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 without traverse of Group II, claims 11-17, in the reply filed on September 29, 2025.
Applicant’s election without traversal of the species of Example M2 from paragraph [0447] of the specification in the reply filed on September 29, 2025 is acknowledged.
Claims 1-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on September 29, 2025.
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. This instant application is a CON of 16/637,099 filed on February 6, 2020, PAT 11795195 issued October 24, 2023, claims priority of JAPAN 2017-155990, filed on August 10, 2017.
Status of Claims
Claims 11-15 are amended, claims 16-17 are cancelled and new claims 18-19 are added, filed on July 27, 2026.
Claim Rejections - 35 USC § 103 (modified)
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.
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 11-15, 18, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over WO 1996033211 (published October 24, 1996, filed with IDS dated July 3, 2023) and Lesma et. al. (“Hemiasterlin analogues incorporating an aromatic, and heterocyclic type C-terminus: design, synthesis and biological evaluation”; Giordano Lesma, Alessandro Sacchetti, Rouli Bai, Giuseppe Basso, Roberta Bortolozzi, Ernest Hamel, Alessandra Silvani, Nadia Vaiana, Giampietro Viola; Mol Divers.;18(2):357–373; published February 6, 2014), in view of US 20150320879 (published November 12, 2015).
WO’211 The use of a hemiasterlin compound of general formula
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wherein: R1 and R70 independently represent a hydrogen atom or an optionally substituted alkyl or acyl group; R2 represents a hydrogen atom or an optionally substituted alkyl or acyl group or is absent when R6 represents a group -CH= as hereinafter described; R73 represents a hydrogen atom or an optional substituent or is absent when R6 represents a methylene group or a group -CH= as hereinafter described; Y represents an optional substituent; n represents 0, 1, 2, 3, or 4; R3 represents a hydrogen atom, or an optionally substituted alkyl group; R74 represents a hydrogen atom, a hydroxy group or an optionally substituted alkyl or acyl group; R7 represents a hydrogen atom or an alkyl group; R75 represents an optionally substituted alkyl group; and i) R6 and R71 independently represent a hydrogen atom or an optionally substituted alkyl or acyl group; and R72 represents a hydrogen atom; or
ii) R71 represents a hydrogen atom or an optionally substituted alkyl or acyl group and R72 represents a hydrogen atom or R71 and R72 each represent radicals so that a double bond is formed between the carbon atoms to which they are attached; and R6 represents an optionally substituted methylene group bonded to the indole moiety thereby to form a tricyclic moiety; or
R6 represents an optionally substituted group -CH= bonded to the indole moiety thereby to form an aromatic tricyclic moiety; for the manufacture of a medicament for use in therapy (see claim 1). WO’211 specifies Y and/or R73 represent optional substituents, said substituents may be independently selected from halogen, especially fluorine (see page 3, line 32-34).
Additionally, Lesma et. al. teaches a representative series of structural analogs of the antimitotic tripeptides hemiasterlins have been designed and synthesized (see Abstract). Lesma et. al. teaches that relative to other known antimitotic agents, hemiasterlins possess an attractive combination of structural simplicity and potent antimitotic activity, making them ideal targets for synthetic modification. A synthetic analog of hemiasterlin 1, taltobulin, wherein a phenyl group replaces the 3-substituted indole ring, advanced to clinical trials. Unlike paclitaxel and vinblastine, taltobulin is a poor substrate for P-glycoprotein drug transporters and maintains toxicity toward cell lines with high expression of multidrug resistant drug pumps. Hemiasterlins and taltobulin contain three highly modified amino acids that are responsible for compound stability and in vivo activity (see Introduction, Fig. 1. Shown below).
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Therefore, it would have been obvious to combine the teachings of WO’211 and Lesma et. al., before the effective filing date of the claimed invention utilizing hemiasterlin derivative scaffold with selectable substituents as cytotoxic payload.
However, both WO’211 and Lesma are silent about cleavable drug linker unit as maleimide amino acid derivative forming hemiasterlin linker conjugate.
