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 I, drawn to a compound of Formula (I); a Drug-Linker compound Q-D, wherein Q is a linker unit and D is a drug unit of Formula (I’); or a Ligand-Drug conjugate compound L-(Q-D)p, wherein L is a ligand unit, Q is a linker unit, D is a drug unit of Formula (I’), and p is an integer ranging from 1-12, and species
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, wherein L is an anti-human transmembrane glycoprotein NMB (anti-gpNMB) antibody hCR011 comprising a VH comprising the amino acid sequence SEQ ID NO:941 and a VL comprising the amino acid sequence SEQ ID NO:942, and p is 4, in the reply filed on 7/22/2026 is acknowledged.
Claims 1, 35-37, 41-66, 70-95, 97-98, 107-108, 114, and 117-122 are pending in the instant application.
Claims 1, 35-37, 41-42, 45, 52-54, 58-61, 66, 70-71, 74, 81-83, 87-90, 95, 97-98, 107-108, 114, and 117-122 are being examined on the merits.
Claims 43-44, 46-51, 55-57, 62-65, 72-73, 75-80, 84-86, and 91-94 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/22/2026.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Information Disclosure Statement
The information disclosure statement filed 1/11/2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered. This objection specifically refers to the following non-patent literature document:
NPL #34:Freshney, R.I., (1987).
The Examiner notes a minor typo regarding the IDS submitted on 1/11/2024:
Regarding NPL #13, “BERTER” should read “BETTER”.
Appropriate correction has been made by Examiner.
Specification
The disclosure is objected to because of the following informalities:
In ¶ [0518], the anti-c-Met antibody is described as comprising a heavy chain variable region comprising an amino acid sequence … of SEQ ID NO:893, and a light chain variable region comprising an amino acid sequence … of SEQ ID NO: 893. The bolded underlined number should read 894, based on the Sequence Table disclosed in ¶ [0880] on page 343-386.
In ¶ [0522], the anti-Axl antibody is described as comprising a heavy chain variable region comprising an amino acid sequence … of SEQ ID NO:933, and a light chain variable region comprising an amino acid sequence … of SEQ ID NO: 933. The bold underlined number should read 934, based on the Sequence Table disclosed in ¶ [0880] on page 343-386.
In ¶ [0563], lines the anti-MICA antibody is described as comprising a heavy chain variable region comprising an amino acid sequence … of SEQ ID NO:340, and a light chain variable region comprising an amino acid sequence … of SEQ ID NO: 340 (see last five lines of page 239). The bolded underlined number should read 341, based on the Sequence Table disclosed in ¶ [0880] on page 343-386.
Appropriate correction is required.
The use of the term Sephadex®, QuadraSil®, and FlowJoTM which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. All trademarks referenced herein should be identified as such with the appropriate notation:
Sephadex® (page 333, ¶ [0845]);
QuadraSil® (page 333, ¶ [0845]; and
FlowJoTM (page 337, ¶ [0857].
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 108, 114, 117, and 119 are objected to because of the following informalities:
In regards to instant claim 117, “wherein p is and integer” should read “wherein p is an integer”;
In regards to instant claim 108 and 114, “SEQ ID Nos. 1 to 1044” should read “SEQ ID NOs:1-1044”; and
In regards to instant claim 119, “SEQ ID Nos.” should read “SEQ ID NOs:”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Claims 108 and 114 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of SEQ ID NOs:1-1044 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use.
First, the alternatives do not share a single structural similarity, because SEQ ID NOs:1-1044 recite distinct heavy chain variable region (VH) and light chain variable region (VL) amino acid sequences, wherein each has its own set of complementarity determining regions (CDRs) that determine antigen specificity and binding. Thus, the different CDRs comprising the VH and VL are necessary to form the antigen binding site, and therefore, the sequences are not interchangeable within the group. The elected species, an anti-gpNMB antibody, requires a specific VH and VL comprising the VH of SEQ ID NO:941 and the VL of SEQ ID NO:942, wherein these two sequences are structurally different from the alternatives.
