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 .
DETAILED ACTION
Claims 1, 8-23, and 47-51 are pending in the instant application.
Claims 2-6 were canceled.
Claims 50-51 are new.
Claims 8-11, 15-16, and 21 were withdrawn previously as not including the Applicant elected species.
Claim Status
Applicant’s election without traverse of: 1) first and second linker moieties of a first enzymatically cleavable moiety comprising a peptide and the second enzymatically cleavable moiety comprises a glycoside; and 2) the linker chemical structure of:
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is under review.
Claims 1, 12-14, 17-20, 22-23, and 47-51 are under examination for the Applicant elected species.
Rejections Withdrawn
The rejection of claims 4 and 6 are moot in view of claim cancelation.
The rejection of claims 1, 12-14, 17-20, 22-23, 47-51 under 35 USC § 103 is withdrawn in view of the claim amendment.
The rejection of claims 1, 12-14, 17-20, 22-23, 47-51 under Nonstatutory Double Patenting is withdrawn in view of the claim amendment.
Claim Rejections Necessitated by Amendment
Regarding the Applicant elected species of:
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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.
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.
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, 12-14, 17-20, 22-23 and 47-51 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015081282 (Rabuka D et al. IDS reference), WO 2018234636 (Satomaa T et al. IDS reference), Alouane A et al. (Angew Chem Int Ed Engl 2015 54(26):7492-509 reference of record), and Filpula D et al. (Advanced Drug Delivery Reviews 60 (2008) 29–49).
Rabuka taught an antibody drug conjugate, wherein the linker-payload is conjugated to the antibody via a hydrazinyl-pyrrolo coupling moiety scheme of:
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(pages 48-49, paragraph 243) to produce:
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(Fig. 2), wherein the linker-payload is:
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(page 216, paragraph 953 and Fig 61), which has a payload of the auristatin MMAD. Rabuka taught a linker component comprising
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wherein R12 is hydrogen (page 5, paragraph 12) and taught successful production of compounds wherein the 4 amino piperidine moiety is conjugated to a carbonyl at the beginning of the linker comprising the moiety
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(Fig 63).
Rabuka taught the linker as including a para-amino-benzyloxy (PABO) pages 74-75, paragraphs 348). Rabuka taught the linker as including a meta-amino-benzyloxycarbonyl (MABC), wherein a carbohydrate or carbohydrate derivative is attached (page 74, paragraphs 344-346) and wherein amino acids can be directly conjugated beside the MABC or PABO linker moiety (AA)-linker, wherein a protease-cleavage moiety and glucuronidase cleavage moiety is also claimed (pages 75-76, paragraph 352). Thus, cleavage moieties in the meta and para positions are claimed by Rabuka. Rabuka taught compounds wherein the self-immolative PABC includes more than one substituent wherein a glucuronide is attached (page 243). Rabuka taught the antibody for conjugation as trastuzumab (page 114, paragraph 492). Regarding instant claims 47, Rabuka taught the conjugate as pharmaceutical composition and a pharmaceutically acceptable excipient (abstract). Rabuka taught the conjugate as a liquid injectable composed of pharmaceutically acceptable carriers and excipients (page 134, paragraph 562). Regarding instant claims 48-49, Rabuka taught a method of administering to a subject an effective amount of a conjugate to treat a condition in a subject (abstract). Rabuka taught methods of treating cancer with the antibody drug conjugate by delivering the chemotherapeutic agent to the subject with cancer (page 135-136, paragraphs 569-570), wherein the antibody conjugate binds to an antigen present on cancer cells (page 120-121, paragraph 516).
Rabuka did not teach a cleavable linker comprising a first cleavable linker and a second cleavable linker wherein the second cleavable moiety hinders cleavage of the first cleavable moiety, but this is obvious in view of Satomaa, Alouane, and Filpula.
Regarding instant claims 1 and 23, Satomaa taught an antibody drug conjugate, wherein the antibody was trastuzumab, the linker comprised a valine- beta-D-glucose-serine, and the drug was an auristatin (page 58, Scheme 3).
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Satomaa taught the glycoside efficiently protected the linker from cathepsin B-induced cleavage and that after β-glucosidase digestion the peptide was cleavable by cathepsin and liberated the free drug (page 60, lines 7-14).
Satomaa taught the valine- beta-D-glucose-serine linker is more stable systemically (page 59, lines 10-21 and Table) and effective against cancer cells (page 60, lines 15-18). Satomaa taught an antibody drug conjugate, wherein the antibody was trastuzumab and the linker comprised Val-Ser(GlcA) (page 60, Scheme 4).
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Satomaa taught the ADC comprising Val-Ser(GlcA) was effective in vitro (page 61, Example 9) and in vivo (pages 61-62, Example 10) which indicates the ADC was effectively cleaved in cancer cells. Regarding instant claims 47-49 Satomaa taught administration of a pharmaceutical composition comprising a trastuzumab-based ADC conjugated at DAR=8 with the maleimidocaproyl-Val-Ser(Glc) linker and a pharmaceutically acceptable excipient of PBS to a subject effectively inhibited tumor growth in vivo compared to the naked antibody treatment (Example 10 Table on page 62).
