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 .
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 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.
Priority
The instant application is a 371 filing of PCT/JP2020/047706, filed 12/21/2020, and claims foreign priority to JP2019-231938, filed 12/23/2019. It is noted that an English translation of the foreign priority document was not provided.
Status of Application, Amendments, and/or Claims
Applicant’s response of 11/19/2025 is acknowledged. Claims 15, 20, 25-26, and 30 are amended and claims 1-14, 19, 24, and 31 are cancelled. Claims 15-18, 20-23, and 25-30 are currently pending and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action of 06/20/2025,
Claims 14, 19-20, 24, and 30 were objected to. The cancellation of claims 14, 19, and 24 has rendered the objection to these claims moot and the rejections are withdrawn. Applicant’s amendment to claims 20 and 30 to define “m” and “p” has overcome the objection and the objections are withdrawn.
Claims 9-10, 12-14, and 31 were rejected under 35 USC 102 (a)(1) and (a)(2) over WO’812 and again over US’458. The cancellation of the claims has rendered the rejections moot and the rejections are withdrawn.
Claims 9 and 11 were rejected under 35 USC 103 over US’812 in view of Dunetz. The cancellation of the claims has rendered the rejections moot and the rejections are withdrawn.
Claim 19 was rejected under 35 USC 103 over US’458 in view of WO’812. The cancellation of the claim has rendered the rejection moot and the rejection is withdrawn.
Claim 24 was rejected under 35 USC 103 over US’458 in view of WO’812 and Dunetz. The cancellation of the claim has rendered the rejection moot and the rejection is withdrawn.
Claims 9-14, 19, 24, and 31 were rejected on the ground of nonstatutory double patenting over US 10,548,986 B2 and US 10,322,192 B2, The cancellation of the claims has rendered the rejections moot and the rejections are withdrawn.
The following grounds of objections are new or maintained and the rejections are maintained.
Nucleotide and/or Amino Acid Sequence Disclosures
The required incorporation by reference paragraph required by 37 CFR 1.821 (c)(1) is missing from the instant specification. See parts 1) a) and b) below.
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Abstract Objection
The abstract amendment filed 11/19/2025 contains compounds that are not marked for removal. It is not clear if applicant intends to keep the compounds in the abstract or if they should be removed. Appropriate correction/clarification is required. See MPEP 608.01(b) for guidelines for the preparation of patent abstracts.
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.
Claim 15-18 and 25-30 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0252458 A1 (Albone, E.F., et al) 07 SEPT 2017 and WO 2018/200812 A1 (Brumi, J.R., et al) 01 NOV 2018.
US’458 teaches linker toxins and antibody drug conjugates that bind to human oncology antigen targets. The linker toxins and conjugates comprise an eribulin drug moiety and can be internalized into target antigen-expressing cells. The disclosure further relates to methods and compositions for use in the treatment of cancer by administering the antibody-drug conjugates (abstract).
US’458 teaches the linker toxin compound Mal-PEG2-Val-Cit-PAB-eribulin, referred to as compound ER-001159569 (page 79, first structure, Figure 2), which is duplicated below:
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The compound ER-001159569 meets the instant limitations of a compound of Formula (B) where m = 2.
US’458 further teaches that the PEG moiety may comprise –(PEG)m–, where m is an integer from 1 to 10 (page 2, [0015]). US’458 teaches that the eribulin used to synthesize the linker toxin disclosed has the structure of eribulin and is attached to the linker via the C-35 amine. Eribulin is a microtubule dynamics inhibitor, which is thought to bind tubulin and induce cell cycle arrest at the G2/M phase by inhibiting mitotic spindle assembly. US’458 further teaches eribulin mesylate, which refers to the mesylate salt of eribulin, which is marketed under the trade name Halaven™ (page 9, [0083]). Eribulin mesylate is a methanesulfonate salt meeting the instant claim 21 limitation of eribulin methanesulfonate.
