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
The amendment filed June 9, 2026 in response to the Office Action of February 17, 2026 is acknowledged and has been entered.
Claims 1 and 5-8 have been amended.
Claims 1, 5-8, 11, 12, 15-23, 26, 27 and 57-59 are pending and under consideration.
In view of amendments on claims 1 and 7, the claim objections set forth in the previous Office Action of February 17, 2026 is hereby withdrawn.
In view of amendments on claim 5 and applicant’s argument, the 112(d) rejection set forth in the previous Office Action of February 17, 2026 is hereby withdrawn.
Information Disclosure Statement
The Information Disclosure Statement (IDS) filed December 3, 2025 have been entered by examiner.
It is noted that IDS must also include a legible copy of Non Patent Literature Document, see MPEP 609.04(a) II. Several references in IDS, including CA, CE, CF, CG and CM, are not considered because the copies provided are not legible, particularly, most figures and tables are unclear and illegible.
Applicant is reminded that each individual associated with the filing and prosecution of a patent application has a duty of candor and good faith in dealing with the U.S. Patent and Trademark Office, which includes a duty to disclose to the Office all information known to that individual to be material to patentability (see 37 C.F.R. §1.56).
Response to Arguments
For the Objections on IDS, Applicant argues:
Applicant requested legible copies of Klempner 2018 (Reference CE) as well as copies of references CA (Arend 2019), CC (Klempner 2022), CD (Klempner 2020), and CF (Yang 2018).
Applicant submits herewith a supplemental IDS that includes (1) a high-resolution PDF of each of the objected-to references, and (2) a PowerPoint document that provides blow-ups of each section of the respective poster.
Applicant’s arguments have been fully considered but they are not persuasive. Although Applicant provides high-resolution PDF and amplified version for these references, these documents are still not legible, particularly, most figures and tables are unclear and illegible. Accordingly, the documents are not considered by the Examiner.
It is noted that these references appears to be Applicant’s (Leap Therapeutic, Inc.) own reports and relevant to the claimed inventions. Applicant is advised to provide new PDFs (or PPT blowups) which are clear, completely legible for all parts (including Figures and Tables).
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 - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located pages 27 and 28, SEQ ID NOs 2, 3, 6 in the specification comprise “Xaa”. However, in Sequence Listing, SEQ ID NOs 2, 3, 6 do not comprise “Xaa”.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
MAINTAINED/MODIFIED REJECTIONS
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 5-8, 11, 12, 15-23, and 57-59 are rejected under 35 U.S.C. 103 as being unpatentable over NCT02013154-ver18 (Record History of 09/17/2018, downloaded from: https://clinicaltrials.gov/study/NCT02013154, of record) in view of Klempner2018 (Klempner et al., EMSO 2018 Congress, Poster Display 660P, Publication Year: 2018, cited as CE in IDS of 12/03/2025) and Chedid (Chedid et al., US Patent 8,148,498 B2, Publication Date: 04/03/2012, of record).
As noted above, the quality of the PDF file for the reference Klempner2018 in IDS is not good enough for a complete evaluation because most figures and tables in the reference filed by applicant are illegible. Examiner made the rejection only based on the data which are barely legible on the poster of Klempner2018 filed by Applicant on December 3, 2025 (the newly submitted copy did not improve the quality of the reference) and also based on a published Abstract of this poster available on line (Klempner et al., Annals of Oncology, Vol. 29, Suppl. 8, Publication Date: October, 2018).