Alouane taught self-immolative linkers result in elimination of leaving groups in the ortho and para position from benzene ring self-immolation groups
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(Fig. 2). Meta position self-immolation triggers would not cause leaving group release. Alouane taught the nature of the aromatic core of a self-immolation group governs the distance between the activation position and the leaving group, independently of any electronic effect, wherein the self-immolation group contributes to reduce steric hindrance in the case of enzyme activation (page 7501, second paragraph).
Filpula taught linker release mechanisms are shown to be kinetically controlled by the design of a hydrolytically labile center and side chains for the steric modulation of the intramolecular elimination reactions and linker self-immolation (abstract). Filpula taught a key attribute of controlled release is introduced in a spacer group which may regulate release kinetics by participation in the elimination chemistry or by providing steric hindrance of hydrolysis (page 33, right paragraph). Filpula taught a benzyl elimination (BE) system whereby hydrolysis results in release of the PEG polymer followed by the classical and rapid 1,4- or 1,6-BE reaction and molecular decomposition to regenerate the amine group of the conjugated drug molecule, wherein refinement of release kinetics is accomplished by introduction of different moieties for trigger and steric hindrance as ortho side chains on the benzyl ring (page 33-34, bridging paragraph and Fig. 4A-B).
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Filpula taught one particularly serviceable BE linker employs a sterically hindered ester by introduction of two flanking ortho methyl groups that prevent rapid hydrolysis of the ester bond and this linker exhibits relatively slow release kinetics compared to non-substituted esters (page 35, left column, second paragraph and Fig. 4A-B). Filpula taught the varieties of trigger moieties and ortho side chains are not limited by the examples shown here and it may be expected that a range of release rates may be tailored using this flexible design format (page 35, left column, second paragraph and Fig. 4A-B). Filpula taught the release mechanism for the various BE linkers proceeds via a common elimination pathway (page 35, left column, second paragraph and Fig. 4A-B).
Regarding instant claims 1, 12-14, 17-20, 22-23, 47 and 50-51, it would have been obvious for a person having ordinary skill in the art to take the antibody drug conjugate of Rabuka, wherein the linker-payload is conjugated to the antibody via a hydrazinyl-pyrrolo coupling moiety scheme of:
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to produce:
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, wherein the linker-payload is:
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, which has a payload of the auristatin MMAD – and:
Include the linker component comprising
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wherein R12 is hydrogen instead of the glutamic acid moiety
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in the linker;
Add: a) a glucoside group to the ADC for a dual enzyme activation in view of Satomaa; b) include substituents in the para and meta positions of the benzyloxycarbonyl in view of Rabuka; c) add the glycoside for steric modulation of the intramolecular elimination reaction, wherein the glycoside is on the benzene ring located beside cathepsin cleavage trigger, wherein the glycoside is in the meta position and amino acid peptide cathepsin cleavage substrate is in the para position, wherein the glycoside is in the meta position relative to the payload and the ortho position relative to the cathepsin cleavage trigger in view of Filpula; and d) expect the glucuronide to sterically block cathepsin cleavage and not cause immolation in view of Alouane and Filpula;
Include a pharmaceutically-acceptable excipient in the antibody drug conjugate for a pharmaceutical composition.
This is obvious because:
Rabuka taught a linker component comprising
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wherein R12 is hydrogen and taught successful production of compounds wherein the 4 amino piperidine moiety is conjugated to a carbonyl at the beginning of the linker comprising the moiety
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;
a) Satomaa taught the valine- beta-D-glucose-serine linker is effective against cancer cells and more stable systemically, wherein glycoside efficiently protected the linker from cathepsin B-induced cleavage and that after β-glucosidase digestion the peptide was cleavable by cathepsin and liberated the free drug, b) Rabuka taught the linker as including a meta-amino-benzyloxycarbonyl (MABC) or para-amino-benzyloxy (PABO), wherein a carbohydrate or carbohydrate derivative is attached and wherein amino acids can be directly conjugated beside the MABC or PABO linker moiety (AA)-linker, wherein protease and glucuronidase cleavable moieties are further taught. Thus, cleavage moieties in the meta and para positions are claimed by Rabuka. Rabuka further taught the self-immolative PABC as including more than one substituent wherein a glucuronide is attached; c) Filpula taught: i) effective linker release controlled by steric modulation of linker self-immolation; ii) a key attribute of controlled release is introduced in a spacer group which may regulate release kinetics by participation in the elimination chemistry or by providing steric hindrance; iii) refinement of release kinetics is accomplished by introduction of different moieties for steric hindrance as ortho side chains on the benzyl ring; iv) flanking ortho groups prevent rapid trigger activation; and v) the varieties of trigger moieties and ortho side chains are not limited and it may be expected that a range of release rates may be tailored using this flexible design format for a common elimination pathway; d) Alouane taught: i) self-immolative linkers result in elimination of leaving groups only in the ortho and para position from benzene ring self-immolation groups; and ii) the self-immolation group contributes to reduce steric hindrance in the case of enzyme activation. Thus, adding the glucuronide of Satomaa to the meta position of the amino-benzyloxycarbonyl of Rabuka would be expected to sterically hinder cleavage of the peptide cleavage group beside the amino-benzyloxycarbonyl;
Rabuka taught the antibody drug conjugate as a pharmaceutical composition with a pharmaceutically-acceptable excipient wherein the composition is injectable which would require a pharmaceutical excipient for the liquid.