US’458 teaches the following synthesis for the Mal-PEG2-Val-Cit-PAB-eribulin (ER-001159569) linker toxin (Figure 2):
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In the synthesis, eribulin was dissolved in DMF and mixed well. N,N-diisopropylethylamine, also known as Hunig’s Base or iPr2Net, and Fmoc-Val-Cit-para-aminobenzyl-para-nitrophenol were added. The mixture was stirred at room temperature for 4-16 hours and monitored with a ninhydrin test kit until the reaction was completed. Diethylamine (Et2NH) was then added to the reaction mixture and stirred for 2 hours at 18-25°C to remove the Fmoc protecting group. Upon completion, the solvent was evaporated under vacuum to afford crude VCP-eribulin and purified on a Zorbax SB-C18 column. VCP-Eribulin was dissolved in DMF and Hunig’s base and DMF were added. The mixture was stirred at 18-25°C for 3 hours and purified by HPLC and solvent was removed to yield mal-(PEG)2-Val-Cit-p-aminobenzyloxycarbonyl (pAB)-eribulin, or mal-(PEG)2-VCP-eribulin (page 61, 2.1.1, [0302]).
US’458 further teaches antibody drug conjugates represented by the formula Ab-(L-D)p; wherein Ab is an internalizing antibody or an internalizing antigen-binding fragment thereof which targets a tumor cell; D is eribulin; L is a cleavable linker that attaches the Ab to D; and p is an integer from 1-20 (page 1, [0008]-[0011]). US’458 also teaches that p can be an integer from 1 to 6, from 2 to 5, or preferably, from 3 to 4. In some embodiments, a pool of ADCs are provided, and the average p in the pool is about 4, for example, 3.5-4.5, such as about 3.8. In some embodiments the linker comprises Mal-(PEG)2-Val-Cit-pAB and p is 4 (page 2, [0018]). US’458 teaches that the antibody moiety is attached via the maleimide moiety (Mal), for instance through a cysteine residue (page 2, [0017]).
US’458 teaches exemplary antibodies for the ADC including MORab-003, a humanized, human folate receptor alpha targeting antibody; MORab-009, a mouse-human chimeric, human mesothelin targeting antibody; and trastuzumab, a humanized, human her2/neu targeting antibody (page 12, [0123]).
US’458 teaches that antibody drug conjugates were prepared using three methodologies. In the first methodology, unpaired cysteines are generated through partial reduction with limited molar equivalents of the non-thiol reducing agent TCEP. The second conjugation strategy utilized reduced disulfide bridging chemistry which rebridges the free thiols of the cysteine residues released during the partial reduction process. The third conjugation strategy employs limited lysine utilization (page 61, [0299]-[0300]). US’458 further teaches an example conjugation of the MORAb-003 antibody to mal-VCP-eribulin using a partial reduction of the antibody with TCEP (page 59, [0288]).
While the antibody drug conjugate taught by US’458 has a linker-drug combination that matches the instantly claimed invention, US’458 differs from the instantly claimed methods in the order of the steps used in the synthesis of the conjugate. Specifically, US’458 does not teach the instantly claimed method in which the linker is synthesized followed by conjugation of the drug and then the antibody. Additionally, while US’458 teaches conjugation of an antibody to the Mal group of the conjugate, US’458 does not explicitly teach the location on the Mal group to which the antibody is bound or that it is in the position shown in Formula (I) of claim 25.
WO’812 teaches compound L1-5 shown below (page 556; Example 1-5):
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L1-5 is a species of Formula (A), where m=1 and X is a nitrophenoxy group.
