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 .
Claims 19, 20, and 22 have been cancelled. Claims 23-30 were added in the preliminary amendment filed 10/31/2023.
Specification
The substitute specification filed 10/31/2023 has been entered.
The disclosure is objected to because of the following informalities:
The instant application and claims recite sequences that require sequence compliance. See at least Gly-Gly-Phe-Gly and Gly-Gly-Gly-Gly-Gly in instant claim 3 and at page 4 of the substitute specification. These sequences should have a sequence identifier. They do not appear to be present in the sequence listing. Applicant should review the specification and claims carefully for other instances where these sequences are recited.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
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 sequence identifiers, 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.
Appropriate correction is required within the time period of response for this Office action.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-18 and 23-29, and the species elected in the reply filed on 7/2/2026 is acknowledged.
Claims 21 and 30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/2/2026.
.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 16-17 and 29 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cai et al. (WO2019/114666, of record, published 20 June 2019).
The English language equivalent Cai et al.(CA 3080236, of record, published 20 June 2019) will be referenced. Cai et al. (U.S. Patent Application Publication 20200347075, of record published 5 November 2020) and Cai et al. (U.S. Patent No. 11,970,506, of record) are also English language equivalents of record.
Cai et al. discloses at least linker A-1 in instant claim 17. See at least claim 80. Pharmaceutical compositions are disclosed in claim 87.
Claims 1, 4, 6-7, 12-13, 15-16, 18, 23-25, 27, and 29 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lannutti et al. (WO 2018/237335, of record).
Lannutti et al. discloses ADC of an anti-ROR1 antibodies with a linker such as Val-Cit (see instant claim 4) and a cytotoxic drug such as a DNA intercalating agent (see instant claim 7). The drug can be duocarmycin or PNU-159682. See instant claim 25. In the formula of claim 1, n is an integer from 1-10 which anticipates an x of 1-8 in instant claims 1 and 13. The drug to antibody ratio (DAR) can be from 1 to 7 anticipating instant claim 15. Pharmaceutical compositions are disclosed. Figure 1 discloses an ADC with an anti ROR1 antibody (“Ab” of instant claim 1) and a maleimidocaproyl attachment group (“M” of instant claims 1, see also instant claim 6, third structure) with Val-Cit (“L” of instant claims 1 and 4, see also instant claim 6, third structure, and claim 23, third structure)) and PABC (“E” of instant claim 1, see also instant claim 6, third structure) and MMAE (“D” of instant claim 1, see also instant claim 6, third structure)) is disclosed. The attachment group (“M” in instant claims) is attached to a sulfhydryl group, S, on the antibody. (See instant claim 12.) See at least Figure 1 and claims of Lannutti et al., in particular claims 1-3, 6-7, and 26-27.
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.
Claims 1-7, 12, 15, 18, 23-25, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Cai et al. (WO2019/114666, of record, published 20 June 2019).
The English language equivalent Cai et al.(CA 3080236, of record, published 20 June 2019) will be referenced. Cai et al. (U.S. Patent Application Publication 20200347075, of record published 5 November 2020) and Cai et al. (U.S. Patent No. 11,970,506, of record) are also English language equivalents of record.
Cai et al. discloses antibody-drug conjugates comprising a bioactive molecule, linkers,
and a targeting moiety. The targeting moiety is linked to the linker via an active group such as a thiol group (i.e. through a sulfur, S, see instant claim 12) to form a conjugate. See at least claim 55. The targeting moiety (A, referenced as Ab in the instant claims) can be a polypeptide that targets ROR1 (see at least claim 56-57) such as an antibody (see at least claim 60). See also page 93 and page 96, line 11. The bioactive molecule (T, referenced as D in the instant claims) can be a cytotoxic drug such as a DNA topoisomerase inhibitor (e.g. a topoisomerase I inhibitor such as camptothecin, hydroxycamptothecin, 9-aminocamptothecin, SN-38, irinotecan, topotecan, belotecan or rubitecan. See at least page 92. Formula II in claim 56 meets the structural limitations of the formula in instant claim 1. See also Formula I in claim 1 as referenced in claim 56. Pharmaceutical compositions are disclosed in claims 40 and 87. See instant claim 18. The structure of claim 38 comprises the elected linking site M (see instant claims 2 and 3). See also at least second through seventh structures list in claim 65. They all meet the limitations of instant claims 1-3 and have connectors (L) meeting the limitations of instant claim 4 as well as structural fragments (E) meeting the limitations of instant claims 1 and 5. Claim 80 discloses an ADC structure meeting the MLED limitations of the instant claims. See instant claim 4, third listed structure; instant claim 6, second listed structure; and instant claim 23, second listed structure. A DAR of 5-8 is disclosed. See page 3, lines 3-4 and instant claim 15.