There is a reasonable expectation of success because:
Rabuka taught successful production of compounds wherein the 4 amino piperidine moiety is conjugated to a carbonyl at the beginning of the linker comprising the moiety
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; and
a) Satomaa taught the linkers with combination peptide cleavable and glucoside cleavable linkers were effective against cancer cells and more stable systemically, wherein glycoside efficiently protected the linker from cathepsin B-induced cleavage and that after β-glucosidase digestion the peptide was cleavable by cathepsin and liberated the free drug; b and c) Filpula taught: i) effective linker release controlled by steric modulation of linker self-immolation; ii) a key attribute of controlled release is introduced in a spacer group which may regulate release kinetics by participation in the elimination chemistry or by providing steric hindrance; iii) refinement of release kinetics is accomplished by introduction of different moieties for steric hindrance as ortho side chains on the benzyl ring; iv) flanking ortho groups prevent rapid trigger activation; and v) the varieties of trigger moieties and ortho side chains are not limited and it may be expected that a range of release rates may be tailored using this flexible design format for a common elimination pathway; Thus, addition of a glucoside group to the ADC for a dual enzyme activation at the position on the benzene ring directly beside a peptide cathepsin cleavage site would be expected to provide the steric hindrance to prevent activation of the cathepsin cleavage trigger for the immolative elimination of the drug payload; and d) Alouane taught: i) self-immolative linkers result in elimination of leaving groups only in the ortho and para position from benzene ring self-immolation groups; and ii) the self-immolation group contributes to reduce steric hindrance in the case of enzyme activation. Thus, adding the glucuronide of Satomaa to the meta position of the amino-benzyloxycarbonyl of Rabuka would be expected to sterically hinder cleavage of the peptide cleavage group beside the amino-benzyloxycarbonyl; Release of the payload would require glucuronidase activity first to remove the glucuronide that is sterically blocking cathepsin cleavage, then cathepsin enzyme activity to release the payload. This two-step enzymatic release would be expected to yield a more stable antibody drug conjugate as taught by Satomaa; and
the antibody drug conjugate in a pharmaceutical composition with a pharmaceutically-acceptable excipient would be required for injection to treat a patient as a liquid.
This would produce a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an antibody drug conjugate of Rabuka, Satomaa, and Alouane, wherein the linker-payload is conjugated to the antibody via a hydrazinyl-pyrrolo coupling moiety scheme of:
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to produce:
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, wherein the linker-payload is:
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which has a payload of the auristatin MMAD and meet the claim limitations of the Applicant elected species in instant claims 1, 12-14, 17-20, 22-23, 47, and 50-51.
Regarding instant claims 48-49, it would have been obvious for a person having ordinary skill in the art to take the pharmaceutical composition comprising a pharmaceutically acceptable excipient and an antibody drug conjugate of Rabuka, Satomaa, and Alouane – and: 1) use the method of Rabuka to administer to a subject an effective amount of a the pharmaceutical composition comprising a pharmaceutically acceptable excipient and an antibody drug conjugate to treat a cancer in the subject, wherein the antibody conjugate binds to an antigen present on cancer cells.
This is obvious because: 1) Rabuka taught a method of administering to a subject an effective amount of a conjugate to treat cancer with the antibody drug conjugate, wherein the antibody conjugate binds to an antigen present on cancer cells.
There is a reasonable expectation of success because: the pharmaceutical composition comprising a pharmaceutically acceptable excipient and an antibody drug conjugate of Rabuka, Satomaa, and Alouane would target cancer cells, wherein the antibody targets an antigen present on cancer cells to selectively deliver the conjugate to the cancer cells for enzymatic metabolism of the linkers and release of the payload to cancer cells.
Response to Arguments
Applicant argues the Office cited Rabuka for teaching most elements of claim 1. Specifically, the Office cited the embodiment shown below, which is shown on page 219, paragraph 953 and FIG. 61).
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The Office alleged that it would have been obvious to add a second cleavable linker to the (*) location of Rabuka, wherein the second cleavable linker includes a glycoside. This modification is alleged to have fulfilled this aspect of the R7 group of the present claims. For motivation to make this modification, the Office alleged that it would have been obvious to (FOA, page 10):
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Specifically, the Office cited Formula (II) of Satomaa for disclosing a structure wherein Y is a saccharide (e.g. a glucoside) cleavable by an enzyme (FOA, page 15). This fulfills Step 2A of the modification proposed above by the Office.