WO’812 teaches a method for synthesizing L1-5 as shown below (page 556; Example 1-5)
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The synthesis taught by L1-5 comprises the following 2 steps:
Step 1: DIEA was added to a solution of Mal-PEG1-Acid, which matches the structure of instant Formula (1) where m=1, in DMF, followed by addition of HATU. The mixture was stirred at room temperature for 5 minutes then was added to a solution of valcit-pab-OH, which matches the structure of instant Formula (2), in DMF. The mixture was stirred at room temperature for 1 hour then concentrated and purified by reverse phase ISCO using a CD18 column, eluted with a mixture of acetonitrile-H2O containing TFA. Fractions were concentrated to obtain MPEG1-vc-pab-OH (page 556, lines 15-26). MEG1-vc-pab-OH has a structure that matches instant Formula (3), where m =1.
Step 2: A solution of MPEG-valcit-pabOH, bis(4-nitrophenyl) carbonate, and DIEA was stirred at room temperature for 2 days. The mixture was then concentrated and purified by silica gel column, eluted with MeOH:DCM, and fractions containing the desired product of L1-5 were collected and concentrated (pages 556, line 27 – page 557, line 4). Bis(4-nitrophenyl) carbonate meets the instant claim limitation of an acylating agent comprising a nitrophenoxy group and, as shown in the synthesis reaction, the combination of MPEG-valcit-pabOH, bis(4-nitrophenyl) carbonate and DIEA lead to acylating of the hydroxyl group of MPEG-valcit-pabOH.
WO’812 further teaches methods in which the linker L1-5 was used in the synthesis of drug conjugates. For instance, example 3-16 (page 592) teaches the synthesis of the compound C9 which comprises the linker L1-5 conjugated to a STING agonist. C9 of WO’812 is shown below:
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WO’812 teaches that C9 was synthesized according to the methods described for C1. In the synthesis of C1, the linker intermediate was added to a solution of CDN intermediate (CDNI-1) in DMF, followed by the addition of DIEA and HOAT. The mixture was stirred at room temperature for 16 hours before being concentrated and purified (page 589, lines 1-9).
WO’812 further teaches methods of conjugating the linker-drug compounds with antibodies in which the linker is conjugated to a cysteine residue engineered into an antibody (page 608, lines 20-24). WO’812 provides the following schematic of the antibody conjugation including the location point of the antibody attached to the Mal group of the linker (page 610, line 5):
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It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of producing Mal-PEG2-VCP-eribulin and the antibody drug conjugates thereof taught by US’458 to use the order of synthesis taught by WO’812, in which the Mal-PEG-Val-Cit-PAB linker is formed by reacting Mal-PEG-Acid with val-cit-pab-OH in the presence of DIEA and HATU followed by reaction with bis(4-nitrophenyl) carbonate and DIEA to form a Mal-PEG-Val-Cit-PAB linker which is then conjugated with the drug and antibody. It would have further been obvious to attach the antibody to the Mal group as taught by US’458 in the position on the Mal group taught by WO’812.
It would have been obvious to use the order of synthesis taught by WO’812 as WO’812 teaches an alternative synthesis method for the production of the same Mal-PEG-Val-Cit-PAB linker and also teaches methods in which the linker is conjugated to a drug and antibody. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’812 teaches a method which results in the same linker as that used in the conjugates of US’458 and uses overlapping reagents such as N,N-Diisopropylethylamine (also known as DIEA, Hünig's base, or iPr2NEt). Additionally, the conjugate C9 taught by WO’812, which uses the Mal-PEG-Val-Cit-PAB linker, demonstrates drug conjugation at the same location in the linker using the same groups, as the eribulin in the ADC taught by US’458 further demonstrating overlapping conjugation methods.
It would have been obvious to attach the antibody in the position on the Mal group taught by WO’812 as WO’812 establishes that the position on the Mal group had been demonstrated for antibody attachment to form antibody drug conjugates. An ordinarily skilled artisan would have had a reasonable expectation of success as both US’458 and WO’812 teach antibody drug conjugates in which an antibody moiety is attached via the maleimide moiety (Mal) through a cysteine residue on the antibody.