Second, the alternatives do not share a common use, because while the elected species bind gpNMB, the alternatives bind other antigens, such as ADAM9, B7-H3, CD19, etc. (see page 216, ¶ [0535]). These antigens differ in structure, expression pattern, and biological function, and they mediate different in vivo physiological responses. An antibody that binds one of the antigens disclosed in ¶ [0535] cannot substitute for an antibody that binds another antigen and still produce the same physiological response. Accordingly, the alternatives do not share a common use that flows from a substantial structural feature.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use. For example, a proper grouping would limit the alternatives to antibodies that bind the same antigen, such as gpNMB, and disclose the CDR sequences required for antigen binding.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 89 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Instant claim 89 depends on independent claim 66, which neither recites nor defines R17. Therefore, instant claim 89 fails to further limit the subject matter of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Interpretation
For the purpose of compact prosecution, instant claim 89 is interpreted to depend from instant claim 70.
It should be noted that such treatment does not relieve Applicants of the responsibility of responding to this rejection. Moreover, if the intended meaning of the claim is different than that posited by the Examiner, additional 35 U.S.C. § 112 and prior art rejections may be readily applied in a subsequent office action.
Claim Rejections - 35 USC § 112(b)
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.
Claim 89 is 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.
Regarding instant claim 89, the claim is dependent on claim 66, which neither recites nor defines R17. Thus, the metes and bound of the claim are unclear as there is no antecedent basis for the limitations in the base claim. MPEP 608.01(n): “If the base claim has been canceled, a claim which is directly or indirectly dependent therein would be rejected as incomplete.” For the purposes of compact prosecution, “claim 66” in line 1 of instant claim 89 will be interpreted as “claim 70”.
Claim Rejections - 35 USC § 112(a)-Written Description
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 108, 114, and119 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 claims contain 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. This is a WRITTEN DESCRIPTION rejection.
Scope of the Claims
Claims 108 and 114 are directed to a ligand-drug conjugate compound of the formula L-(Q-D)p, wherein Q is a Linker Unit, D is a drug unit of Formula (I’), p is an integer from 1-12, and L is a ligand unit that binds to a target antigen comprising the amino acid sequence of any one of SEQ ID NOs:1-1044 or at least 80%, 85%, 90%, 95%, 98% or 99% identical to the amino acid sequence of any one of SEQ ID NOs:1-1044. Claim 119 requires that the ligand-drug conjugate compound of the following formula
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, hereinafter compound 3.1 (see instant disclosure page 212, ¶ [0533]), binds to human transmembrane glycoprotein NMB (gpNMB), wherein L is an anti-human transmembrane glycoprotein NMB (anti-gpNMB) antibody comprising the amino acid sequence that is at least 80, 85, 90, 95, 98, or 99% identical to the amino acid sequence of any one of SEQ ID NOs:935-944.
The invention as disclosed in claims 108 and 119 encompass a genus of heavy and light chain variable regions, CDR regions, etc. comprising variability in the heavy and light chain variable regions and CDR regions, which are claimed as having the function of specifically binding to a target antigen, e.g. gpNMB. This means that the variability in sequence identity can also occur in the CDRs, the domains that are critical for the antibody binding to its target, which one of ordinary skill in the art would understand to result in unpredictable binding characteristics with no reasonable expectation of maintaining gpNMB antigen binding. Additionally, the instant disclosure does not provide an adequate number of species of the claimed genus nor does the disclosure provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision what variation can occur to the light and heavy chains, particularly in the CDR regions, such that the obtained structure would result in the claimed functions.
The invention as disclosed in claim 114 encompasses any targeting agent, of any structure, that specifically binds any target moiety, provided only that the agent contains one of the 1044 recited sequences somewhere within it.
Scope of Disclosed Species
Regarding instant claims 108 and 114, the amino acid sequences SEQ ID NOs:1-1044 represent 67 antibodies that the Applicant was in possession of at the time of filing (see page 216, ¶ [0535] and pages 230-268, ¶ [0549]-[0622], for the full list). Pages 216-222, ¶ [0536]-[0539] of the instant disclosure list the amino acid sequences of the heavy and light chain variable regions for each ligand of compound 3.1, pages 222-226, ¶ [0540]-[0545], list the amino acid sequences of the corresponding heavy and light chains, and pages 226-229, ¶ [0546]-[0548] list the amino acid sequences of the corresponding complementarity determining regions. Except for the anti-gpNMB antibody, the remaining 66 antibodies are recited only as sequence listings without any other accompanying characterization.