US’879 teaches about Ligand-Drug Conjugates, Drug-Linkers, Linkers, and Ligand-Linker Conjugates comprising a self-stabilizing linker assembly component (see Abstract). US’879 teaches a compound having the formula (shown below):
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or a suitably protected form and/or salt thereof, wherein D′ is a Drug unit, Detection unit or Stability unit; LO is an optional secondary linker assembly that is present; and BU is a Basic unit; HE is a hydrolysis enhancer unit comprising an electron withdrawing group; the circle represents a scaffold, wherein the scaffold is a C1-8 alkylene, C1-8 heteroalkylene, C6-10 arylene, or C4-10 heteroarylene, and optionally having a functional group from a reactive site suitable for attachment to LO (see claim 1).
US’879 teaches that in the drug-Linker units, the Linker portion comprises a self-stabilizing linker assembly. In another group of embodiments, Ligand-Linker conjugates are provided, where the Linker portion comprises a self-stabilizing linker assembly. In some embodiments, the Linker portion further comprises an optional secondary linker assembly)(LO). In some embodiments, the secondary linker assembly is a releasable linker assembly which comprises a Cleavable unit and optionally one or more of a Stretcher and a Spacer unit. In some other embodiments, the secondary linker assembly is a non-releasable linker assembly which comprises one or more of a Stretcher unit and a Spacer unit. In still other embodiments, the invention provides methods of treating cancer, immune disease, infectious diseases and other diseases and disorders using a Ligand-Drug Conjugate comprising a self-stabilizing linker assembly (see [0060]).
US’879 further discloses the cleavable unit is present has the formula -(AA-AA)1-6-; wherein AA is at each occurrence independently selected from an amino acid; the cleavable unit is present and conjugated directly to the Drug unit; the cleavable unit is present and conjugated directly to the Drug unit via a cleavable peptide (see [0207], [0208], [0209]). The Cleavable unit is capable of forming a cleavable bond with a Drug unit or a Spacer unit. Reactive groups for forming cleavable bonds can include, for example, sulfhydryl groups to form disulfide bonds, aldehyde, ketone, or hydrazine groups to form hydrazone bonds, carboxylic or amino groups to form peptide bonds, and carboxylic or hydroxy groups to form ester bonds (see [0302]).
In some embodiments, the Cleavable unit will comprise one amino acid or one or more sequences of amino acids. The Cleavable unit can comprise, for example, a monopeptide, a dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide or dodecapeptide unit (see [0305]).
US’879 specifies that each amino acid can be natural or unnatural and/or a D- or L-isomer provided of course that there is a cleavable bond. In some embodiments, the Cleavable unit will comprise only natural amino acids. In some aspects, the Cleavable unit will comprise 1 to 12 amino acids in contiguous sequence (see [0306]). In some embodiments, each amino acid is independently selected from the group consisting of alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine (see [ 0307]). In certain embodiments, the Cleavable unit can comprise only natural amino acids. In other embodiments, the Cleavable unit can comprise only non-natural amino acids. In some embodiments, the Cleavable unit can comprise a natural amino acid linked to a non-natural amino acid. In some embodiments, the Cleavable unit can comprise a natural amino acid linked to a D-isomer of a natural amino acid (see [0313]).
US’879 further discloses that in some embodiments, the Cleavable unit will comprises a peptide and will comprise from 1 to 12 amino acids. In some such embodiments, the peptide will be conjugated directly to the Drug unit and the Spacer unit will be absent (see [0314]). In some embodiments, the Cleavable unit —WW— will be represented by -(-AA-) 1-12-, or (-AA-AA-)1-6 wherein AA is at each occurrence independently selected from natural or non-natural amino acids. In one aspect, AA is at each occurrence independently selected from natural amino acids. One of skill in the art would appreciate that amino acids are typically linked to the Drug unit or Spacer unit through functional units present in the amino acid, e.g., its carboxylic acid or amino termini (see [0315]).
At the time before the effective filling date of the claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to use the hemiasterlin derivative as taught in WO’211 and Lesma et. al., may be appropriately modified to facilitate a conjugation reaction with maleimide linker (as in the instant claim ), with target moiety, and formation of a conjugate antibody-maleimide linker- hemiasterlin derivative as taught by US’879 to arrive at the presently claimed invention. One of skill in the art would appreciate that amino acids are typically linked to the Drug unit or Spacer unit through functional units present in the amino acid, e.g., its carboxylic acid or amino termini(see [0315], US’879). The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in synthesizing antibody conjugates with an antibody bound to maleimide by a thiol bond via cysteine present in the antibody disulfide bonds, and bind the maleimide amino acid linker to the hemiasterlin derivative with an expectation to use as an anticancer agent and use other anticancer agents in combination as potent cytotoxic and anti-mitotic compositions.