Regarding claim 26, as discussed above, US’458 teaches conjugates comprising antibodies including MORab-003 and MORab-009. US’458 further teaches the sequences for the HCDRs/LCDRs, heavy/light chain variable regions, and heavy/light chains of MORab-003 and MORab-009 (pages 13-26). The sequences for MORab-003 and MORab-009 disclosed by US’458 are identical to those recited in instant claim 26 (i)-(iv) and (ix)-(xii) as discussed below and shown in the ABSS alignments provided:
MORab-003: US’458 discloses MORab-003 as having a heavy chain and light chain of SEQ ID NOs: 1 and 6, respectively. The sequences are identical to instant claim 26 (iv) SEQ ID NOs: 1 and 6, respectively, as shown in the ABSS alignments below. The sequences of US’458 SEQ ID NOs: 1 and 6, shown in the alignments below, also comprise the HCDRs/LCDRs of instant claim 26 (i) and (ii) as well as the heavy and light chain variable regions of instant claim 26 (iii). US’458 also breaks down these individual sequences in the tables spanning pages 13-26.
Instant SEQ ID NO: 1 aligned with US’458, SEQ ID NO: 1
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Instant SEQ ID NO: 6 aligned with US’458, SEQ ID NO: 6
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MORab-009: US’458 discloses MORab-009 as having a heavy chain and light chain of SEQ ID NOs: 325 and 326, respectively. The sequences are identical to instant claim 26 (xii) SEQ ID NOs: 305 and 306, respectively, as shown in the ABSS alignments below. The sequences of US’458 SEQ ID NOs: 325 and 326, shown in the alignments below, also comprise the HCDRs/LCDRs of instant claim 26 (ix) and (x) as well as the heavy and light chain variable regions of instant claim 26 (xi). US’458 also breaks down these individual sequences in the tables spanning pages 13-26.
Instant SEQ ID NO: 305 aligned with US’458, SEQ ID NO: 325
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Instant SEQ ID NO: 306 aligned with US’458, SEQ ID NO: 326
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Claim 20-23 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0252458 A1 (Albone, E.F., et al) 07 SEPT 2017 in view of WO 2018/200812 A1 (Brumi, J.R., et al) 01 NOV 2018 and Dunetz, J.R., et al (2016) Large-Scale applications of amide coupling reagents for the synthesis of pharmaceuticals Org. Process Res. Dev. 20; 140-177.
The teachings of US’458 are as discussed above.
While the drug conjugate taught by US’458 has a linker-drug combination that matches the instant compound of Formula (B), US’458 differs from the instantly claimed methods in the order of the steps used in the synthesis of the conjugate. Specifically, US’458 does not teach the instantly claimed method in which a mixture is prepared comprising an acetylating agent comprising a phenoxy group or a nitrophenoxy group, a compound of Formula (3) and eribulin or a salt thereof; where the hydroxyl group in Formula (3) is acetylated resulting in a compound of Formula (A) which is then reacted with the eribulin or salt thereof to produce the compound of Formula (B).
The teachings of WO’812 are as discussed above.
As discussed above, WO’812 teaches a method of producing a compound, MPEG1-vc-pab-OH, which has the structure of instant Formula (3). WO’812 further teaches a mixture comprising MPEG1-vc-pab-OH and bis(4-nitrophenyl) carbonate, which meets the instant limitation of an acetylating agent that comprises a nitrophenoxy group (page 556, example 1-5). This reaction results in the linker L1-5, which is then reacted with a drug to form a linker-drug conjugate using DIEA and HOAT.
Dunetz is a review evaluating coupling reagents used in the condensation of an acid and amine for the synthesis of drug candidates (page 140, right column, Introduction). Dunetz teaches coupling reagents including HATU (page 146) as well as DCC, EDAC (page 144, right column, 2.3; page 145, Figure 5), and DMTMM (page 147, Figure 9; page 148, Scheme 11; page 148, left column, paragraph 2).