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However, Y in Satomaa is merely attached to R3 (an amino acid side chain), whereas the second cleavable linker in claim 1 is attached to a particular phenyl ring.
Step 2B of the Office's modification involves moving cleavable saccharide Y of Satomaa to the (*) meta position of the benzyloxycarbonyl group of Rabuka's structure. For motivation, the Office referred to pages 74-76 of Rabuka (FOA, page 6) as shown below.
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Applicant respectfully submits Rabuka fails to teach or suggest placing the saccharide of Satomaa at the meta position as claimed.
Cited paragraphs 344-346 of Rabuka state that a tether can have the MABC or MABO chemical structures below. Additionally, the R group can be a carbohydrate or a carbohydrate derivative (paragraph 346), e.g. the saccharide of Satomaa.
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Critically, however, placing the Satomaa glucoside at the R position of the Rabuka structures would result in the gluocoside being para to the oxymethylene (-CH2O-) group. In contrast, in claim 1 the glucoside cleavable linker is meta to the oxymethylene group (i.e. at R7). Rabuka fails to suggest the meta position because Rabuka implies that there is a special technical benefit to the para position, i.e. because Rabuka discloses neither the meta position nor the ortho position. Hence, an artisan would have lacked a reason to switch from para to either the meta or the ortho position, e.g. because Rabuka suggests this would remove an unnamed but important technical benefit of the para position.
Finally, the other cited passages in Rabuka fail to remedy this deficiency. The other chemical structures on pages 74-75 lack an R group that is described as a carbohydrate.
Accordingly, Applicant respectfully submits that the cited art fails to teach or suggest a glucoside-containing cleavable group (i.e. R7) at a position that is meta to the oxymethylene group and therefore requests that the rejection be withdrawn.
In response, Applicant's arguments filed 6/4/2026 have been fully considered
but they are not persuasive. An updated rejection is above, wherein teachings of Filpula are included to further show that a person having ordinary skill in the art would obviously include a glucoside group to the ADC above for a dual enzyme activation at the position on the benzene ring directly beside a peptide cathepsin cleavage site and further expect the glycoside to provide the steric hindrance to prevent activation of the cathepsin cleavage trigger for the immolative elimination of the drug payload.
Regarding addition of a second cleavable linker to the (*) location of Rabuka and Satomaa, Satomaa taught an antibody drug conjugate, wherein the antibody was trastuzumab, the linker comprised a valine- beta-D-glucose-serine, and the drug was an auristatin (page 58, Scheme 3).
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Satomaa taught the glycoside efficiently protected the linker from cathepsin B-induced cleavage and that after β-glucosidase digestion the peptide was cleavable by cathepsin and liberated the free drug (page 60, lines 7-14). Thus, Satomaa taught Formula (II) and an ADC that comprised a PABO wherein both a cathepsin cleavage site and a β-glucosidase site were present. Movement of the glycoside from within the cathepsin cleavage site of Satomaa to the benzene ring at the meta position as shown in Filpula
would also sterically hinder the cathepsin cleavage site in view of Filpula. Filpula taught: i) effective linker release controlled by steric modulation of linker self-immolation; ii) a key attribute of controlled release is introduced in a spacer group which may regulate release kinetics by participation in the elimination chemistry or by providing steric hindrance; iii) refinement of release kinetics is accomplished by introduction of different moieties for steric hindrance as ortho side chains on the benzyl ring; iv) flanking ortho groups prevent rapid trigger activation; and v) the varieties of trigger moieties and ortho side chains are not limited and it may be expected that a range of release rates may be tailored using this flexible design format for a common elimination pathway (citations above); Alouane taught: i) self-immolative linkers result in elimination of leaving groups only in the ortho and para position from benzene ring self-immolation groups; and ii) the self-immolation group contributes to reduce steric hindrance in the case of enzyme activation. Thus, adding the glucuronide of Satomaa to the meta position of the amino-benzyloxycarbonyl of Rabuka would be expected to sterically hinder cleavage of the peptide cleavage group beside the amino-benzyloxycarbonyl;
Regarding Rabuka, Rabuka taught the linker as including a para-amino-benzyloxy (PABO) pages 74-75, paragraphs 348) and including a meta-amino-benzyloxycarbonyl (MABC), wherein a carbohydrate or carbohydrate derivative is attached (page 74, paragraphs 344-346), wherein amino acids can be directly conjugated beside the MABC or PABO linker moiety (AA)-linker, wherein a protease-cleavage moiety and glucuronidase cleavage moiety is also claimed (pages 75-76, paragraph 352). Rabuka taught linkers wherein dual cleavage sites are present in the on the immolative benzene ring:
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(page 243) and the linker as (AA)p-MABC-(AA)p (pages 75-76, paragraph 352). Thus, cleavage moieties in the meta and para positions are claimed by Rabuka. Rabuka taught compounds wherein the self-immolative PABC includes more than one substituent wherein a glucuronide is attached (page 243). Thus, inclusion of a glycoside and a peptide on a self immolative MABC is taught by Rabuka. Adding a glycoside to the meta position in view of Satomaa, Filpula, and Alouane for steric inhibition of cathepsin cleavage located in the para position would be obvious with a reasonable expectation of success as described above.