In regards to instant claim 114, the claim as recited requires that the ligand, L, need only contain a single recited sequence among 1,044 amino acid sequences, which includes individual CDRs as short as seven amino acid residues (see for example, page 272, Table D1 that discloses SEQ ID NO:935 as an anti-gpNMB CDRH1). However, the specification discloses no structural feature common to the members of the claimed genus. The 1,044 sequences are directed to 67 different antigens and share no disclosed common motif or framework that correlates with the targeting function required of the ligand. The only unifying attribute of the claimed genus of instant claim 114 is the functional attribute disclosed by definition of the ligand unit (see §Ligand Unit L starting on page 152, ¶ [0427]). A functional limitation does not describe the structure of the genus. See MPEP 2161.01(a). Instant claim 114, therefore, reads on any polypeptide of any length and any overall structure comprising any one sequence among 1,044 sequences, wherein the sequences span multiple, structurally unrelated binding specificities.
Regarding instant claim 119, the specification describes compound 3.1 comprising an anti-gpNMB antibody comprising CDR H1-H3 comprising amino acid sequences SEQ ID NOs:935-937, respectively, and CDR L1-L3 comprising amino acid sequences SEQ ID NOs:938-940, respectively (pages 271-277, ¶ [0630]-[653]; Tables D1 and D2 on pages 272-273). Furthermore, the disclosure states that compound 3.1 comprising the anti-gpNMB antibody comprises a heavy chain comprising the amino acid sequence SEQ ID NO:943 that comprises a heavy chain variable region, VH, comprising the amino acid sequence of SEQ ID NO:941, and a light chain comprising the amino acid sequence SEQ ID NO:944 comprising the light chain variable region, VL, comprising the amino acid sequence of SEQ ID NO:942 (page 276-277, ¶ [0648]-[0649]).
However, the specification provides no examples that test variability within the 1,044 sequences, and the added limitation of instant claim 119 does not cure the underlying lack of support for the variation that can occur in the CDR regions. Furthermore, the specification does not describe any ligand comprising an isolated CDR, and provides no disclosure from which one of skill in the art could conclude that such a ligand would retain the specific binding function that is required of the ligand unit.
State of the Prior Art
At the time of filing, conventional antibody functionality was known to depend on the entire structure, particularly a full complement of six CDRs. It is understood by one of ordinary skill in the art that mutation to CDRs is unpredictable and that each construct requires function testing (Sela-Culang et al, “The structural basis of antibody-antigen recognition”, 2013, Fron. Immuno., 4(302): 1-13; hereinafter Sela-Culang). Sela-Culang reviews the structural basis of antibody-antigen recognition in the state of the art. Naturally occurring conventional antibodies have six hypervariable loops are commonly termed complementary determining regions (CDRs) and are widely assumed to be responsible for antigen recognition (page 1, Abstract; page 3, “The Role of CDRs and their Definition” section). A person of ordinary skill in the art would understand that although the above basics of antibody-antigen binding are known, the specifics of antibody structure (e.g., within the CDRs) that underlie the antigen recognition are not well characterized (page 1, “The Motivations for, and Applications of, the Study of Ab-Ag Recognition” Section).
It is well established that changes in the amino acid sequence of the variable region of an antibody create new antibodies with highly unpredictable binding characteristics. See for example Chen et al (Chen et al, “Enhancement and destruction of antibody function by somatic mutation: unequal occurrence is controlled by V gene combinatorial associations”, 1995, The EMBO Journal, 14(12):2784-2794). Chen teaches that the substitution of a single amino acid can totally ablate antigen binding (Figure 1), however, the reference additionally teaches that the same substitution in closely related antibodies can have opposite effects. The authors compared the effects of identical substitution in related antibodies D16 and T15, and as shown in Figure 3, some substitutions increased antigen binding in one antibody while ablating it in the other. Additionally, Rudikoff et al (Rudikoff et al, “Single amino acid substitution altering antigen-binding specificity”, 1982, PNAS 79:1979-1983) teach that such is necessary and conventional to define an antibody that specifically binds a cognate antigen.