Dunetz further teaches that the coupling agent can be added to a mixture of the acid and amine coupling partners (page 148, left column, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of producing Mal-PEG2-VCP-eribulin taught by US’458 to use the order of synthesis taught by WO’812, including step 2 in which Mal-PEG-val-cit-pab-OH is reacted with bis(4-nitrophenyl) carbonate and DIEA to form a Mal-PEG-Val-Cit-PAB linker which is then reacted with the drug which, in the case of eribulin taught by US’458, would result in the compound of instant Formula (B). It would have further been obvious to have the Mal-PEG-val-cit-pab-OH, bis(4-nitrophenyl) carbonate, and eribulin in a mixture based on the teachings of Dunetz.
It would have been obvious to use the order of synthesis taught by WO’812 as WO’812 teaches an alternative synthesis method for the production of the same Mal-PEG-Val-Cit-PAB linker used by US’458 and also teaches methods in which the linker is conjugated to a drug and antibody. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’812 teaches a method which results in the same linker as that used in the conjugates of US’458 and uses overlapping reagents such as N,N-Diisopropylethylamine (also known as DIEA, Hünig's base, or iPr2NEt). Additionally, the conjugate C9 taught by WO’812, which uses the Mal-PEG-Val-Cit-PAB linker, demonstrates drug conjugation at the same location in the linker as the eribulin in the ADC taught by US’458 also using an amide coupling reaction further demonstrating overlapping conjugation methods.
It would have been obvious to modify step 2 of the synthesis to have the Mal-PEG-val-cit-pab-OH, bis(4-nitrophenyl) carbonate, and eribulin in a mixture as Dunetz teaches that amide coupling agents can be added to a mixture of acids and amine coupling partners. An ordinarily skilled artisan would have had a reasonable expectation of success as Dunetz is teaching methods of amide coupling which is the type of reaction taught by US’458 and WO’812 for synthesis of the linker-drug conjugate.
Response to Arguments
Applicant's arguments filed 11/19/2025 have been fully considered but they are not persuasive.
With regards to the rejections of claims 15-18 and 25-30 under 35 USC 103 over US’458 and WO’812, applicant argues that US’458 does not teach Formula A or the claimed method of producing Mal-(PEG)2-Val-Cit-PABC-eribulin by reacting the linker of formula A with eribulin. Applicant argues that US’458 does not provide motivation to seek alternative production methods for the claimed linker-eribulin conjugate. Applicant further argues that nothing in WO’812 remedies this deficiency as the reference does not teach or suggest conjugating a linker with eribulin, but rather with STING agonists. Applicant argues that the rejection does not explain why one of ordinary skill in the art would look to a reference on a STING agonist or be motivated by such a reference for use with the eribulin conjugate of US’458.
These arguments, however, are not persuasive. Explicit motivation in the prior art is not required in order establish a prima facie case of obviousness. MPEP 2143 provides 7 exemplary rationales that may be used to support a conclusion of obviousness, KSR (A)-(G), only one of which requires that there be some teaching, suggestion, or motivation in the prior art. The instant rejection relies on KSR (A), combining prior art elements according to known methods to yield predictable results. As described in MPEP 2143 I.A., the rationale does not require explicit motivation in the art. Rather, the obviousness rationale requires that the prior art include each claimed element with the only difference between the claimed invention and the prior art a lack of actual combination of elements; a finding that one of ordinary skill in the art could have combined the elements as claimed by known methods; and that the results of the combination would have been predictable.
As discussed in detail in the rejections of the instant office action, US’458 teaches a linker-toxin conjugate of Mal-PEG2-Val-Cit-PAB-eribulin, the structure of which is a species of Formula (B) where m is 2. While the method of making the compound disclosed by US’458 differs from the instantly claimed methods, WO’812 demonstrates that such methods were known for producing the same linker, Mal-PEG2-Val-Cit, for the synthesis of drug conjugates. As WO’812 teaches methods of producing drug conjugates using the same linker as that of US’458, it would have been obvious to use the method order of WO’812 to produce the conjugate of US’458.