Cai et al. fairly suggests ADC having an anti-ROR1 antibody and a drug such as a DNA topoisomerase I inhibitor such as camptothecin, hydroxycamptothecin, 9-aminocamptothecin, SN-38, irinotecan, topotecan, belotecan or rubitecan meeting the limitations of the instant claims.
Claims 1-15, 18, 23-25, and 27-28 are rejected under 35 U.S.C. 103 as being unpatentable over Cai et al. (WO2019/114666, of record, published 20 June 2019) as applied to claims 1-5, 7, 12, 15, 18, 23-25, and 27, above, and further in view of Tian et al. (WO 2022/188652).
Cai et al. (WO2019/114666, of record, published 20 June 2019) is applied as above.
The English language equivalent Cai et al. (CA 3080236, of record, published 20 June 2019) will be referenced.
Cai et al. does not disclose the sequences for the anti-ROR1 antibodies required by instant claims 8-11, 13-14, and 28.
Tian et al. (WO 2022/188652 was published 15 September 2022 and filed 28 February 2022). Its English language equivalent is U.S. Patent Application Publication 2024/0018237 (published 18 January 2024 and filed 28 February 2022). The inventors differ from those of the instant application. It is by other. Tian et al. is valid prior art under 102(a)(2). Applicant cannot rely upon the certified copies of the foreign priority applications to overcome this rejection because a translation of said applications has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216. Neither of CN 202110615214X and CN 2021109411343 are in English. The effective filing date of the instant claims is 23 May 2022, the filing date of PCT/CN2022/094559.
The English language equivalent Tian et al. (U.S. Patent Application Publication 2024/0018237, published 18 January 2024, filed 28 February 2022) will be referenced.
Tian et al. discloses an anti-ROR antibody having a VH of SEQ ID NO: 86 and a VL of SEQ ID NO: 92. SEQ ID NOS: 86 and 92 correspond to the sequences of instant SEQ ID NOS: 1 and 2, respectively, for anti-ROR1 antibody 19F6.Hu35V1. The corresponding CDRs according to Chothia, Abm, Kabat, and IMGT are disclosed. See Table 4-1. Addition of a heavy chain constant region (CH) of SEQ ID NO: 119 to the VH of SEQ ID NO: 86 is disclosed. Addition of a light chain constant region (CL) of SEQ ID NO: 120 to the VL of SEQ ID NO: 92 is disclosed. See at least paragraph [0443]. SEQ ID NO: 119 corresponds to instant SEQ ID NO: 22 and SEQ ID NO: 120 corresponds to instant SEQ ID NO: 23. Conservative substitutions are permitted. See at least paragraph [0314] and claim 5, part (19), and instant claim 28. The disclosure of Tian et al. meets the sequence limitations of instant claims 8-11 and the 14. Antigen binding fragments are disclosed. See at least claim 9. Pharmaceutical compositions are disclosed. See at least claim 22. Conjugates with toxins are disclosed. Antibody drug conjugates (ADC) are disclosed. See at least claims 18-19 and paragraph [0003-0004].