Further, Herold (Herold et al, “Determinants of the assembly and function of antibody variable domains”, 2017, Nature Scientific Reports, 7(12276):1-17; hereinafter Herold) teaches that it should be emphasized that there is no correlation between experimentally determined change in antibody binding affinity and a given mutation and additionally that no such correlation is expected, because antigen binding is affected by each CDR loop differently and changes thereto can, in principle, affect antigen binding affinity in an unpredictable way (page 14, paragraph 2). Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex ( page 14, paragraph 3). Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al (Rudikoff et al, “Single amino acid substitution altering antigen-binding specificity”, 1982, PNAS 79:1979-1983). Rudikoff et al teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
At the time of filing, Jefers (Jefers and Simantov, WO2010135547A1, hereinafter Jefers) teaches human monoclonal antibodies, such as Mabl. 10.2 and Mabl 15.2, that specifically bind to GPNMB comprising heavy and light chain variable regions comprising a specific combination of amino acid sequences (page 3-4, ¶ [0006]-[0008]; page 5, ¶ [00011]). Additionally, Jefers teaches CDR regions of heavy and light chains of the monoclonal antibodies that bind to GPNMB comprising a specific combination of HCDR1-3 and LCDR1-3. (page 4-5, ¶ [0009]-[00010]; Tables 1-30). Jefers further discloses that the antibody specifically binds GPNMB with very high affinities (Kd), wherein the monoclonal antibodies disclosed are capable of binding GPNMB with a Kd less than, but not limited to, 10-7, 10-8, 10-9, 10-10, 10-11, 10-12, 10-13 or 10-14 M (page 41-42, ¶ [000123]).
The prior art, however, does not teach a known structure activity relationship for HCDR1-3 and LCDR1-3 in an anti-gpNMB antibody that would allow prediction of CDR residues that specifically bind to gpNMB antigens. Thus, making changes to the CDR sequence of an antibody sequence is a highly unpredictable process and one skilled in the art could not a priori make any predications regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required function(s).
Conclusion
As indicated by the art, a full complement of 6 CDRs are required for antigen binding and a skilled artisan cannot predict which CDR residues may be changed and still result in an antibody that binds a target antigen, e.g. gpNMB. Written description can be met if the claims recite the minimal structure that is needed to perform the function recited in the claims. Above, the art indicates that the 6 CDRs in an antibody antigen-binding domain are the minimal structure that binds to a target antigen. Specifically, Applicant claims 108, 114, and 119 would need to recite the 6 CDRs in the antibody that bind specific antigens, such as gpNMB, without variability in the sequences thereof.
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.
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.
Claims 1, 35 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Mendelsohn (WO2015183978A1, Priority to May 28, 2014, IDS entered on 1/11/2024; hereinafter Mendelsohn), and further in view of Senter (US20050009751A1, Priority to April 30, 2001; hereinafter Senter).
Regarding instant claims 1, 35, and 36 , Mendelsohn teaches ((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-hvdroxypropanamido)-N,3- dimethylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2- methylpropanoyl-L-phenylalanine comprising the structure
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(pages 49-51, Example 14). Mendelsohn teaches that this compound was effective against cancer cells when it was used in an in vitro cytotoxicity experiment using PC3 cells or HCC-1954 cells (page 7, ¶ [0034]-[0035]; FIGs 21 and 22). Mendelsohn also teaches (S)-N-((3R,4S, 5S)-1-((S)-2-((1R,2R)-3-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-2-((S)-2-(dimethylamino)-3-hydroxypropanamido)-N,3-dimethylbutanamide comprising the structure
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, wherein the stereochemistry of the C-OH at the beginning of the compound (indicated with the solid rectangle) comprises
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stereochemistry (page 54, Example 18). Mendelsohn further teaches that this compound was also effective against cancer cells as shown in an in vitro cytotoxicity experiment using PC3 and HCC-1954 cells (pages 7-8, ¶ [0038]-[0039]; FIGs. 25 and 26).
However, Mendelsohn does not teach the compound of Example 14 comprising an alcohol(C-OH) instead of a carboxylic acid (COOH) at the end of the compound, wherein the carboxylic acid is highlighted in the box below.
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.
The deficiency is resolved by Senter.
Senter teaches compound 32,
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, wherein auristatin derivatives with a carboxy terminal exchange of COOH with a C-OH are disclosed as effective cytotoxic compounds to cancer cells (page 58, ¶ [0348], Example 5; pages 64-65, ¶ [0384], Example 20; Table 2)
Regarding instant claims 1, 35, and 36, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the compound of Example 14,
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, by exchanging the stereochemistry of
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at the beginning of the compound (indicated by solid rectangle) with
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of the compound in Example 18 of Mendelsohn, and exchanging the COOH at the end of the molecule (indicated by dotted rectangle) with a C-OH in view of Compound 32 of Senter. This is obvious because, Mendelsohn teaches the compound of Example 14 and Example 18, wherein both compounds were effective cytotoxic compounds to cancer cells, and Senter teaches that compound 32, an auristatin derivative, comprising carboxyl terminal exchange of COOH with C-OH is an effective cytotoxic compound to cancer cells. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant compound,
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or a salt thereof.
