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 of the below-listed species in the reply filed on 08/25/2026 is acknowledged.
Elected Species:
Linker species of formula La-Bp-(Lb-Lc)m.
PNG
media_image1.png
292
390
media_image1.png
Greyscale
The Lb structure fragment is:
PNG
media_image2.png
98
274
media_image2.png
Greyscale
The Lc fragment is:
The branching unit (B) is:
PNG
media_image3.png
212
340
media_image3.png
Greyscale
The La extension unit is:
PNG
media_image4.png
196
304
media_image4.png
Greyscale
The complete linker structure is:
PNG
media_image5.png
388
736
media_image5.png
Greyscale
For the above-listed structures, it is further noted that the elected species comprises an R’ of -CH2CH2-, p = 1, m = 2, t = 2, each r = 2, each q = 7, and s = 2.
Additionally, because Applicant did not distinctly and specifically point out any errors in the restriction/election requirement, the election has been treated as an election without traverse (MPEP 818.03(a)).
Claim Status
Claims 6, 12, 14-16, 18-22, 24-25, 27-29, 31, 33-37, 39-44, 46-50, 52, and 54-88 have been cancelled and claims 1-5, 7-11, 13, 17, 23, 2630, 32, 38, 45, 51, and 53 have been amended, as requested in the preliminary amendment filed on 12/15/2023. Following the amendment, claims 1-5, 7-11, 13, 17, 23, 26, 30, 32, 38, 45, 51, and 53 are pending in the instant application.
Claims 11, 17, 23, 26, 30, 32, 38, 45, 51 and 53 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species of invention in the Response filed 08/25/2026, there being no allowable generic or linking claim.
Claims 1-5, 7-10, and 13 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, it is noted that the claim to foreign priority has not been perfected as no English translation of the foreign priority document has been provided.
Claims 1-5, 7-10, and 13 have an effective filing date of May 19, 2022 corresponding to PCT/CN2022/093808 because the claim to foreign priority has not been perfected.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/15/2023 and 07/10/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The abstract of the disclosure is objected to because the abstract refers to a formula, reciting “the Lb structure being selected from the following Formula”, but no formula(s) are included. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claim 1 is objected to because of the following informalities: the claim recites “the Lb structure fragment is selected from the following formula”, but should read “the Lb structure fragment is of the following formula” or something similar as there is no list or alternatives to select from. Appropriate correction is required.
Claim 4 is objected to because of the following informalities: the claim recites “the Lb fragment is selected from the following formulas”, but should read “the Lb structure fragment is of the following formula” or something similar as there is no list or alternatives to select from. Appropriate correction is required.
Claim 5 is objected to because of the following informalities: the claim recites “wherein B is selected from the following formula”, but should read “wherein B is of the following formula” or something similar as there is no list or alternatives to select from. Appropriate correction is required.
Claim 8 is objected to because of the following informalities: the claim recites “is capable of linking to the ligand unit via position(s) 3 and/or 4 of succinimide/succinimide”, but should read “is capable of linking to the ligand unit via position(s) 3 and/or 4 of succinimide”. Appropriate correction is required.
Claim 10 is objected to because of the following informalities: the claim recites “wherein La is selected from the following formula”, but should read “wherein La is of the following formula” or something similar as there is no list or alternatives to select from. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2, 5, 7, 9, and 13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
With regard to claim 2, as currently presented the claim has multiple sturtual interpretations and is therefore indefinite. Claim 2 recites the linker according to claim 1, “further comprising an Lb-Lc structure fragment, wherein the Lb structure fragment is linked to an Lc fragment via a carbonyl group, wherein the Lc fragment is a releasable assembly unit and is capable of linking a drug unit”. As presented, it becomes unclear if (i) the Lb structure fragment of claim 1 is further linked to an “Lb-Lc structure fragment”, such that the resulting linker comprises two Lb structure fragments and an Lc fragment or (ii) the Lb structure fragment of claim 1 is further linked to a single Lc fragment to yield a “Lb-Lc” structure fragment. Thus, the claim has multiple structural interpretations and is therefore indefinite. For the purposes of applying art, claim 2 is being interpreted consistent with the full structure of the elected species, such that the Lb structure fragment of claim 1 is further linked to a single Lc fragment to yield a “Lb-Lc” structure fragment, which is also consistent with the structure presented in dependent claim 4.