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.
Claims 1, 12-14, 17-20, 22-23, and 50-51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 and 27-31 of copending Application No. 18/291,841. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding instant claims 1, 12-14, 17-20, and 22-23, ‘841 taught an antibody drug conjugate with the structure:
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in copending claim 9, which overlaps with the Applicant elected species and contains a cleavable linker for linking an antibody to a drug, wherein the cleavable linker comprises a first cleavable moiety and a second cleavable moiety that hinders cleavage of the first cleavable moiety.
‘841 further taught an antibody drug conjugate with various Markush structures of formula I
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, wherein antibodies, linkers, and drugs are further defined in copending claims 1-8 and 11-26. Copending claim 27 taught a pharmaceutical composition comprising the antibody drug conjugate of claim 1 and a pharmaceutically-acceptable excipient. Copending claim 29 taught a method of treating cancer in a subject, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition of Claim 27, wherein the administering is effective to treat cancer in the subject. Copending claim 30 further defined the cancers of copending claim 29.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant notes that this rejection was repeated, i.e. on both pages 21 and 24. Applicant argues the '841 application has an effective filing date of July 28, 2022, whereas the present application has an effective filing date of January 22, 2020. As such, the present application is the earlier filed of the two pending applications. As set forth in this response, the remaining rejections of the present application have been addressed and should be withdrawn
In response, Applicant's arguments filed 6/4/2026 have been fully considered
but they are not persuasive. This is an anticipatory style nonstatutory double patenting rejection. According to MPEP §804, "If a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent, thereby converting the provisional nonstatutory double patenting rejection in the other application into a nonstatutory double patenting rejection upon issuance of the patent." MPEP §804(I)(B)(l)(b)(i).
Claims 1, 12-14, 17-20, 22-23, and 47-51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 and 27-31 of copending Application No. 18/291,841.
The claims of copending ‘841 teach the limitations of claims 1, 4, 6, 12-14, 17-20, 22-23, and 50-51 for the reasons set forth above.
‘841 is described above.
The claims of ‘841 do not describe a single embodiment of the Applicant elected species in a pharmaceutical composition with a pharmaceutically acceptable excipient for the treatment of cancer, but this is obvious in view of ‘841 teaching the genus of formula I teaching these claims.
Regarding instant claims 47-49, it would have been obvious for a person having ordinary skill in the art to take the ADC of:
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in copending claim 9 and: 1) adding a pharmaceutically-acceptable excipient as taught by copending claim 27; and 2) using the pharmaceutical composition in a method of treating cancer in a subject, the method comprising: administering to the subject a therapeutically effective amount of the pharmaceutical composition above, wherein the administering is effective to treat cancer in the subject as taught by copending claim 29.
This is obvious because: 1) ‘841 taught a pharmaceutical composition comprising: an antibody drug conjugate of formula I and a pharmaceutically-acceptable excipient in copending claim 27; and 2) ‘841 taught a method of treating cancer in a subject, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition of formula I with a pharmaceutically effective excipient, wherein the administering is effective to treat cancer in the subject.
There is a reasonable expectation of success because: 1) the pharmaceutical composition comprising a pharmaceutically acceptable excipient and an antibody drug conjugate would allow treatment of patients; and 2) the composition would target cancer cells, wherein the antibody targets an antigen present on cancer cells to selectively deliver the conjugate to the cancer cells for enzymatic metabolism of the linkers and release of the payload to cancer cells.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant notes that this rejection was repeated, i.e. on both pages 21 and 24. Applicant argues the '841 application has an effective filing date of July 28, 2022, whereas the present application has an effective filing date of January 22, 2020. As such, the present application is the earlier filed of the two pending applications. As set forth in this response, the remaining rejections of the present application have been addressed and should be withdrawn
In response, Applicant's arguments filed 6/4/2026 have been fully considered
but they are not persuasive. This is an obvious style nonstatutory double patenting rejection. According to MPEP §804, "If a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent, thereby converting the provisional nonstatutory double patenting rejection in the other application into a nonstatutory double patenting rejection upon issuance of the patent." MPEP §804(I)(B)(l)(b)(i). The provisional nonstatutory double patenting rejection is not the only rejection remaining.
Claims 1, 12-14, 17-20, 22-23, and 47-51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,564,989 and WO 2018234636 (Satomaa T et al. IDS reference).
Regarding instant claims 1, 12-14, 17-20, 22-23, patented claim 15 taught the compounds:
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. ‘989 patented claim 1 taught a polypeptide linker camptothecin conjugate, wherein patented claims 2-14 claim further details of the conjugate. ‘989 patented claim 16 taught a pharmaceutical composition comprising: a conjugate of claim 1; and a pharmaceutically-acceptable excipient. ‘989 patented claim 17 taught a method comprising: administering to a subject an amount of a conjugate of claim 1.