Regarding claims 11, 12, and 14, US’879 teaches the compound has the formula of: STR00100 (shown below) or a suitably protected form and/or salt thereof, wherein D′ is a Drug unit; LO is a secondary linker assembly; and BU is a Basic unit; HE is a hydrolysis enhancer unit comprising an electron withdrawing group; the circle represents a scaffold, wherein the scaffold is a C1-8 alkylene, C1-8 heteroalkylene, C6-10 arylene, or C4-10 heteroarylene, and optionally having a functional group from a reactive site suitable for attachment to LO; the subscript r is 1; and the subscript a is 1, or has the formula of: STR00101 (shown below) or a suitably protected form and/or salt thereof, wherein the subscript a is 1; —W— is an optional Cleavable unit, the subscript w′ is 0 or 1; —Y— is an optional Spacer unit, the subscript y′ is 0 or 1; -A- is a Stretcher unit; -A′-is an optional Stretcher unit component at the terminus of A, the subscript a′ is 0 or 1; the subscript u ranges from 1 to 20, wherein when u ranges from 2 to 20, A is present, and when u is 1, A is present or absent; and BU, HE, the subscripts a and r and the circle are as previously defined (see claim 2).
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STR00100 STR00101
US’879 specifies “Substituted alkyl” and “substituted aryl” mean alkyl and aryl, respectively, in which one or more hydrogen atoms are each independently replaced with a substituent. Typical substituents include, but are not limited to, —X, —R, —O−, —OR, —SR, —S−, —NR 2, —NR 3, ═NR, —CX3, —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO2, ═N2, —N3, —NRC(═O)R, —C(═O)R, —C(═O)NR2, —C(—O)R, —C(═O)X, —C(═S)R, —CO2R, where each X is independently a halogen: —F, —Cl, —Br, or —I; and each R is independently —H, —C1-C20 alkyl, —C6-C20 aryl, —C3-C 14 heterocycle, a protecting group or a prodrug moiety. Alkylene, carbocycle, carbocyclo, arylene, heteroalkyl, heteroalkylene, heterocycle, heterocyclo, heteroaryl, and heteroarylene groups as described above may also be similarly substituted (see [0051]). In some embodiments, the Cleavable unit —WW— will be represented by -(-AA-) 1-12-, or (-AA-AA-)1-6 wherein AA is at each occurrence independently selected from natural or non-natural amino acids. In one aspect, AA is at each occurrence independently selected from natural amino acids. One of skill in the art would appreciate that amino acids are typically linked to the Drug unit or Spacer unit through functional units present in the amino acid, e.g., its carboxylic acid or amino termini (see [0315]). In another embodiment, each amino acid is independently selected from the group consisting of the following L-(natural) amino acids: alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, tryptophan and valine (see [0308]). In another embodiment, each amino acid is independently selected from the group consisting of the following D-isomers of these natural amino acids: alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, tryptophan and valine (see [0309]).
Regarding claims 13 and 15, US’879 teaches that in some embodiments, Ligand-Drug Conjugates have the formula:
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STR00013
or a pharmaceutically acceptable salt thereof, wherein the Ligand portion is an antibody (Ab), the subscript p ranges from 1 to 20 (preferably 1 to 12), and M1, BU, LO are as described in any of the embodiments provided herein, and D is a Drug unit. For example, in some aspects, LO is a releasable linker assembly, and BU is —(CH2)xNH2, —(CH2)xNHRa, and —(CH 2)xNRa2, wherein x is an integer of from 1-4 and each Ra is independently selected from the group consisting of C1-6 alkyl and C1-6 haloalkyl, or two Ra groups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group. In yet other aspects, LO is a releasable linker assembly, and BU is —CH2NH2, —CH2CH2NH2, —CH2CH2CH2NH2, or —CH2CH2CH2CH2NH2. In some aspects, the Ab can be replaced by a non-antibody protein (see [0115]).
