrates an example of an ADC with a phenyl acyl hydrazone, and the remaining cited references simply relate to heterocycles per se or an ADC comprising DM1 and a non-cleavable linker. Therefore, it is submitted that there is no guidance or suggestion in Bruml to motivate a person skilled in the art to modify the linker of Bruml to, for example, incorporate acyl hydrazone as taught by the Ducry and then further modify the linker to include heterocycloalkyl and heteroaromatic groups as generically disclosed in Verma, Shen, Raghav and Valverde.
There is no fully supported reasoning as to why a person skilled in the art, beginning with the exemplified linkers of Bruml (which do not comprise acyl hydrazones), would be motivated to look to Ducry for that particular example of a phenyl acyl hydrazone, and then look to the remaining references for active heterocycles in order to specifically make the sequential linker group elections and combinations to arrive at the present linkers and there is no fully supported reasoning as why a person skilled in the art, given the unpredictability of modifications to the linker to the stability and efficacy of the ADC, would have expected that combining the various prior art elements "would be expected to yield predictable results with a reasonable expectation of success".
The above have been fully considered, but are deemed not persuasive.
With regard to the deficiencies of the references as argued individually, it is noted that, it has been held that one cannot show non-obviousness by attacking references individually where, as here, the rejections are based on combinations of references. In re Keller, 208 USPQ 871 (CCPA 1981). With regard to the lack of motivation to combine the references, it is noted that:
There is no requirement that an “express, written motivation to combine must appear in prior art references before a finding of obviousness.” See Ruiz v. A.B. Chance Co., 357 F.3d 1270, 1276, 69 USPQ2d 1686, 1690 (Fed. Cir. 2004).
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992); see also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP 2144(I).
Obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).
As noted in the previous Office Action (08/12/2025), Bruml was relied upon for its teachings regarding ADC linker components (i.e., cleavable linkers) that include alkylene groups (including substituted alkylene groups and/or alkylene groups wherein one or more methylene groups are replaced), carbonyl groups, amine groups, triazole groups, and hydrazone groups (Pages 209-216), further evidenced by Ducry, wherein an antibody is linked via amide linkage and wherein the drug is linked via a disulfide (Page 290 and 207, respectively). Verma, Shen, Raghav, and Valverde all teach various triazole compounds which are known to have many biological activities and are shown to enhance biological activities/improve pharmacological properties when added/incorporated into known structures; thus one of ordinary skill in the art would expect that the incorporation of a substituted 1,2,4-triazole (e.g., a substituted triazol-3-one) would be likely to improve biological properties of ADCs when incorporated as a linker component. Furthermore, the combination of Bruml, Verma, Shen, Raghav, and Valverde demonstrate that triazoles may be substituted/incorporated in various manners; Verma teaches the incorporation of a carbonyl at the 3-position, Verma and Bruml further suggest that bonds with other moieties may be achieved via the non-carbonyl carbon and the N groups of the ring may be substituted/further participate in bonding and Shen, Raghav, and Valverde further teach various derivatives of triazoles that retain/improve biological activity and/or other properties. Thus, one of ordinary skill in the art could reasonably arrive at a 1,2,4,-traizole wherein there is a carbonyl at the 2-position and wherein the N at the 4-position could be substituted with, for example, a methyl group. It is well established in the art that substitution of a hydrogen for a methyl group is obvious absent unexpected results. It is generally 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 a 1,2,4-triazole, which further includes a carbonyl at position-3, to a “methyl” (e.g., at the N at position-4) as required by the instant claims. Thus, Bruml is utilized to establish the use of cleavable linkers in ADCs (as evidenced by Ducry), wherein said linker may comprise a hydrazone moiety and other specified structural elements of the instantly claimed linker. It was acknowledged the “Ring A” as instantly defined was not disclosed or suggested by Bruml nor Ducry. Verma, Shen, Raghav, and Valverde demonstrate that triazoles may be substituted/incorporated in various manners, and their incorporation into known structures (e.g., structures having biological/pharmacological functions) enhances/improves the activities of these known structures. Thus, it would have been reasonably expected that incorporating a triazole (which would fit the definition of “Ring A”) into an ADC. English was solely relied upon to demonstrate the DM1 and trastuzumab have been shown to be effective in the context of ADCs. With regard to the argument that the ADC of English employs a non-cleavable linker, it is noted that Bruml Page 128 indicates that cleavable elements are selected based upon their mechanism of cleavage such that the selected components yielding a cleavable linker are selected such that “the linker is substantially stable in vivo until the immunoconjugate binds to or enters a cell, at which point either intracellular enzymes or intracellular chemical conditions (pH, reduction capacity) cleave the linker to free the Drug moiety” (see Lines 22-25). It would therefore be within the purview of one of ordinary skill in the art to select a cleavable linker wherein the drug may be specifically released at desired times/locations rather than, in the case of non-cleavable linkers, relying on the complete degradation of an ADC to exert maximal therapeutic effects. As such, it is maintained that it would have been within the purview of one having ordinary skill in the art to modify the linker of Bruml, which may incorporate a hydrazone moiety as evidenced by Ducry, to (1) add an element instantly defined as “Ring A” in view of the teachings Verma, Shen, Raghav, and Valverde, wherein the addition of such a group would reasonably be expected to enhance/improved properties of the ADC as suggested by the prior art references, and (2) use DM1 as the drug, which has been established as an effective drug for use in ADCs, including ADCs wherein the antibody is anti-HER2 antibody trastuzumab.
In view of the above, the above-listed claim rejections (indicated as “Maintained”) as set forth in the last Office action are maintained. It is specifically noted that, with regard to the provisional nonstatutory double patenting rejections listed above, Applicant has requested the rejections be held in abeyance. As such, no arguments have been presented and the provisional nonstatutory double patenting rejections listed above are therefore maintained.
Conclusion
Claims 32, 35-36, 40-41, 46, and 53-66 are pending. Claims 40, 46, 53-54, and 63 are withdrawn. Claims 32, 35-36, 41, 55-62, and 64-66 are rejected. No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642