Applicant argues that WO’812 teaches conjugation with STING agonists, not eribulin, however, WO’812 is not required to teach each and every limitation of the claimed methods in order to demonstrate a prima facie case of obviousness as the rejection relies on the combination of applied references and what the combination would have suggested to one of ordinary skill in the art. See MPEP 2145 (IV). As discussed above, US’458 teaches a structure that meets the limitations of Formula (B) comprising a species of the claimed linker and eribulin. Therefore, WO’812 is not required to teach these limitations. Rather WO’812 is applied in the rejection to demonstrate that alternative orders for synthesizing the drug conjugate would have been obvious in view of the prior art, including those of the instantly claimed methods. Applicant does not provide any evidence that suggests that the drug taught by WO’812 is critical in the conjugation process disclosed or that the conjugation process could not be applicable to other drugs, particularly those that are already taught to comprise the same linker formed by the method.
Furthermore, the references US’458 and WO’812 are both in the field of antibody drug conjugates and both teach the use of the same linker to form said ADCs, demonstrating that they are analogous art. It has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992).
Applicant further argues that a replacement of the conjugation process would not have had any expectation of success, absent hindsight considerations based on the instant specification. Applicant argues that eribulin has a complex structure with several potential reaction sites that could contribute to the generation of impurities when producing a linker-eribulin conjugate. Applicant argues that Formula A, which is the linker intermediate, has two reaction sites, one at the p-NO2 carbamate moiety and the other at the maleimide moiety. Applicant argues that, conversely, the conjugation process disclosed by US’458 has a single reaction site in step 1 (reacting Fmoc-VCP-PNP with eribulin), thus limiting side reactions with eribulin. Applicant argues that a person of ordinary skill in the art would understand that the presence of multiple reaction sites on Formula A increases the potential for generating impurities due to side reactions and that one would not have been motivated to use a more complex reaction process or reasonable expectation of success.
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).
While applicant argues that eribulin has a complex structure with several potential reaction sites, US’458 demonstrates the feasibility of forming the claimed conjugate where the same linker is conjugated to the same site of eribulin. Additionally, WO’812 teaches a method that produces the intermediate linker of instantly claimed Formula A and exemplifies its use in forming a linker drug conjugate where the drug is linked to the p-NO2 carbamate moiety. Results which demonstrate that, even if there are two linking sites on the intermediate linker, successful conjugation to the p-NO2 carbamate moiety can be achieved. It is also noted that, as discussed in the rejection, WO’812 teaches the use of the maleimide moiety for antibody conjugation demonstrating motivation to conjugate the drug to the p-NO2 carbamate moiety. Furthermore, it is noted that the instant claims do not require any particular yield of the eribulin conjugate and; therefore, even if some impurities are formed following the method of WO’812, such method would still meet the instant claim limitations.
Applicant further argues that the claimed method provides unexpected improvements over the methods disclosed in US’458. For example, a higher yield of the final product and a higher yield of synthetic intermediates. Applicant cites [0010], [0150], [0152], and [0373], and Example 3 for support. Specifically, applicant argues that the method provided a higher yield (71%) of Mal-(PEG)2-Val-Cit-PABC-eribulin than the method of US’458, which only produced a yield of 38%. Applicant also argues that the linker intermediate Mal-(PEG)2-Val-Cit-PABC-PNP (Formula A) had a 51% yield.
While applicant does demonstrate increased yield of the claimed conjugate, and a high intermediate linker yield, the yield of the conjugate and linker are latent properties of the method that was used to produce the linker and conjugate. Which is to say that the intermediate/conjugate yield would flow naturally from the method that is used to produce it.
While the instant disclosure does provide a comparison to the teachings of US’458, the disclosure does not provide a comparison to the conjugation method taught by WO’812, which teaches the same general steps of the instantly claimed invention, in order to demonstrate that the instantly claimed method comprises a critical element that results in higher yield than the methods that were disclosed in the prior art.