It is noted that as evidenced by paragraph [0086] of the instant publication US 2022/0381786 A1, antibody DKN-01 comprises the HC and LC amino acid sequence of SEQ ID NO: 17 and SEQ ID NO: 18 respectively. SEQ ID NO: 17 and SEQ ID NO: 18 do not comprise the CDRs recited by claim 1, as shown below:
Alignment of SEQ ID NO: 17 with HCDRs 1-3:
Query Match 84.5%; Score 172.3; Length 445;
Best Local Similarity 42.2%;
Matches 35; Conservative 1; Mismatches 0; Indels 47; Gaps 2;
Qy 1 GFTFSSYTMS--------------TISGGGFGTYYPDSVK-------------------- 26
|||||||||| ||||||||||||||||
Db 26 GFTFSSYTMSWVRQAPGKGLEWVATISGGGFGTYYPDSVKGRFTISRDNAKNSLYLQMNS 85
Qy 27 -------------PGYHNYYFDI 36
|||:||||||
Db 86 LRAEDTAVYYCARPGYNNYYFDI 108
Alignment of SEQ ID NO: 18 with LCDRs 1-3:
Query Match 78.8%; Score 114.3; Length 214;
Best Local Similarity 35.1%;
Matches 26; Conservative 0; Mismatches 1; Indels 47; Gaps 2;
Qy 1 HASDSISNSLH---------------YGRQSIQ--------------------------- 18
||||||||||| | |||||
Db 24 HASDSISNSLHWYQQKPGQAPRLLIYYARQSIQGIPARFSGSGSGTDFTLTISSLEPEDF 83
Qy 19 -----QQSESWPLH 27
|||||||||
Db 84 AVYYCQQSESWPLH 97
Because all the examples in the instant specification is based on antibody DKN-01, no experimental data are disclosed for the antibodies of instant claim 1.
NCT02013154-ver18 teaches treating Relapsed or Refractory Esophageal Cancer or Gastro-Esophageal Junction Tumors with DKN-01 (page 12, § Experimental: DKN-01 Monotherapy)
NCT02013154-ver18 teaches that the patients in the cohort for DKN-01+Pembrolizumab have recurrent or metastatic Esophageal Cancer, Gastroesophageal Junction Cancer, or Gastric Adenocarcinoma with Wnt signaling alterations (page 9, § Detailed Description – Part F).
NCT02013154-ver18 teaches that patients must be refractory or intolerant to at least one prior therapy(ies) (page 14, §Inclusion Criteria).
NCT02013154-ver18 teaches that prior treatment anti-PD1/PD-L1 monoclonal antibody is permitted in patients if the disease is primary refractory and the patients are not intolerant of pembrolizumab (page 15, lines 6-9).
Regarding claims 21-23, NCT02013154-ver18 teaches that DKN-01 antibody is administered to esophageal or gastroesophageal junction cancer patients on Days 1 and 15 and paclitaxel is administered on Days 1, 8, 15, and 22 (see page 12, § Experimental: Part E).
NCT02013154-ver18 teaches DKN-01 monotherapy, DKN-01+Pembrolizumab combination and DKN-01 + paclitaxel combination for treating esophageal or gastroesophageal junction cancer and recurrent or metastatic Esophageal Cancer, Gastroesophageal Junction Cancer, or Gastric Adenocarcinoma. However, NCT02013154-ver18 does not teach a subject previously determined to have a DKK1 expression % positive value of 20 or above in a sample of the subject’s cancer, or antibodies with the claimed CDR combination, or with a LCVR comprising SEQ ID NO: 7 and HCVR comprising SEQ ID NO: 8, or with a LCVR comprising SEQ ID NO: 9 and HCVR comprising SEQ ID NO: 10, or with a heavy chain comprising SEQ ID NO: 19 and a light chain comprising SEQ ID NO: 16.
Klempner2018 teaches that Dickkopf-1 (DKK1) is a modulator of the Wnt and PI3K/AKT signaling pathways and contributes to an immunosuppressive tumor microenvironment by activating MDSCs and Tregs (§ Abstract – Background).
Klempner2018 teaches that DKN-01 (D), an mAb against DKK1, acts on innate immune cells, and in preclinical studies demonstrates upregulation of both PD-L1 and IFNγ-related chemokines, suggesting a role for immune checkpoint combination (§ Abstract – Background).
Klempner2018 teaches that anti-PD-1 plus DKN-01 shows additive antitumor effects in the B16 syngeneic mouse model; clinical studies are underway. Gastroesophageal (GE) cancers commonly overexpress DKK1 and harbor Wnt pathway alterations (§ Abstract – Background).
Klempner2018 teaches that DKN-01 + Pembrolizumab is well tolerated and shows encouraging early efficacy signal in advanced GE cancer. A subset of patients with features typically associated with lower response to single agent anti-PD-1 therapy exhibited prolonged clinical benefit (§ Abstract – Conclusions).
Klempner2018 teaches DKN-01 has demonstrated activity as a monotherapy an in combination with paclitaxel in heavily pretreated patients with esophagogastric cancer (last point of § Background)
Klempner2018 teaches that DKN-01 in combination with Pembrolizumab shows clinical efficacy to both anti-PD-1/PD-L1 naïve and refractory patients with esophagogastric cancer (§ Efficacy).