US’879 teaches in certain selected embodiments, the Functional Agent-Linker Conjugate is represented by the formula:
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STR00017
or a salt thereof, wherein the circle, HE, BU, LO and D′ have the meanings provided above and D is a Drug unit. Additionally, each of the specifically recited selected embodiments for the circle, HE, BU, LO and D′ (for Formula above or any of the conjugates provided herein) are equally applicable to these Drug-Linker Conjugates. In preferred aspects D′ is a Drug unit, D (see [0124]). US’879 acknowledges the skilled artisan will understand that for particularly strong electron withdrawing groups such as fluoro, trifluoromethyl, and nitro, the group can be further from the maleimide (see [0064]).
As discussed above by WO’211, hemiasterlin derivatives may have optional substituents, said substituents may be independently selected from halogen, especially fluorine (see page 3, line 32-34).
Regarding claims 18 and 19, WO’211 teaches structural analogs of the antimitotic tripeptides hemiasterlins have been designed and synthesized, as potential inhibitors of tubulin polymerization (see Abstract); the tubulin/microtubule system plays a key role during mitosis, and disturbing its dynamic equilibrium can prevent cell division and induce apoptosis; this system has been recognized as an established target of many anticancer drugs (see Introduction). US’879 teaches bioconjugates prepared with an IgG 1 antibody and self-stabilizing maleimide linkers with varying spacing between the maleimide and the basic group (see [0009] and FIG. 4). US’879 provides hydrolysis kinetic profiles for bioconjugates prepared with an IgG1 antibody and various N-substituted maleimides (see [0010], FIG. 5); where “antibody” herein is used in the broadest sense and specifically covers intact monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments that exhibit the desired biological activity. An intact antibody has primarily two regions: a variable region and a constant region. The variable region binds to and interacts with a target antigen. The variable region includes a complementary determining region (CDR) that recognizes and binds to a specific binding site on a particular antigen (see [0020]). US’879 specifies Ligand Drug conjugate (e.g., an Antibody Drug Conjugate (ADC) or the like), whereby the covalent attachment, e.g., the linker, between the Drug moiety (D) and the Ligand unit (e.g., an antibody (Ab)) is broken, resulting in the free Drug, or other metabolite of the conjugate dissociated from the antibody inside the cell (see [0029]).
US’879 teaches in yet other selected embodiments, Ligand-Drug Conjugates have the formula:
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or a pharmaceutically acceptable salt thereof, wherein the Ligand portion is an antibody (Ab), the subscript p ranges from 1 to 20 (preferably 1 to 12), and M1, BU, LO are as described in any of the embodiments provided herein, and D is a Drug unit. For example, in some aspects, LO is a releasable linker assembly, and BU is —(CH2)xNH2, —(CH2)xNHRa, and —(CH2)xNRa 2, wherein x is an integer of from 1-4 and each Ra is independently selected from the group consisting of C1-6 alkyl and C1-6 haloalkyl, or two Ra groups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group. In yet other aspects, LO is a releasable linker assembly, and BU is —CH2NH2, —CH2CH2NH2, —CH2CH2CH2NH2, or —CH2CH2CH2CH2NH2 (see [0115]); In yet other selected embodiments, the Ligand-Drug Conjugates have the formula:
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or a pharmaceutically acceptable salt thereof wherein the Ligand portion is an antibody (Ab) and the subscript p ranges from 1 to 20 (preferably 1 to 12) and M1, BU, and LO are as described in any of the embodiments provided herein, and D is a Drug unit. For example, in some aspects, LO is a releasable linker assembly, and BU is —(CH2)xNH2, —(CH2)xNHRa, and —(CH2)xNRa 2, wherein x is an integer of from 1-4 and each Ra is independently selected from the group consisting of C1-6 alkyl and C1-6 haloalkyl, or two Ra groups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group. In yet other aspects, LO is a releasable linker assembly, and BU is —CH2NH2, —CH2CH2NH2, —CH2CH2CH2NH2, or —CH2CH2CH2CH2NH2 (see [0116]).
Response to Arguments
Applicant's arguments filed 07/27/2026 have been fully considered but they are not persuasive.
Applicants argument WO '436 does not provide a reason to select the specific L1-Z24 compound as a lead compound for further modification. WO'436 broadly discloses that the chemical compound Z with antiblastic activity may be selected from compounds Z1 to Z24. WO '436 further discloses that preferred maleimide linkers for conjugation to chemical compounds include linkers L1 to L12. WO'436 then lists numerous possible chemical compound Z-linker L combinations, including L1-Z24, among many other combinations –Examiner would like to remind the Applicant that in the Applicant's election without traversal of the species of Example M2 led to the examination performed with reference to the prior art WO’436. With the Applicant’s amendments to claims, new grounds of rejection have been necessitated. Examiner would like to remind the Applicant that the rejection of record was that it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of WO’211, Lesma et. al., and US’879 to utilize antibody conjugates like hemiasterlin-antibody conjugate with a maleimide linker with an expectation to use as an anticancer agent.