MPEP 716.02 (b)(III) states “Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims.” MPEP 716.02 (e) states “An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979).” The MPEP also states that “Showing unexpected results over one of two equally close prior art references will not rebut prima facie obviousness unless the teachings of the prior art references are sufficiently similar to each other that the testing of one showing unexpected results would provide the same information as to the other.”
Furthermore, the method used to obtain the results that applicant proposes are unexpected are not commensurate in scope with the instantly claimed invention.
MPEP 716.02(d) states “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.”
For instance, the independent claim limits the method of producing the compound of Formula B by the general reactions that were used to synthesize the compound without claiming any specific reagents/reaction conditions. In the instant specification, the method disclosed produces the intermediate linker with a 51% yield, as discussed by applicant in the response. WO’812 teaches the same general method steps of the instantly claimed invention to produce the same intermediate linker of LI-5, which is a species of instantly claimed Formula A, where m=2. WO’812 teaches that the method used resulted in LI-5 yield of 80% (pages 556-557), suggesting that the reagents and/or reaction conditions used in the method of production play a critical role in the yield of the compound produced.
With regards to the rejection of claims 20-24 under 35 USC 103, applicant argues that Dunetz does not remedy the deficiencies of US’458 and WO’812 discussed above and does not disclose methods of producing linker-drug conjugates.
Applicant’s arguments concerning US’458 and WO’812 were not persuasive for the reasons discussed in detail above and; therefore, Dunetz is not required to remedy any supposed deficiency. Rather, Dunetz is applied in order to demonstrate that it would have been obvious to have the Mal-PEG-val-cit-pab-OH, bis(4-nitrophenyl) carbonate, and eribulin in a mixture.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US 10,548,986 B2
Claims 9-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. US 10,548,986 B2 in view of US 2017/0252458 A1 (Albone, E.F., et al) 07 SEPT 2017, WO 2018/200812 A1 (Brumi, J.R., et al) 01 NOV 2018 and Dunetz, J.R., et al (2016) Large-Scale applications of amide coupling reagents for the synthesis of pharmaceuticals Org. Process Res. Dev. 20; 140-177.
US’986 claims an antibody-drug conjugate of Formula (I): Ab-(L-D)p wherein Ab is an internalizing anti-HER2 antibody or fragment thereof comprising HCDRs 1-3 of SEQ ID NOs: 71-73, respectively and LCDRs 1-3 of SEQ ID NOs: 74-76, respectively, as defined by the Kabat numbering system; or HCDRs of SEQ ID NOs: 191-193, respectively and LCDRs 1-3 of SEQ ID NOs: 194-196, respectively, as defined by the IMGT numbering system; D is eribulin; and L is a cleavable linker comprising Mal-(PEG)2-Val-Cit-pAB; and p is an integer from 1 to 8 (claim 1). US’986 further claims compositions comprising multiple copies of the antibody-drug conjugate where the average p of the ADC is from about 3.2 to 4.4 (claim 2). US’986 claims that the antibody has a heavy and light chain variable region of SEQ ID NO: 27 and 28, respectively and a human IgG1 heavy chain constant domain or human Ig kappa light chain constant domain (claims 3-5). US’986 claims that p is from 1-4 and a pharmaceutical composition comprising the ADC and a pharmaceutically acceptable carrier (claims 6-7). US’986 further claims methods of treating a patient with cancer that expresses HER2 comprising administering a therapeutically effective amount of the ADC (claims 8-13).
The heavy and light chain variable regions of SEQ ID NOs: 27 and 28 claimed in US’986 are identical to instant SEQ ID NOs: 27 and 28, respectively, as claimed in instant claim 26 (vii).
The claims of US’986 claim an antibody-drug-conjugate comprising the same linker, Mal-(PEG)2-Val-Cit-pAB, conjugated to the same drug, eribulin, and antibody of the instantly claimed invention. The claims of US’986 differs from the instantly claimed invention in that the instantly claimed invention is drawn to methods of making the conjugate claimed in US’986.
