DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restriction
Applicant timely traversed the election of species requirement in the reply filed on 10MAR2026 and upon further consideration the restriction requirement mailed on 15JAN2026 is hereby withdrawn.
Claim Status
Claims 1-139 have been canceled.
Claims 140, 145-147, 149, and 151-155 have been amended.
Claims 140-155 are pending in the instant application and examined on the merits (i.e., Claim(s) 140 is/are independent).
Priority
The present application is a Continuation of Application No.16/940,326 filed on 27JUL2020, which claims priority to Korean Republic Application No.10-2019-0109807, filed 04SEP2019, and Korean Republic Application No.10-2020-0041527, filed 06APR2020. Applicant’s claim for the benefit of prior-filed applications is acknowledged.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 13JUN2023, 14AUG2023, 14NOV2023, 12DEC2023, 29MAY2024, 06SEP2024, 27NOV2024, 01MAY2025, 12JAN2026, and 10MAR2026 is/are acknowledged and the references cited therein have been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
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 – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d) (see for example, p 13, 25, 29, and claim 147).
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.
Claim Objections
Claim 147 is objected to because of the following informalities:
Claim 147 recites “CVIM” which is an amino acid sequence that requires a SEQ ID NO to appropriately identify the sequences. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 141-142 and 146-147 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 141-142 recite the broad recitation of 90% homology, and the claim also recites 95% or more homology which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Examiner notes that amending the claims to: “…variable region comprising: i) the amino acid sequence of SEQ ID NO: 48/56; ii) the amino acid sequence comprising at least 90% homology of SEQ ID NO: 48/56; or iii) the amino acid sequence comprising at least 95% homology of SEQ ID NO: 48/56.” would obviate the rejection.
Claim 146 recites the limitation "The ADC of claim 140, wherein the antibody…comprises an amino acid motif which can be recognized by isoprenoid transferase at the C-terminus of the antibody" wherein the antibody of the ADC of claim 140 could be a single chain fragment, wherein there would only be a single C-terminus; however, the antibody could also be a monoclonal antibody comprising four C-terminus corresponding to two HCs and two LCs, (p 8) and therefore in the instance of the single chain, it is unclear how y = 2 because the isoprenoid transferase is used for conjugating the cytotoxin via the specific linker and in the instance of the monoclonal antibody, it is unclear whether the amino acid motif which can be recognized by isoprenoid transferase (i.e., CVIM) is at the C-terminus of all four chains or just two. Therefore there is insufficient antecedent basis for this limitation in the claim. Claim 147 is also rejected since it depends from claim 146 but does not remedy this deficiency.
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.
Written Description
Claims 149-155 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In the instance of claims 149 and 153, the specification teaches that a therapeutically effective amount of the ADC is administered (p 87). Claims 150-152 and 154-155 are also rejected since they depend on claims 149 and 153, but do not remedy this deficiency. Examiner notes that amending the claim to: “A method of treating a disease or disorder associated with over-expression of ROR1 in a subject, comprising administering a therapeutically effect amount of the ADC of claim 140 or 148 to the subject” (i.e., claims 149 or 153, respectively) or of similar nature would obviate the rejection.
In the instance of claims 152 and 155, the specification teaches that a chemotherapeutic agent may be a therapeutic co-agent with no specific definition and the working examples do not teach any examples wherein the ADC is co-administered with essentially any chemotherapeutic agent. Although Pretelli, et al., teach that there have been an increasing number of clinical trials testing ADCs in different combinations with other anticancer agents such as traditional chemotherapy, ICIs, monoclonal antibodies, and small targeted agents, they also teach that combining ADCs with cytotoxic agents poses challenges, primarily due to the risk of overlapping toxicities and therefore requires significant knowledge of how the different drugs of the ADCs interact with the cancer cells and/or how the drugs of the ADCs or the chemotherapy influences the antigen expression of the antibody target (Pretelli, et al., Explor Target Antitumor Ther, 2024, 5, 714-741, see abstract and combination in clinical development section). For example combination of a pyrrolobenzodiazepine dimer-based ADC with well-known chemotherapeutic agent, cisplatin would likely cause significant overlapping toxicity to the patient and/or may result in cross-resistance. Therefore, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genus of administration of the ADC with essentially any chemotherapeutic agent that treats cancer in a subject, at the time the instant application was filed.