Applicant argues the present specification confirms that the compound corresponding to L1-Z24 is treated as a Comparative Example compound, not as a compound of the present invention – The instantly claimed compound M2 (corresponding to L1-Z24 of WO’436) was the species selected by the Applicant in reply to the Restriction requirement, reply filed on September 29, 2025. With the Applicant’s amendments to claims, new grounds of rejection have been necessitated. Examiner would like to remind the Applicant that the rejection of record was that it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of WO’211, Lesma et. al., and US’879 to utilize antibody conjugates like hemiasterlin-antibody conjugate with a maleimide linker with an expectation to use as an anticancer agent.Applicant argues the present specification demonstrates unexpected results relative to the Comparative Example compound corresponding to L1-Z24…- Also, Examiner would like to remind the Applicant that "A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue." In re Corkill, 771 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). In Corkhill, the claimed combination showed an additive result when a diminished result would have been expected. This result was persuasive of nonobviousness even though the result was equal to that of one component alone. Evidence of a greater than expected result may also be shown by demonstrating an effect which is greater than the sum of each of the effects taken separately (i.e., demonstrating "synergism"). Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). However, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991). Applicants who allege the inventor discovered the source of a problem must provide evidence substantiating the allegation, either by way of affidavits or declarations, or by way of a clear and persuasive assertion in the specification. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979) (unsubstantiated statement of counsel was insufficient to show appellants discovered source of the problem); In re Kaslow, 707 F.2d 1366, 217 USPQ 1089 (Fed. Cir. 1983).
Applicant argues the corresponding antibody-drug conjugates prepared from the claimed compounds maintained strong cytotoxic activity. Thus, the claimed compounds achieve a favorable balance of properties: reduced cellular toxicity of the free payload-linker compound, while maintaining strong cytotoxic activity when incorporated into an antibody-drug conjugate. This result would not have been reasonably expected from WO'436 or US'879. WO'436 merely lists L1-Z24 among numerous possible linker-payload combinations. US '879 likewise does not teach that introducing the presently claimed lysine, glutamic acid, or lysine-glutamic acid structures into an L1-Z24-type payload-linker would reduce membrane permeability and free payload-linker toxicity without impairing ADC cytotoxic activity – The teachings of WO’211 and US’879 motivates synthesizing antibody conjugates with an antibody bound to maleimide by a thiol bond, and bind the maleimide amino acid linker to the hemiasterlin derivative with an expectation to use as an anticancer agent and use other anticancer agents in combination as potent cytotoxic and anti-mitotic compositions. Further, it is noted that it is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006).
Applicant argues the present specification further explains that this advantageous effect is attributable to reduced membrane permeability. In particular, the drug moiety of the claimed compounds has low cell membrane permeability, such that the drug moiety is less likely to passively diffuse into normal cells. This supports the conclusion that the claimed compounds are not merely predictable variants of the Comparative Example compound, but instead provide an unexpected safety-related advantage while preserving ADC activity. –US’879 teaches that once inside the cell, one or more specific peptide sequences within the Linker unit are cleaved, resulting in release of the Drug or Drug unit. The released Drug or Drug unit is then free to migrate in the cytosol and induce cytotoxic or cytostatic activities. In an alternative embodiment, the Drug is cleaved from the Ligand-Drug Conjugate outside the target cell, and the Drug or Drug unit subsequently penetrates the cell (see [0359]). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).
Applicant argues WO '436 and US '879, whether considered individually or in combination, fail to teach or suggest the presently claimed compounds and fail to provide a reasonable expectation of success in achieving the demonstrated balance of reduced free payload-linker cellular toxicity and maintained ADC cytotoxic activity. - In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Conclusion
No claim is 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ARCHANA VARADARAJ whose telephone number is (571)272-2366. The examiner can normally be reached Monday-Friday 10:00am-5:00pm.
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/KOYELI BANERJEE/ Examiner, Art Unit 1658
/Melissa L Fisher/ Supervisory Patent Examiner, Art Unit 1658
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