It would have been obvious to make an ADC according to Cai et al. using the anti-ROR1 antibody 19F6.Hu35V1 of Tian et al. and thereby arriving at ADC embodiments of the instant claims. One would have been motivated to do so as Cai et al. suggests using anti-ROR1 antibodies in the disclosed ADC and Tian et al. provides a suitable anti-ROR1 antibody. The sequences of Tian et al. meet the limitations of claims 8-11 and 14.
Claims 1-18 and 23-29 are rejected under 35 U.S.C. 103 as being unpatentable over Lannutti et al. (WO 2018/237335, of record), Cai et al. (WO2019/114666, of record, published 20 June 2019), Bao et al. (WO 2020/259258, published 30 December 2020), Bao et al. (WO 2022/204947, published 6 October 2022, filed 30 March 2021), and Tian et al. (WO 2022/188652).
Lannutti et al. is applied as above. Lannutti et al. discloses antibody drug conjugates (ADC) of anti-ROR1 antibodies having the formula Ab-((L)m-(D))n where Ab is the antibody, L is a linker, and D is a cytotoxic drug, m is 0 or 1 and n is an integer from 1 to 10. See claim 1. Any cytotoxic drug can be used. Camptothecin is specifically disclosed. See at least paragraphs [0085 and 0087]. In the formula of claim 1, n is an integer from 1-10 which meets the limitation of an x of 1-8 in instant claims 1 and 13. The drug to antibody ratio (DAR) can be from 1 to 7. See paragraph [0016] and instant claim 15. Pharmaceutical compositions are disclosed. See paragraph [0017] and instant claims 28-29. The attachment group (“M” in the instant claims) is attached to a sulfhydryl group, S, on the antibody. See at least paragraphs [0108, 0113] and Figure 1 and instant claim 12. Linkers can include polypeptides having four or more amino acid residues such as Gly-Gly-Phe-Gly (the elected connector “L” in instant claim 1). See at least paragraph [0090 and 0098]. Lannutti et al. does not disclose the anti-ROR1 antibody sequences required by instant claims 8-11 and 13-14. Lannutti et al. does not disclose the elected cytotoxic drug moiety (D) of instant claims 26, compound 1-8.
Cai et al. is applied as above. Cai et al. discloses antibody-drug conjugates comprising a bioactive molecule, linkers, and a targeting moiety. The targeting moiety is linked to the linker via an active group such as a thiol group (i.e. through a sulfur, S, see instant claim 12) to form a conjugate. See at least claim 55. The targeting moiety (A, referenced as Ab in the instant claims) can be a polypeptide that targets ROR1 (see at least claim 56-57) such as an antibody (see at least claim 60). See also page 93 and page 96, line 11. The bioactive molecule (T, referenced as D in the instant claims) can be a cytotoxic drug such as a DNA topoisomerase I inhibitor such as camptothecin. See at least page 92. Pharmaceutical compositions are disclosed in claims 40 and 87. See instant claims 18 and 29. The structure of claim 38 comprises the elected linking site M (see instant claims 2 and 3). Cai et al. does not disclose the anti-ROR1 antibody sequences required by instant claims 8-11 and 13-14. Cai et al. does not disclose the elected cytotoxic drug moiety (D) of instant claims 26, compound 1-8.
Bao et al. (WO 2020/259258) is in Chinese. An English language equivalent is U.S. Patent Application Publication 2022/0233708 (published 28 July 2022, filed 5 June 2020). The English language equivalent will be referenced. Bao et al. (’258) discloses antibody drug conjugates with the linker having the structure Gly-Gly-Phe-Gly (the elected L in instant claim 1), including the elected NH-CH2 structural fragment of E in instant claim 1. See at least the structure in paragraph [0012] corresponding to this structure. Bao et al. (‘258) further discloses cytotoxic drugs related to camptothecin and meeting the structural limitations of at least structure 1-3 in instant claim 26. See at least paragraphs [0023-0024]. This structure differs from the elected drug D by having fluorine (F) rather than chlorine (Cl) attached to the ring.