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 140-143, 145, 148-151, and 153-154 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-38 of U.S. Patent No. 11,707,533, herein referred to as “’533.” Although the claims at issue are not identical, they are not patentably distinct from each other because the anti-ROR1 pyrrolobenzodiazepine ADC and the method of treatment of cancer of the ‘533 patent anticipates the anti-ROR1 pyrrolobenzodiazepine ADC and the method of treatment of cancer of the instant application. Specifically, the claimed anti-ROR1 antibody and the cytotoxic agent comprise the same HCDRs1-3/LCDRs1-3 and the cytotoxic agent/linker, respectively of claims 1 and 34-35 of the ‘533 patent anticipate the products of claims 141 and 148 of the instant application and the method of treatment of a disease with over-expression of ROR1 or cancer comprise the step of administering said ADC of claims 37-38 of the ’533 patent anticipates the method of claim 149 and 153 of the instant application.
Issued claims of the ‘533 patent:
Instant Application patent claims, underline corresponds to direct mapping to claim 1 of the ‘533 patent and italics corresponds to the additional claim limitations.
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140. An antibody-drug conjugate represented by [Formula 1] or a pharmaceutically acceptable salt thereof: [Formula I] Ab—(X)y wherein Ab is an anti-ROR1 antibody comprising a heavy chain variable region comprising a CDRH1, a CDRH2, and a CDRH3; and a light chain variable region comprising a CDRL1, a CDRL2 and a CDRL3;
wherein CDRH1 comprises the amino acid sequence of SEQ ID NOs: 4; CDRH2 comprises the amino acid sequence of SEQ ID NOs: 11; CDRH3 comprises the amino acid sequence of SEQ ID NOs: 19; CDRL1 comprises the amino acid sequence of SEQ ID NOs: 27; CDRL2 comprises the amino acid sequence of SEQ ID NOs: 35; CDRL3 comprises the amino acid sequence of SEQ ID NOs: 42;
x is:
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y is 2. (See OA.APPENDIX for sequence alignments)
141. The antibody-drug conjugate of claim 140, wherein the antibody comprises a heavy chain variable region having either: i) a sequence according to SEQ ID NO: 48; or ii) a sequence having at least 90% or at least 95% or more homology to the amino acid sequence of SEQ ID NO: 48. (See OA.APPENDIX for sequence alignments)
142. The antibody-drug conjugate of claim 140, wherein the antibody comprises a light chain variable region having either: i) a sequence according to SEQ ID NO: 56; or ii) a sequence having at least 90% or at least 95% or more homology to the amino acid sequence of SEQ ID NO: 56. (See OA.APPENDIX for sequence alignments)
143. The antibody-drug conjugate of claim 140, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 48 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 56. (See OA.APPENDIX for sequence alignments)
145. The antibody-drug conjugate of claim 140, wherein the antibody is an IgG1 fully human monoclonal antibody and the ROR1 is human ROR1 or mouse ROR1.
148. The antibody-drug conjugate of claim 140, wherein the antibody- drug conjugate has a structure according to:
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or a pharmaceutically acceptable salt thereof.
149. A method of treating a disease or disorder associated with over- expression of ROR1 in a subject, comprising administering an antibody-drug conjugate of claim 140 to the subject.
150. The method of claim 149, wherein the disease is cancer.
151. The method of claim 150, wherein the cancer is chronic lymphocytic leukemia (CLL), B-cell leukemia, lymphoma, acute myeloid leukemia (AML), Burkitt lymphoma, mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), Diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and marginal zone lymphoma (MZL), breast cancer, renal cancer, ovarian cancer, gastric cancer, liver cancer, lung cancer, colorectal cancer, pancreatic cancer, skin cancer, bladder cancer, testicular cancer, uterine cancer, prostate cancer, non-small cell lung cancer (NSCLC), neuroblastoma, brain cancer, colon cancer, squamous cell carcinoma, melanoma, myeloma, cervical cancer, thyroid cancer, head and neck cancer, or adrenal cancer.