The teachings of US’458, WO’812, and Dunetz are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’986 to include a method of producing the ADC claimed by US’986 that includes the synthesis methods disclosed by US’458, WO’812, and Dunetz which, combined, teach methods that render obvious the instantly claimed methods. It would have been obvious to include these known methods in the claims of US’986 with a reasonable expectation of success as the methods encompass known synthesis techniques to create antibody drug conjugates comprising the same Mal-PEG-Val-Cit-pAB linker conjugated to a drug and antibody.
US 10,322,192 B2
Claims 9-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. US 10,322,192 B2 in view of US 2017/0252458 A1 (Albone, E.F., et al) 07 SEPT 2017, WO 2018/200812 A1 (Brumi, J.R., et al) 01 NOV 2018 and Dunetz, J.R., et al (2016) Large-Scale applications of amide coupling reagents for the synthesis of pharmaceuticals Org. Process Res. Dev. 20; 140-177.
US’195 claims an antibody-drug conjugate of Formula (I): Ab-(L-D)p wherein Ab is an internalizing anti-folate receptor alpha antibody or fragment thereof comprising HCDRs 1-3 of SEQ ID NOs: 2-4, respectively and LCDRs 1-3 of SEQ ID NOs: 7-9, respectively, as defined by the Kabat numbering system; or HCDRs of SEQ ID NOs: 13-15, respectively, and LCDRs 1-3 of SEQ ID NOs: 16-18, respectively, as defined by the IMGT numbering system; D is eribulin; and L is a cleavable linker comprising Mal-(PEG)2-Val-Cit-pAB; and p is an integer from 1 to 8 or 3.6-4.4 (claims 1 and 6). US’195 further claims compositions comprising multiple copies of the antibody-drug conjugate where the average p of the ADC is from about 3.2 to 4.4 (claim 4). US’195 claims that the antibody has a heavy and light chain variable region of SEQ ID NO: 23 and 24, respectively and a human IgG1 heavy chain constant domain and/or human Ig kappa light chain constant domain (claims 3-5). US’195 further claims methods of treating a patient with cancer that expresses folate receptor alpha comprising administering a therapeutically effective amount of the ADC (claims 8-13).
The heavy and light chain variable regions of SEQ ID NOs: 23 and 24 claimed in 23 and 24 are identical to instant SEQ ID NOs: 23 and 24, respectively, as claimed in instant claim 26 (iv).
The claims of US’195 claim an antibody-drug-conjugate comprising the same linker, Mal-(PEG)2-Val-Cit-pAB, conjugated to the same drug, eribulin, and antibody of the instantly claimed invention. The claims of US’195 differ from the instantly claimed invention in that the instantly claimed invention is drawn to methods of making the conjugate claimed in US’195.
The teachings of US’458, WO’812, and Dunetz are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’195 to include a method of producing the ADC claimed by US’195 that includes the synthesis methods disclosed by US’458, WO’812, and Dunetz which, combined, teach methods that render obvious the instantly claimed methods. It would have been obvious to include these known methods in the claims of US’195 with a reasonable expectation of success as the methods encompass known synthesis techniques to create antibody drug conjugates comprising the same Mal-PEG-Val-Cit-pAB linker conjugated to a drug and antibody.
Response to Arguments
Applicant's arguments filed 11/19/2025 have been fully considered but they are not persuasive. Applicant argues that US’986 and US’192 do not claim the instantly claimed method of producing Mal-(PEG)2-Val-Cit-PABC-eribulin by reacting the linker of Formula A with eribulin. Applicant argues that none of the secondary references teach or suggest the claimed methods or the unexpected benefits of producing the linker-eribulin conjugate with the claimed methods.
Applicant’s arguments are analogous with those concerning the rejection under 35 USC 103, which were not found to be persuasive for the reasons discussed in detail above, and the rejections under nonstatutory double patenting are; therefore, maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693