Klempner2018 teaches: 1) the combination demonstrated clinical activity in evaluable subject with GEJ/Gastric adenocarcinoma ORR: 23.5%, DCR: 58.6%); 2) the combination is effective regardless of PD-L1 expression level; 3) ORR and DCR are similar regardless of number of prior therapies (top part of col. 4).
Klempner2018 teaches measuring DKK1 expression % positive value in cancer sample to determine DKK1 expression level (the last column, description of the top Figure).
Klempner2018 teaches that elevated tumor expression of DKK1 may correlated with better clinical outcome in a patient with esophagogastric cancer treated with DKN-01 + Pembrolizumab (§ Conclusions, bottom part of the last column).
Klempner2018 teaches that a patient with a tumor DKK1 H-score of 78 responds to the combination treatment, however a patient with a tumor DKK1 H-score of 4 shows progressive disease under the same treatment (top part of the last column). Because the quality of the Figure is too low, the DKK1 expression % positive value is difficult to determine. However, based on the H-score calculation method described in the Figure, H-score of 78 would have a DKK1 expression % positive value between 26 (all positive cells have a score of 3) and 78 (all positive cells have a score of 1). Based on the teachings of Klempner2018, it would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to identify esophagogastric cancer patients with elevated tumor expression of DKK1, for example with a DKK1 H-score of 78 and above, which would overlap a DKK1 expression % positive value of at least 20 or above as instantly claimed. Because for calculating H-score, all DKK1 expression positive cells (including weak to strong expression) and percentages need to be counted, thus the DKK1 expression % positive value is essentially obtained during calculating H-score. Thus, the patient with a H-score 78 reads on “the subject previously determined to have a DKK1 expression % positive value of 20 or above in a sample of the subject’s cancer”.
Chedid teaches a human engineered anti-DKK1 antibody with a LCVR comprising the amino acid sequence of SEQ ID NO: 13 and a HCVR comprising the amino acid sequence of SEQ ID NO: 11 (claim 3 (i)); As shown below, SEQ ID NO: 13 and SEQ ID NO: 11 of Chedid are identical to SEQ ID NO: 7 and SEQ ID NO: 8, respectively:
Alignment of SEQ ID NO: 13 of Chedid to SEQ ID NO: 7 of the instant application:
US-12-754-637-13
Query Match 100.0%; Score 564; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVLTQSPATLSLSPGERATLSCHASDSISNSLHWYQQKPGQAPRLLIYYGRQSIQGIPA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVLTQSPATLSLSPGERATLSCHASDSISNSLHWYQQKPGQAPRLLIYYGRQSIQGIPA 60
Qy 61 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQSESWPLHFGGGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQSESWPLHFGGGTKVEIK 107
Alignment of SEQ ID NO: 11 of Chedid to SEQ ID NO: 8 of the instant application:
US-12-754-637-11
Query Match 100.0%; Score 637; Length 119;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATISGGGFGTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATISGGGFGTYY 60
Qy 61 PDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPGYHNYYFDIWGQGTTVTVSS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPGYHNYYFDIWGQGTTVTVSS 119
Chedid teaches a human engineered anti-DKK1 antibody with a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 and light chain comprising the amino acid sequence of SEQ ID NO: 19 (claim 5 (a)). As shown below, SEQ ID NO: 17 and SEQ ID NO: 19 of Chedid are identical to SEQ ID NO: 19 and SEQ ID NO: 16, respectively:
Alignment of SEQ ID NO: 17 of Chedid to SEQ ID NO:19 of the instant application:
US-12-754-637-17
Query Match 100.0%; Score 2376; Length 445;
Best Local Similarity 100.0%;
Matches 445; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATISGGGFGTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATISGGGFGTYY 60
Qy 61 PDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPGYHNYYFDIWGQGTTVTVSSA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPGYHNYYFDIWGQGTTVTVSSA 120
Qy 121 STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG 180
Qy 181 LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVF 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVF 240
Qy 241 LFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 LFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR 300
Qy 301 VVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKN 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 VVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKN 360
Qy 361 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGN 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGN 420
Qy 421 VFSCSVMHEALHNHYTQKSLSLSLG 445
|||||||||||||||||||||||||
Db 421 VFSCSVMHEALHNHYTQKSLSLSLG 445
Alignment of SEQ ID NO: 19 of Chedid to SEQ ID NO:16 of the instant application:
US-12-754-637-19
Query Match 100.0%; Score 1117; Length 214;
Best Local Similarity 100.0%;
Matches 214; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVLTQSPATLSLSPGERATLSCHASDSISNSLHWYQQKPGQAPRLLIYYGRQSIQGIPA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVLTQSPATLSLSPGERATLSCHASDSISNSLHWYQQKPGQAPRLLIYYGRQSIQGIPA 60
Qy 61 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQSESWPLHFGGGTKVEIKRTVAAPSVFIFPP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQSESWPLHFGGGTKVEIKRTVAAPSVFIFPP 120
Qy 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
Qy 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
||||||||||||||||||||||||||||||||||
Db 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
It is also noted that SEQ ID NO: 7 and SEQ ID NO: 9 of the instant application have the identical sequence; and SEQ ID NO: 8 and SEQ ID NO: 10 of the instant application have the identical sequence. Taken together, Chedid teaches the antibodies of instant claims 1, 15, 16, and 18.