‘989 does not teach the conjugate as an antibody drug conjugate or exact linker chemical structure of the Applicant elected species, but this is obvious in view of Satomaa teaching effective antibody drug conjugates and other claimed chemical conjugates of ‘989 that contain a 4-amino piperidine linker moiety.
Regarding instant claims 1, 4, 6, and 23, Satomaa taught an antibody drug conjugate, wherein the antibody was trastuzumab, the linker comprised a valine- beta-D-glucose-serine, and the drug was an auristatin (page 58, Scheme 3).
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Satomaa taught the glycoside efficiently protected the linker from cathepsin B-induced cleavage and that after β-glucosidase digestion the peptide was cleavable by cathepsin and liberated the free drug (page 60, lines 7-14).
Satomaa taught the valine- beta-D-glucose-serine linker is more stable systemically (page 59, lines 10-21 and Table) and effective against cancer cells (page 60, lines 15-18). Satomaa taught an antibody drug conjugate, wherein the antibody was trastuzumab and the linker comprised Val-Ser(GlcA) (page 60, Scheme 4).
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Satomaa taught the ADC comprising Val-Ser(GlcA) was effective in vitro (page 61, Example 9) and in vivo (pages 61-62, Example 10) which indicates the ADC was effectively cleaved in cancer cells. Regarding instant claims 47-49 Satomaa taught administration of a pharmaceutical composition comprising a trastuzumab-based ADC conjugated at DAR=8 with the maleimidocaproyl-Val-Ser(Glc) linker and a pharmaceutically acceptable excipient of PBS to a subject effectively inhibited tumor growth in vivo compared to the naked antibody treatment (Example 10 Table on page 62).
Regarding instant claims 1, 12-14, 17-20, 22-23, 47, and 50-51, it would have been obvious for a person having ordinary skill in the art to take the polypeptide linker conjugate of patented claim 15 of:
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and:
conjugate an antibody in view of Satomaa teaching antibody drug conjugates effectively target and treat cancer;
exchange the
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of the linker conjugate for
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as used in a separate linker wherein the 4-amino piperidine joins the carbonyl to a PEG linker as taught by ‘989;
exchange the camptothecin for an auristatin as taught by Satomaa; and
produce a pharmaceutical composition comprising the antibody drug conjugate and a pharmaceutically-acceptable excipient as taught by ‘989.
This is obvious because: 1) Satomaa taught antibody drug conjugates effectively target and treat cancer. Thus attaching the linker conjugate to an antibody would target cancer cells.; 2) ‘989 taught the
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and
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as used in a separate linker conjugates to conjugate the carbonyl to a PEG linker; 3) Satomaa taught antibody drug conjugates effectively target and treat cancer when conjugated to an auristatin; and 4) ‘989 patented claim 16 taught a pharmaceutical composition comprising: a conjugate of claim 1; and a pharmaceutically-acceptable excipient.
There is a reasonable expectation of success because: 1) Satomaa taught antibody drug conjugates effectively target and treat cancer. Thus attaching the linker conjugate to an antibody would target cancer cells; 2) the
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are both used in a separate linker conjugates to conjugate the carbonyl to a PEG linker; 3) Satomaa taught antibody drug conjugates effectively target and treat cancer when conjugated to an auristatin; 4) a pharmaceutical composition comprising: a conjugate and a pharmaceutically-acceptable excipient would allow for administration of the composition to a subject, which Satomaa taught is effective. This would meet the claim limitations of instant claims 1, 12-14, 17-20, 22-23, 47, and 50-51.
Regarding instant claims 48-49, it would have been obvious for a person having ordinary skill in the art to take the pharmaceutical composition of ‘989 and Satomaa above – and: 1) use the method of Satomaa to administer to a subject an effective amount of the pharmaceutical composition comprising a pharmaceutically acceptable excipient and an antibody drug conjugate to treat a cancer in the subject, wherein the antibody conjugate binds to an antigen present on cancer cells.
This is obvious with a reasonable expectation of success because: 1) Satomaa taught antibody drug conjugates effectively target and treat cancer and taught an effective method.
Response to Arguments
Applicant respectfully requests that the rejection be held in abeyance until patentable subject matter is identified in this application.
In response, Applicant's arguments filed 6/4/2026 have been fully considered
but they are not persuasive. A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an objection or requirements as to form (see 37 CFR 1.111(b) and MPEP §714.02).
Claims 1, 12-14, 17-20, 22-23, and 47-51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 12,187,745 and WO 2018234636 (Satomaa T et al. IDS reference).
Regarding instant claims 1, 12-14, 17-20, 22-23, patented claim 15 taught the compounds:
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. ‘745 patented claim 1 taught a polypeptide linker camptothecin conjugate, wherein patented claims 2-14 claim further details of the conjugate.