Bao et al. (WO 2022/204947) is in Chinese. There does not appear to be an English language equivalent. A machine translation is made of record; however, the chemical structures are only present in the WO 2022/204947 document. Bao et al. (‘947) shows camptothecin related cytotoxic drugs for conjugation meeting the limitations of the elected drug D and having chlorine attached to the ring. See at least abstract where R2 could be methyl (a C1-5 alkyl) and R3 could be chlorine (a halogen). See also bottom of page 2 of machine translation of the description where R2 is preferably a methyl group and where R3 is preferably chlorine. This drug would meet the limitations of the elected drug D of instant claim 26, compound 1-8.
Tian et al. is applied as above and teaches the elected antibody sequences of the anti-ROR1 antibody 19F6.Hu35V1.
It would have been obvious to conjugate the anti-ROR1 antibody 19F6.Hu35V1 (and conservatively substituted versions thereof) using the structure of Cai et al. claim 38 as “M” in instant claim 1 and using the Gly-Gly-Phe-Gly linker of Bao et al. (‘258) as the “L” and “E” structures in instant claim 1 in order connect the camptothecin related cytotoxic drugs of Bao et al. (‘258) or more particularly Bao et al. (‘947) as “D” in instant claim 1. This would result in the product of at least ADC A-10 and ADC A-11 in instant claim 14 having the linker of at least A-10 and A-11 in instant claim 16 and having the drug of at least claim 26, compound 1-8. Lannutti et al. also discloses the Gly-Gly-Phe-Gly linker. Each of the components would have been known to those of ordinary skill in the art and routinely used in conjugation. The desirability of conjugating anti-ROR1 antibodies to cytotoxic drugs related to camptothecin would have been known as taught by Cai et al. and Lannutti et al. The claimed conjugates, linkers, and pharmaceutical compositions would have been obvious.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 8-10 and 28 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the specific CDR, VH/VL, and HC/LC disclosed for anti-ROR1 antibody 19F6-Hu35V1 (the elected antibody), does not reasonably provide enablement for all variants encompassed by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Claim 8 recites particular CDR sequences “or a variant thereof.” Claim 8 also recites “wherein, the variant … has a sequence identity of at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% as compared to the sequence from which it is derived, or the variant has a substitution, deletion or addition of one or several amino acids as compared to the sequence from which it is derived.”
Claim 9 recites particular VH/VL sequences “or a variant thereof.” Claim 9 also recites “wherein the variant has a sequence identity of at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% as compared to the sequence from which it is derived, or the variant has a substitution, deletion or addition of one or several amino acids as compared to the sequence from which it is derived.” Note that the variant sequences are not required to retain the CDRs requires for binding to ROR1.
The specific sets of CDRs recited in claim 8 have been disclosed as corresponding to anti-ROR1 antibodies that bind.
The specific VH/VL sequences recited in claim 9 have been disclosed as corresponding to anti-ROR1 antibodies that bind.
The specification does not disclose or suggest which amino acids could be deleted and still retain the required antigen binding. The specification does not disclose or suggest those amino acids that could be inserted (or where) and still retain the required antigen binding. The specification does not disclose or suggest which amino acids could be substituted (and replaced with which amino acid) and still retain the required antigen binding. Inserting and/or deleting amino acids in the framework regions would have been expected to disrupt the three-dimensional configuration of the six CDRs required for antigen binding. Substituting, adding, and/or deleting amino acids within the CDRs would have been expected to disrupt antigen-binding. The specification provides no examples or guidance.
The scope of the claim is not enabled.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 25 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 25, the phrase “e.g” or “for example” in multiple places renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 25 is additionally indefinite in reciting “and/or” implying that multiple different drugs (e.g. auristatin and duocarmycin) may be conjugated to the same antibody at the same time. Claim 7 upon which claim 25 depends recites the different classes of drugs individually and not as conjugating multiple different drugs (D). Clarification is requested.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE P ALLEN whose telephone number is (571)272-0712. The examiner can normally be reached 7:00-3:30 EST Monday-Friday.
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/Marianne P Allen/Primary Examiner, Art Unit 1647
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