With regard to claims 5 and 13, the claims have multiple structural interpretations and are therefore indefinite. More specifically, claim 5 and 13 each recite the limitation “wherein r is any integer independently selected from 1-4” and claim 13 further recites the limitation “wherein q is any integer independently selected from 1-20”. As currently worded, it is unclear if (i) each r and q is independently selected, and thus can be different, (ii) all instances of r must be the same and all instances of q must be the same, or (iii) some combination thereof. For the purpose of applying art and in view of the full structure of the elected species, claims 5 and 13 are being interpreted such that all instances of r must be the same and all instances of q must be the same.
With regard to claims 7 and 13, the claims are considered to be ambiguous due to the recitation of “optionally substituted” R’ and R” groups. It is unclear how many substituents may be added, and what possible combination(s) of substituents can be reasonably used together. As such, one of ordinary skill in the art would not be able to reasonably ascertain the metes and bounds of the claims.
With regard to claim 9, the claim is considered to be ambiguous and there are no recitations of “and”/“or” between the listed limitations, and as such it is unclear if all of the limitations are required, one of the limitations are required, or some of the limitations are required. As such, one of ordinary skill in the art could not reasonably ascertain the metes and bounds of the claim.
Further with regard to claim 13, the claim is considered to be ambiguous because it is unclear as to what the wavy bond represents in the listed structures. The type of bond is not defined by the claim nor by the specification, and as such the structures are ambiguous. For the purpose of applying art, the wavy bond is being interpreted as a single bond, of any orientation.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by WO 2021/151984 A1 (herein after referred to as “Kraiem”).
Kraiem teaches antigen-binding proteins capable of binding to Nectin-4 polypeptides conjugated to chemotherapeutic agents, for use in increasing sensitivity of tumors to the chemotherapeutic agents, for use in the treatment of cancers characterized by Nectin-4-expressing tumor cells; in one embodiment, the present invention provides conjugates of an anti-Nectin-4 antibody to a camptothecin analogue, such as exatecan or SN-38, through a cleavable linker (Abstract). Exemplary linkers can have the structure of Compound 9a, 9b, 9c and 9d, wherein such linkers can be conjugated to an antibody via cysteine in the antibody after the interchain disulfide bounds are reduced with a reducing agent residues (Page 66); the structure of compound 9c is reproduced below:
PNG
media_image6.png
328
644
media_image6.png
Greyscale
It is specifically noted that Kraiem Compound 9c comprises an exact match to the instantly elected Lb structure of instant claim 1, wherein q = 7. Additionally, Kraiem Compound 9c further comprises a PABC unit, wherein the amino group of the PABC unit is linked to the fragment corresponding to Lb via a carbonyl of the Lb fragment; it is specifically noted that PABC is a releasable assembly unit, wherein upon cathepsin cleavage of the Val-Ala peptide the PABC undergoes self-immolation to release the free drug. Thus, Kraiem anticipates instant claims 1-2.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-5, 7-10, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2021/151984 A1 (herein after referred to as “Kraiem”) in view of WO 2021/173773 A1 (herein after referred to as “Li”) and WO 2014/194030 A2 (herein after referred to as “Widdison”).