‘745 does not teach the conjugate as an antibody drug conjugate or exact linker chemical structure of the Applicant elected species, but this is obvious in view of Satomaa teaching effective antibody drug conjugates and other claimed chemical conjugates of ‘745 that contain a 4-amino piperidine linker moiety.
Regarding instant claims 1 and 23, Satomaa taught an antibody drug conjugate, wherein the antibody was trastuzumab, the linker comprised a valine- beta-D-glucose-serine, and the drug was an auristatin (page 58, Scheme 3).
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Satomaa taught the glycoside efficiently protected the linker from cathepsin B-induced cleavage and that after β-glucosidase digestion the peptide was cleavable by cathepsin and liberated the free drug (page 60, lines 7-14).
Satomaa taught the valine- beta-D-glucose-serine linker is more stable systemically (page 59, lines 10-21 and Table) and effective against cancer cells (page 60, lines 15-18). Satomaa taught an antibody drug conjugate, wherein the antibody was trastuzumab and the linker comprised Val-Ser(GlcA) (page 60, Scheme 4).
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Satomaa taught the ADC comprising Val-Ser(GlcA) was effective in vitro (page 61, Example 9) and in vivo (pages 61-62, Example 10) which indicates the ADC was effectively cleaved in cancer cells. Regarding instant claims 47-49 Satomaa taught administration of a pharmaceutical composition comprising a trastuzumab-based ADC conjugated at DAR=8 with the maleimidocaproyl-Val-Ser(Glc) linker and a pharmaceutically acceptable excipient of PBS to a subject effectively inhibited tumor growth in vivo compared to the naked antibody treatment (Example 10 Table on page 62).
Regarding instant claims 1, 12-14, 17-20, 22-23, 47, and 50-51, it would have been obvious for a person having ordinary skill in the art to take the polypeptide linker conjugate of patented claim 15 of:
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and:
conjugate an antibody in view of Satomaa teaching antibody drug conjugates effectively target and treat cancer;
exchange the
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of the linker conjugate for
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as used in a separate linker wherein the 4-amino piperidine joins the carbonyl to a PEG linker as taught by ‘745;
exchange the camptothecin for an auristatin as taught by Satomaa; and
produce a pharmaceutical composition comprising the antibody drug conjugate and a pharmaceutically-acceptable excipient as taught by Satomaa.
This is obvious because: 1) Satomaa taught antibody drug conjugates effectively target and treat cancer. Thus attaching the linker conjugate to an antibody would target cancer cells.; 2) ‘745 taught the
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as used in a separate linker conjugates to conjugate the carbonyl to a PEG linker; 3) Satomaa taught antibody drug conjugates effectively target and treat cancer when conjugated to an auristatin; and 4) Satomaa taught a pharmaceutical composition comprising an ADC and a pharmaceutically-acceptable excipient.
There is a reasonable expectation of success because: 1) Satomaa taught antibody drug conjugates effectively target and treat cancer. Thus attaching the linker conjugate to an antibody would target cancer cells; 2) the
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are both used in a separate linker conjugates to conjugate the carbonyl to a PEG linker; 3) Satomaa taught antibody drug conjugates effectively target and treat cancer when conjugated to an auristatin; 4) a pharmaceutical composition comprising: a conjugate and a pharmaceutically-acceptable excipient would allow for administration of the composition to a subject, which Satomaa taught is effective. This would meet the claim limitations of instant claims 1, 4, 6, 12-14, 17-20, 22-23, 47, and 50-51.
Regarding instant claims 48-49, it would have been obvious for a person having ordinary skill in the art to take the pharmaceutical composition of ‘745 and Satomaa above – and: 1) use the method of Satomaa to administer to a subject an effective amount of the pharmaceutical composition comprising a pharmaceutically acceptable excipient and an antibody drug conjugate to treat a cancer in the subject, wherein the antibody conjugate binds to an antigen present on cancer cells.
This is obvious with a reasonable expectation of success because: 1) Satomaa taught antibody drug conjugates effectively target and treat cancer and taught an effective method.
Response to Arguments
Applicant respectfully requests that the rejection be held in abeyance until patentable subject matter is identified in this application.
In response, Applicant's arguments filed 6/4/2026 have been fully considered
but they are not persuasive. A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an objection or requirements as to form (see 37 CFR 1.111(b) and MPEP §714.02).
Claims 1, 12-14, 17-20, 22-23, and 47-51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 and 34-40 of copending Application No. 18/958,957 and WO 2018234636 (Satomaa T et al. IDS reference).
Regarding instant claims 1, 12-14, 17-20, 22-23, copending claim 15 taught a method of treating cancer in a subject comprising administering to the subject an effective amount of a conjugate wherein the conjugate is:
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or
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. ‘957 claim 1 taught a method of treating cancer in a subject comprising administering to the subject an effective amount of a polypeptide linker camptothecin conjugate, wherein copending claims 2-14 claim further details of the conjugate. Copending claims 34-40 teach treatment of various cancer types.