153. A method of treating cancer in a subject, comprising administering an antibody drug conjugate of claim 148 to the subject.
154. The method of claim 153, wherein the cancer is chronic lymphocytic leukemia (CLL), B-cell leukemia, lymphoma, acute myeloid leukemia (AML), Burkitt lymphoma, mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), Diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and marginal zone lymphoma (MZL), breast cancer, renal cancer, ovarian cancer, gastric cancer, liver cancer, lung cancer, colorectal cancer, pancreatic cancer, skin cancer, bladder cancer, testicular cancer, uterine cancer, prostate cancer, non-small cell lung cancer (NSCLC), neuroblastoma, brain cancer, colon cancer, squamous cell carcinoma, melanoma, myeloma, cervical cancer, thyroid cancer, head and neck cancer, or adrenal cancer.
In this instance, because claims 37-38 of the ‘533 patent is silent on the species of disease over-expressing ROR1 and cancer, the specification was consulted to determine the scope of the generic terms of “disease over-expressing ROR1” and cancer” in the ‘533 patent. Per the specification of the ‘533 patent, a disease over-expressing ROR1 encompasses chronic lymphocytic leukemia (i.e., cancer), B cell leukemia, etc. (col 65, lines 6-20).
Therefore, because the anti-ROR1 antibody, linker, and cytotoxic moiety of the ‘533 patent anticipates the product of the instantly claimed invention and because the method of treatment of the ‘533 patent comprises administering said ADC, which anticipates the method of the instantly claimed invention, there is no clear difference in the scope between the products/methods of the instant application and the ’533 patent.
Claims 146-147 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-38 of U.S. Patent No. 11,707,533, herein referred to as “’533” as applied to claims 140-143, 145, 148-151, and 153-154 and in further view of Palsuledesai, et al., (ACS Chem Biol, 2015, 10, 51-62), herein referred to as “Palsuledesai.”
The issued claims of the ‘533 patent are recited above.
However, they do not claim: The ADC, wherein the antibody is bonded to X via a thioether bond; the thioether bond includes a sulfur atom of a cysteine of the antibody; and the antibody comprises an amino acid motife which can be recognized by isoprenoid transferase at the C-terminus of the antibody, wherein the motif has the sequence CVIM.
Nevertheless, Palsuledesai teaches that the CVIM sequence is normally farnesylated in mammalian cells and the properties of FTase to specifically modify a single cysteine residue located at the C-terminal CVIM motif and to incorporate isoprenoid analogs containing bioorthoganol functionalities have been exploited for site-specific modifications of proteins (i.e., allowing for the preparation of a wide array of protein conjugates in a site-specific manner) (see Fig 1, Peptide substrate specificity section and Biotechnological applications section).
It would have been obvious to artisans to modify the issued ADC, wherein the cytotoxin is conjugated via a linker to the antibody as recited in claim 8 of the ‘533 patent to include a site-specific bioconjugation technique, wherein the C-terminus of the antibody is modified by CVIM which can be recognized by FTase for site-specific bioconjugation, as taught by Palsuledesai. This is because Palsuledesai teaches that the CVIM motif allows for site-specific protein modification. One would have been motivated to do so, given the direction by the ‘533 patent that the linker of claim 8 could be site-specifically conjugated to the antibody utilizing FTase technology. There would have been a reasonable expectation of success, given the knowledge that by modifying the C-terminus with a CVIM motif and utilizing an appropriate linker taught by Palsuledesai would lead to site-specific conjugation of the cytotoxin to the C-terminus of the antibody.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMANTHA L. HOPKINS whose telephone number is (703)756-4666. The examiner can normally be reached Mon-Thurs 6:00 AM to 4:00 PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at (571)272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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