Chedid teaches a method of treating cancer comprising administering to a patient in need thereof an effective amount of the human engineered DKK-1 antibody or antigen-binding fragment thereof (claim 9).
It would have prima facie been obvious to one of ordinarily skilled in the art before the time the invention was filed to use DKN-01, or DKN-01 in combination with Pembrolizumab, or DKN-01 in combination with paclitaxel to treat various esophagogastric cancers as taught by NCT02013154-ver18, to further stratify patients by DKK1 expression level and to identify esophagogastric cancer patients with elevated tumor expression of DKK1, for example with a DKK1 expression H-score at least 78 which is obviously overlapping with the claimed range as set forth above, because Klempner2018 teaches that high DKK1 expression in tumor may correlated with the clinical response to the DKK1 targeted therapy and a patient with predetermined H-score of 78 (reads on a subject previously determined to have a DKK1 expression % positive value of at least 26) respond to the combination therapy, but a patient with low H-score shows progressive disease, and to substitute DKN-01 with another DKK1 antibody with a LCVR comprising the amino acid sequence of SEQ ID NO: 13 and a HCVR comprising the amino acid sequence of SEQ ID NO: 11 (claim 3 (i), Chedid), or another DKK1 antibody with a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 and light chain comprising the amino acid sequence of SEQ ID NO: 19 (claim 5 (a)), because the antibody is also an antibody specific for DKK1 and Chedid teaches that the antibodies are suitable for cancer treatment. Given the similarity between the antibody taught by Chedid and DKN-01, one of ordinary skill in the art would have had expected that a treatment comprising DKK1 antibody would be effective for treating esophagogastric cancer with high DKK1 expression. The motivation would be to expand the options for the combination and to make use of the antibody of Chedid.
Regarding claims 5-8, 11, 12 and 57-59, NCT02013154-ver18 teaches DKN-01 monotherapy, DKN-01+Pembrolizumab combination and DKN-01 + paclitaxel combination for treating esophageal or gastroesophageal junction cancer and recurrent or metastatic Esophageal Cancer, Gastroesophageal Junction Cancer, or Gastric Adenocarcinoma. Klempner2018 teaches that DKN-01 in combination with Pembrolizumab shows clinical efficacy to both anti-PD-1/PD-L1 naïve and refractory patients with esophagogastric cancer (§ Efficacy), including GEJ or gastric cancer (§ Key Inclusion Criteria, and the table on top of column 2). In addition, Klempner2018 teaches: 1) the combination demonstrated clinical activity in evaluable subject with GEJ/Gastric adenocarcinoma ORR: 23.5%, DCR: 58.6%); 2) the combination is effective regardless of PD-L1 expression level; 3) ORR and DCR are similar regardless of number of prior therapies (top part of col. 4). Given the teachings Klempner2018, one of ordinary skill in the art would have had a reasonable expectation that the antibody taught by Chedid would be effective for the patient populations as claimed
Regarding claim 20, the patients in the NCT02013154-ver18are humans.
Regarding claims 17 and 19, as set forth above, the antibodies of these claims do not comprise the CDRs recited by claim 1. However, as evidenced by paragraph [0086] of the instant publication US 2022/0381786 A1, antibody DKN-01 comprises the HC and LC amino acid sequence of SEQ ID NO: 17 and SEQ ID NO: 18 respectively. Thus, DKN-01 would read on the instant claims 17 and 19. Thus, NCT02013154-ver18, Klempner2018, and Chedid also teach claims 17 and 19.