Kraiem teaches antigen-binding proteins capable of binding to Nectin-4 polypeptides conjugated to chemotherapeutic agents, for use in increasing sensitivity of tumors to the chemotherapeutic agents, for use in the treatment of cancers characterized by Nectin-4-expressing tumor cells; in one embodiment, the present invention provides conjugates of an anti-Nectin-4 antibody to a camptothecin analogue, such as exatecan or SN-38, through a cleavable linker (Abstract). Exemplary linkers can have the structure of Compound 9a, 9b, 9c and 9d, wherein such linkers can be conjugated to an antibody via cysteine in the antibody after the interchain disulfide bounds are reduced with a reducing agent residues (Page 66); the structure of compound 9c is reproduced below:
PNG
media_image6.png
328
644
media_image6.png
Greyscale
It is specifically noted that Kraiem Compound 9c comprises an exact match to the instantly elected Lb structure of instant claim 1, wherein q = 7. Additionally, Kraiem Compound 9c further comprises a PABC unit, wherein the amino group of the PABC unit is linked to the fragment corresponding to Lb via a carbonyl of the Lb fragment; it is specifically noted that PABC is a releasable assembly unit, wherein upon cathepsin cleavage of the Val-Ala peptide the PABC undergoes self-immolation to release the free drug. Furthermore, it is noted that the 3-Mal component of Kraiem Compound 9a reads on the instantly claimed La unit, wherein 3-Mal is a maleimide-type linker fragment, wherein after reaction with an antibody, is conjugated to the antibody via cysteine residues in the antibody after the interchain disulfide bounds are reduced with a reducing agent (Page 66). When conjugated to an antibody, the 3-Mal group reads on the
PNG
media_image7.png
152
215
media_image7.png
Greyscale
instantly elected structure:
wherein s = 2, Mal-3 is conjugated to the antibody, and the carbonyl connects to the rest of the linker structure.
However, it is noted that Kraiem does not teach or suggest conjugates that comprise a releasable assembly unit corresponding to the elected species -NH-CH2-O-CH2-C(=O)- (see claim 3, for example) nor the instantly elected branching unit B (see claim 5, for example). These deficiencies are remedied by Li and Widdison.
Li teaches that camptothecin exhibits significant antitumor activity by inhibiting
topoisomerase I, an enzyme that is overexpressed in a variety of tumor cell lines and essential for
DNA synthesis, and because of its broad-spectrum antitumor activity and unique mechanism of action, there have been substantial efforts towards developing clinical analogues of camptothecin; however, camptothecin and most of its derivatives have poor solubility and inactivity at physiological conditions, which have limited the clinical development of suitable camptothecin analogues (Paragraph 0003). Accordingly, camptothecin as toxin used in ADCs may overcome those limitations and there remains a need for therapeutically effective camptothecin derivatives and a need for new ADCs for therapeutic use (Paragraph 0004). Li discloses new cytotoxic agents according to Formula (I), which can then be combined with peptide linkers to form payloads according to Formula (II), which can in turn can be used to prepare conjugates with cell binding agents (Formula (III)); compounds of Formula (III) include ADCs that are useful for treating cell proliferative diseases such as cancers (Paragraph 0005). Notably, Formula (II) of Li corresponds to: D-L1-L2-Q’-CH2-NH-E-Z (Paragraph 0033; Pages 6-16 for full definitions and specific embodiments). Specifically, Li teaches exemplary
PNG
media_image8.png
190
536
media_image8.png
Greyscale
embodiments of compounds of Formula (II) including PL5, reproduced below (see Page 14):
which comprises, from left to right, (i) a maleimide-type linker, (ii) a Val-Ala dipeptide, (iii) NH-CH2-O-CH2-C(=O)-NH-CH2, and (iv) a camptothecin. It is specifically noted that, according to Li Formula (II), the maleimide-type linker corresponds to Z, the Val-Ala dipeptide corresponds to E, Q’ corresponds to O, L2 corresponds to CH2C(=O)NH, and L1 corresponds to CH2 (i.e., C1 alkyl). Notably, the full conjugate comprising PL5 is PL5’, which is reproduced below (see Page 91), and is a specific embodiment of Li Formula (III):
PNG
media_image9.png
218
576
media_image9.png
Greyscale
wherein C is a monoclonal antibody and p is the drug to antibody ratio, with an average number ranging from about 2-10 (Paragraph 000456). Li further teaches compounds of the invention (e.g., any compound according to Formula (III)) can be used accordingly for the treatment of various cancers, wherein in some embodiments, a camptothecin conjugate can be used to deliver a drug to a tumor cell or cancer cell (Paragraph 000658). In one embodiment, the cell binding agent of a camptothecin conjugate binds to or associates with a cancer-cell or a tumor-cell-associated antigen, and the camptothecin conjugate can be taken up (internalized) inside the tumor cell or cancer cell through receptor-mediated endocytosis or other internalization mechanism, and once inside the cell, the drug is released via peptide cleavage within the cell, or in an alternative embodiment, the free drug is released from the camptothecin conjugate outside the tumor cell or cancer cell, and the free drug subsequently penetrates the cell (Id.). Thus, Li suggests that the linkers of the invention are cleavable/releasable such that free drug is released in vivo; notably, Li teaches the structure of the free drugs at Page 68, for example. Thus, Li reads on a releasable assembly unit of -NH-CH2-O-CH2-C(=O)-, corresponding to the instantly elected Lc unit.