Claims 37, 41-42, 45, 52-54, 58-61, 66, 70-71, 74, 81-83, 87-90, 95, 97-98, 107, and 117-118 are rejected under 35 U.S.C. 103 as being unpatentable over Mendelsohn (WO2015183978A1, Priority to May 28, 2014, IDS entered on 1/11/2024; hereinafter Mendelsohn), and Senter (US20050009751A1, Priority to April 30, 2001; hereinafter Senter) as applied to claim 1 above, and further in view of Jin (US20220267467A1, Priority to July 19, 2019; hereinafter Jin).
The combined teachings of Mendelsohn and Senter are discussed above.
However, the combined teachings of Mendelsohn and Senter do not teach a Drug-Linker compound Q-D, wherein Q is a linker unit and D is a drug unit of Formula (I’); or a Ligand-Drug conjugate compound L-(Q-D)p comprising the structure of compound 3.1,
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, wherein L is an anti-gpNMB antibody and p is an integer from 1-12.
The deficiency is resolved by Jin.
In regards to instant claims 66, 90, 97, 107, and 118, Jin teaches antibody drug conjugates (ADCs) comprising: (1) an antibody that specifically binds to a tumor antigen, e.g. GPNMB (page 17, ¶ [0117]-[0123], §Antibody); and (2) a linker-drug intermediate, e.g. “MC-vc-PAB-MMAE”, wherein MC is maleimide-caproyl, vc is the dipeptide of Val-Cit, and PAB is para-aminobenzyl (page 17, ¶ [0124]-[0128], §Drug and §Linker). The linker unit, “MC-vc-PAB” is the same as the linker unit Q comprising Z’-A-RL-Y (instant claims 37, 60-61, and 89), wherein Z’ is MC (instant claims 41-42 and 70), A is a bond (instant claims 45 and 74), RL is the dipeptide linker Val-Cit (instant claims 52-54 and 81-83), and Y is PAB (instant claims 58-59 and 87-88). Regarding instant claim 71, Jin also teaches conjugating the antibody to the MC-vc-PAB-MMAE linker-drug intermediate by utilizing the thiol group of natural cysteines in the antibody to form the antibody drug conjugate (page 7, ¶ [0009]; page 20, ¶ [0191]-[0199], Example 1). Furthermore, in regards to instant claims 95, 98, and 117, Jin teaches that an average of four free thiols after partial reduction for IgG1 type antibodies is preferred as ADCs with the drug to antibody ratio (DAR) as 4 exhibit the best therapeutic index in vivo (page 7, ¶ [0009]; FIGs. 1-6). Jin also discloses that the MMAE-conjugated ADCs have high potency in inhibiting cell growth in HCC1954, HCC827, and Raji cells (FIG. 13).
Regarding instant claims 37, 41-42, 45, 52-54, and 58-61, it would have been obvious for a person having ordinary skill in the art at the time of filing to substitute the MMAE of the linker drug intermediate “MC-vc-PAB-MMAE” as taught by Jin with the auristatin compound
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as taught by the combined teachings of Mendelsohn and Senter. This is obvious because, the combined teachings of Mendelsohn and Senter teach that the compound of Example 14 comprising the stereochemistry of
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of Example 18 in the beginning of the compound and a carboxyl terminal exchange of COOH with C-OH would still result in an effective cytotoxic compound to cancer cells, and Jin teaches the linker-drug intermediate, e.g. “MC-vc-PAB-MMAE”, which is used to conjugate an antibody that inhibited the growth of cancer cells. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant drug linker compound, Q-D, wherein Q is a linker unit comprising Z’-A-RL-Y wherein Z’ is MC,
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, A is a bond, RL is the dipeptide Val-Cit,
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, and Y is PAB,
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.