‘957 does not teach the conjugate as an antibody drug conjugate or exact linker chemical structure of the Applicant elected species, but this is obvious in view of Satomaa teaching effective antibody drug conjugates and other claimed chemical conjugates of ‘957 that contain a 4-amino piperidine linker moiety.
Regarding instant claims 1 and 23, Satomaa taught an antibody drug conjugate, wherein the antibody was trastuzumab, the linker comprised a valine- beta-D-glucose-serine, and the drug was an auristatin (page 58, Scheme 3).
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Satomaa taught the glycoside efficiently protected the linker from cathepsin B-induced cleavage and that after β-glucosidase digestion the peptide was cleavable by cathepsin and liberated the free drug (page 60, lines 7-14).
Satomaa taught the valine- beta-D-glucose-serine linker is more stable systemically (page 59, lines 10-21 and Table) and effective against cancer cells (page 60, lines 15-18). Satomaa taught an antibody drug conjugate, wherein the antibody was trastuzumab and the linker comprised Val-Ser(GlcA) (page 60, Scheme 4).
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Satomaa taught the ADC comprising Val-Ser(GlcA) was effective in vitro (page 61, Example 9) and in vivo (pages 61-62, Example 10) which indicates the ADC was effectively cleaved in cancer cells. Regarding instant claims 47-49 Satomaa taught administration of a pharmaceutical composition comprising a trastuzumab-based ADC conjugated at DAR=8 with the maleimidocaproyl-Val-Ser(Glc) linker and a pharmaceutically acceptable excipient of PBS to a subject effectively inhibited tumor growth in vivo compared to the naked antibody treatment (Example 10 Table on page 62).
Regarding instant claims 1, 12-14, 17-20, 22-23, 47, and 50-51, it would have been obvious for a person having ordinary skill in the art to take method of treating cancer in a subject comprising administering to the subject an effective amount of a conjugate wherein the conjugate is:
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in copending claim 15 and:
conjugate an antibody in view of Satomaa teaching antibody drug conjugates effectively target and treat cancer;
exchange the
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of the linker conjugate for
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as used in a separate linker wherein the 4-amino piperidine joins the carbonyl to a PEG linker as taught by ‘957;
exchange the camptothecin for an auristatin as taught by Satomaa; and
produce a pharmaceutical composition comprising the antibody drug conjugate and a pharmaceutically-acceptable excipient as taught by Satomaa which would further be required in the cancer treatment method of ‘957.
This is obvious because: 1) Satomaa taught antibody drug conjugates effectively target and treat cancer. Thus attaching the linker conjugate to an antibody would target cancer cells.; 2) ‘957 taught the
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as used in a separate linker conjugates to conjugate the carbonyl to a PEG linker; 3) Satomaa taught antibody drug conjugates effectively target and treat cancer when conjugated to an auristatin; and 4) Satomaa taught a pharmaceutical composition comprising an ADC and a pharmaceutically-acceptable excipient.
There is a reasonable expectation of success because: 1) Satomaa taught antibody drug conjugates effectively target and treat cancer. Thus attaching the linker conjugate to an antibody would target cancer cells; 2) the
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are both used in a separate linker conjugates to conjugate the carbonyl to a PEG linker; 3) Satomaa taught antibody drug conjugates effectively target and treat cancer when conjugated to an auristatin; 4) a pharmaceutical composition comprising: a conjugate and a pharmaceutically-acceptable excipient would allow for administration of the composition to a subject, which Satomaa taught is effective. This would meet the claim limitations of instant claims 1, 12-14, 17-20, 22-23, 47, and 50-51.
Regarding instant claims 48-49, it would have been obvious for a person having ordinary skill in the art to take the pharmaceutical composition of ‘957 and Satomaa above – and: 1) use the method of Satomaa to administer to a subject an effective amount of the pharmaceutical composition comprising a pharmaceutically acceptable excipient and an antibody drug conjugate to treat a cancer in the subject, wherein the antibody conjugate binds to an antigen present on cancer cells.
This is obvious with a reasonable expectation of success because: 1) Satomaa taught antibody drug conjugates effectively target and treat cancer and taught an effective method and ‘957 taught treatment with the drug linker.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant argues the '957 application has an effective filing date of January 13, 2022, whereas the present application has an effective filing date of January 22, 2020. As such, the present application is the earlier filed of the two pending applications. As set forth in this response, the remaining rejections of the present application have been addressed and should be withdrawn
In response, Applicant's arguments filed 6/4/2026 have been fully considered
but they are not persuasive. According to MPEP §804, "If a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent, thereby converting the provisional nonstatutory double patenting rejection in the other application into a nonstatutory double patenting rejection upon issuance of the patent." MPEP §804(I)(B)(l)(b)(i). The provisional nonstatutory double patenting rejection is not the only rejection remaining.
Conclusion
Claims 1, 12-14, 17-20, 22-23, and 47-51 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN J SKOKO III whose telephone number is (571)272-1107. The examiner can normally be reached M-F 8:30 - 5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Z Wu can be reached at (571)272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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