Widdison teaches a branched linker compound with reactive moieties for forming covalent bonds with multiple cytotoxic agents (drugs) and/or a cell-binding agent (CBA); a cytotoxic compound comprising a branched linker moiety with a reactive group for forming a CBA-drug conjugates; a modified cell-binding agent comprising a branched linker moiety with a reactive group for forming a CBA-drug conjugates; and conjugates so formed. Such conjugates
PNG
media_image10.png
122
386
media_image10.png
Greyscale
and/or cytotoxic compounds may be effective for treating a range of diseases, such as cancer, with a relatively high activity at a relatively low, non-toxic dose (Abstract). Widdison teaches that antibody-drug conjugates (ADC) and cell binding agent-drug conjugates are emerging as a powerful class of anti-tumor agents with efficacy across a range of cancers, wherein cell binding agent-drug conjugates (such as ADCs) are commonly composed of three distinct elements: a cell-binding agent (e.g., antibody); a linking component; and a cytotoxic moiety; the linking component of ADC is an important element in developing targeted anticancer agents that possess an optimal therapeutic window, i.e., therapeutic activity at a low, non-toxic dose, and Widdison identifies the need for targeted therapies such as ADCs and other cell binding agent-drug conjugates having a new class of linking components (Paragraphs 02-03). In one of the provided distinct embodiments, conjugates of the invention are represented by the formulas, or pharmaceutically acceptable salts thereof, shown on Pages 38-41. One exemplary formula is reproduced below (see Page 38):
PNG
media_image11.png
376
518
media_image11.png
Greyscale
wherein it is noted that, as defined by the invention, CBA is a cell-binding agent, [XX] for each occurrence is independently an amino acid residue, R1 and R2 are each independently H or an alkyl, m is an integer from 1-5, and JCB’ is generally a group capable of being conjugated to the cell-binding agent. A specific embodiment corresponding to the general structure above is shown below (see Page 42):
which comprises, from left to right, (i) a cell-binding agent, (ii) a maleimide-type linker, (iii) the branching unit (wherein the amino acid units are all glycine), and (iv) two cytotoxic agents (D) attached to each branch of the branching unit. It is specifically noted that camptothecin is provided as an exemplary cytotoxic drug useful in the treatment of cancer (see Paragraphs 114-115), and thus camptothecin is also suitable for use in the compounds of Widdison. Furthermore, Widdison provides exemplary [XX]1-10 embodiments, wherein in certain embodiments, the peptide represented by [XX]2-10 is cleavable by a protease, and the protease is a protease (i) expressed in tumor tissue or (ii) a lysosomal protease (Paragraph 74). The cleavable peptide refers to peptides containing a cleavage recognition sequence of a protease; a cleavage recognition sequence for a protease is an amino acid sequence recognized by the protease during proteolytic cleavage, wherein Widdison further indicates that many protease cleavage sites are known in the art, and these and other cleavage sites can be included a linker, a spacer, or a linker moiety (Paragraph 75); Widdison further provides exemplary peptides cleavable by lysosomal proteases (e.g., cathepsins) (Paragraphs 77-78). Widdison further teaches the use of spacers in compounds of the invention, wherein a spacer includes a chemical moiety interposed between any two chemical groups; for example, in some embodiments, one end of the spacer is linked to a cytotoxic drug, or a reactive functional group that can form a covalent bond with a cytotoxic drug, and in some embodiments, one end of the spacer is linked to a branched scaffold (Paragraph 80). In some embodiments, the spacer is interposed between (1) a cytotoxic drug, or a reactive functional group that can form a covalent bond with a cytotoxic drug; and (2) a branched scaffold; a spacer may be attached to a reactive functional group at one end to form a linker moiety that can further react with a cell-binding agent or a cytotoxic drug (Id.). In certain embodiments, the spacer creates a desired distance between the two chemical groups to, for example, avoid stereo hindrance or to promote molecular flexibility; in certain embodiments, the presence of the spacer does not hinder, inhibit, or otherwise negatively affect the function of the flanking chemical groups (e.g., the ability of the cell-binding agent to bind a target molecule on a cell, or the cytotoxicity of the cytotoxic drug), and in certain embodiments, the spacer confers additional beneficial characteristics, such as enhanced potency, solubility, serum stability, and/or efficacy, to the immunoconjugate or linker compound comprising the spacer. Thus, Widdison suggests additional spacer/linker components may also be used to link the branching unit to the cytotoxic drugs in conjugates of the invention.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the camptothecin conjugates of Kraiem, based on the teachings of Li and Widdison, to arrive at the instantly elected species of linker corresponding to the structure reproduced below:
PNG
media_image5.png
388
736
media_image5.png
Greyscale
PNG
media_image6.png
328
644
media_image6.png
Greyscale
wherein R’ is -CH2CH2-, t = 2, each r = 2, and each q = 7. One would have been motivated to modify the structure of Compound 9c of Kraiem below:
PNG
media_image10.png
122
386
media_image10.png
Greyscale
such that the compound includes a branching unit according to Widdison:
PNG
media_image12.png
228
384
media_image12.png
Greyscale
wherein the JCB’-(CR1R2)m corresponds to the 3-Mal of Kraiem (i.e., JCB’ corresponds to the succinimide, R1 and R2 are each H, and m=2), each [XX] corresponds to a glycine residue and is repeated twice (i.e., [XX]2, corresponding to Gly-Gly) further wherein, as also suggested by Widdison, there is a spacer (i.e., linker) unit between the [XX] and D portions, wherein the spacer-drug is the linker-drug portion of Kraiem corresponding to:
PNG
media_image13.png
45
116
media_image13.png
Greyscale
and further wherein the cleavable PABC unit above could be replaced by the cleavable linker structure taught by Li:
because all of the references identify a need to develop better ADCs, wherein Widdison suggests that the linking component of ADC is an important element in developing targeted anticancer agents that possess an optimal therapeutic window, i.e., therapeutic activity at a low, non-toxic dose, and that such properties are achievable using linkers comprising the branching units of the invention, and substituting the cleavable linker unit of Kraiem for that of Li would still yield a conjugate capable of cleavage in the lysosome to release free drug, as suggested by Li. Thus, one of ordinary skill in the art would have a reasonable expectation of success of developing a conjugate, said conjugate comprising the instantly elected linker structure above, wherein such a conjugate would reasonably be expected to be capable, by way of the linker, of releasing free drug in the lysosome and/or have improved therapeutic properties (e.g., sufficient activity at lower doses) as suggested by the combination of Kraiem, Li, and Widdison.
Conclusion
Claims 1-5, 7-11, 13, 17, 23, 26, 30, 32, 38, 45, 51, and 53 are pending. Claims 11, 17, 23, 26, 30, 32, 38, 45, 51 and 53 are withdrawn. Claims 1-5, 7-10, and 13 are rejected. No claims are allowed.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
Prosecution Insights