Regarding instant claims 66, 70-71, 74, 81-83, 87-90, 95, 97-98, 107, and 117-118, it would have been obvious for a person having ordinary skill in the art at the time of filing to substitute the MMAE of the ADC or a pharmaceutical composition comprising the ADC comprising an anti-gpNMB antibody that specifically binds GPNMB conjugated to “MC-vc-PAB-MMAE” with a DAR of 4 as taught by Jin with the auristatin compound
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as taught by the combined teachings of Mendelsohn and Senter. This is obvious because, the combined teachings of Mendelsohn and Senter teach that the compound of Example 14 comprising the stereochemistry of
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Example 18 in the beginning of the compound and a carboxyl terminal exchange of COOH with C-OH would still result in an effective cytotoxic compound to cancer cells, and Jin teaches treating cancer by using ADCs comprising an antibody that specifically binds to a tumor antigen, e.g. GPNMB, conjugated to a linker-drug intermediate, “MC-vc-PAB-MMAE”, wherein an average of four free thiols after partial reduction is preferred as ADCs with the DAR as 4 exhibit the best therapeutic index in vivo. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant ligand-drug conjugate or a pharmaceutical composition comprising the ligand-drug conjugate of compound 3.1,
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, wherein L is an anti-gpNMB antibody and p=4.
Claims 108, 114, 119-122 are rejected under 35 U.S.C. 103 as being unpatentable over Mendelsohn (WO2015183978A1, Priority to May 28, 2014, IDS entered on 1/11/2024; hereinafter Mendelsohn), Senter (US20050009751A1, Priority to April 30, 2001; hereinafter Senter) and Jin (WO2021013068A1, Priority to July 19, 2019; hereinafter Jin) as applied to claims1, 37, 66, and 118 above, and further in view of Pandit (US Patent No. 11,208,485B2, Priority to October 11, 2018; hereinafter Pandit).
The combined teachings of Mendelsohn, Senter, and Jin are discussed above.
However, the combined teachings of Mendelsohn, Senter, and Jin do not teach compound 3.1, wherein p=4 and L is an anti-gpNMB antibody, wherein the antibody comprises a VH comprising the amino acid sequence SEQ ID NO:941 comprising CDR H1-H3 comprising the amino acid sequences SEQ ID NOs:935-937, respectively, and a VL comprising the amino acid sequence SEQ ID NO:942 comprising CDR L1-L3 comprising the amino acid sequences SEQ ID NOs:938-940, respectively.
The deficiency is resolved by Pandit.
Pandit teaches multispecific polypeptide constructs, wherein the antigen binding domain binds the tumor associated antigen, e.g. gpNMB, wherein the antigen binding domain of gpNMB comprises a Fab fragment comprising a Fd comprising the amino acid sequence set forth in SEQ ID NO:101 (identical to instant SEQ ID NO:941 comprising CDRH1-H3 comprising the amino acid sequences set forth in SEQ ID NOs:935-937, respectively), and a LC comprising the amino acid sequence set forth in SEQ ID NO:102 (identical to instant SEQ ID NO:942 comprising CDRL1-L3 comprising the amino acid sequences set forth in SEQ ID NOs:938-940) (§Antigen Binding Domain starting on page 35, column 42; page 37, column 48, lines 34-46).
Regarding instant claim 108, 114, 119, and 120-122, it would have been obvious for a person having ordinary skill in the art at the time of filing to substitute the anti-gpNMB antibody (L) of
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wherein p=4 as taught by the combined teachings of Mendelsohn, Senter, and Jin with the anti-gpNMB antibody comprising amino acid sequences SEQ ID NOs:101 and 102 of Pandit
This is obvious because, the combined teachings of Mendelsohn, Senter, and Jin teach an ADC comprising
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, wherein L is an anti-GPNMB antibody and p=4, and Pandit teaches multispecific polypeptide constructs comprising an antigen binding domain that binds to gpNMB, wherein the antigen binding domain comprises a Fab fragment comprising a Fd comprising the amino acid sequence set forth in SEQ ID NO:101, and a LC comprising the amino acid sequence set forth in SEQ ID NO:102, which are identical to instant SEQ ID NOs: 941 and 942, respectively. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant ligand drug conjugate, compound 3.1, wherein p=4, and L is an anti-gpNMB antibody, wherein the instant antibody comprises a VH comprising the amino acid sequence instant SEQ ID NO:941 comprising CDR H1-H3 comprising the amino acid sequences instant SEQ ID NOs:935-937, respectively, and a VL comprising the amino acid sequence instant SEQ ID NO:942 comprising CDR L1-L3 comprising the amino acid sequences instant SEQ ID NOs:938-940, respectively.
Conclusion
No claims are allowable.
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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