Claims 26 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over NCT02013154-ver18 (Record History of 09/17/2018, downloaded from: https://clinicaltrials.gov/study/NCT02013154, of record) in view of Klempner2018 (Klempner et al., EMSO 2018 Congress, Poster Display 660P, Publication Year: 2018, cited as CE in IDS of 12/03/2025) and Chedid (Chedid et al., US Patent 8,148,498 B2, Publication Date: 04/03/2012, of record), as applied to claims 1, 5-8, 11, 12, 15-23, and 57-59 above, and further in view of De Lange (De Lange et al., Annals of Oncology 15: 484-488, Publication Year: 2004, of record).
NCT02013154-ver18, Klempner2018 and Chedid teach the claimed DKK1 antibody alone or in combination with Pembrolizumab or paclitaxel in method of claim 1. However, NCT02013154-ver18, Klempner2018 and Chedid do not teach the antibody in combination with two additional therapeutic agents such as gemcitabine and cisplatin.
De Lange teaches that cisplatin has some activity as a single agent in advanced gastric cancer and in a variety of other solid tumors (page 484, col. 1, para. 2).
De Lange teaches that Preclinical studies have shown additive and synergistic effects of gemcitabine and cisplatin in combination. Gemcitabine may increase the formation of DNA–platinum adducts, while cisplatin may increase the incorporation of gemcitabine into DNA (page 484, col. 2, para. 2).
De Lange teaches that cisplatin–gemcitabine regimen had moderate efficacy in patients with advanced gastric cancer, with manageable toxicity (§ Abstract – Conclusions).
De Lange teaches that it may be possible to build on this combination with addition of agents with non-overlapping side effects (page 488, col. 1, para. 3).
De Lange teaches that cisplatin has some activity as a single agent in advanced gastric cancer and in a variety of other solid tumors (page 484, col. 1, para. 2).
De Lange teaches that Preclinical studies have shown additive and synergistic effects of gemcitabine and cisplatin in combination. Gemcitabine may increase the formation of DNA–platinum adducts, while cisplatin may increase the incorporation of gemcitabine into DNA (page 484, col. 2, para. 2).
De Lange teaches that cisplatin–gemcitabine regimen had moderate efficacy in patients with advanced gastric cancer, with manageable toxicity (§ Abstract – Conclusions).
De Lange teaches that it may be possible to build on this combination with addition of agents with non-overlapping side effects (page 488, col. 1, para. 3).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use DKK1 antibody alone or in combination with Pembrolizumab or paclitaxel in method of claim 1, as taught by NCT02013154-ver18, Klempner2018 and Chedid, and to develop a new combination the DKK1 antibody + cisplatin + gemcitabine, because De Lange teaches cisplatin-gemcitabine are effective for treating gastric cancer, the combination shows manageable toxicity, cisplatin and gemcitabine show synergistic activity and can be combined with additional agents, NCT02013154-ver18, Klempner2018 and Chedid teaches DKK1 antibody (e.g. the antibody taught by Chedid) is suitable for combination therapy, DKK1 antibody function through different mechanism, one of ordinary skill in the art would have had a reasonable expectation that the combination would be more effective for method of claim 1. The motivation would have been to develop a more effective cancer treatment and to expand the options for cancer treatment.
Response to Arguments
For the 103 rejection, Applicant argues that H-score and “% positive” are differently scored, as shown below:
1. H-Score and %Positive score are NOT Directly Linked
Specifically, the process requires computing proportions of cells stained O dots per cell (Bin-0), 1-3 dots per cell (Bin-1), 4-9 dots per cell (Bin-2), and 10 or more dots per cell (Bin-3) (by dividing the numbers of cells having the number of dots in the specified ranges - known as bins - by the total number of cells in the sample). These counts produce the numbers referred to as %bins: %Bin-0, %Bin-1, %Bin-2, and %Bin-3. The %Bin numbers are plugged into the formula in para. [0194]:
H-score = (%Bin-3 x 3) + (%Bin-2 x 2) + (%Bin-1 x 1) + (%Bin-0 x 0).
It can be seen that the theoretical maximum H-score is 300, and the theoretical minimum is 0. Note, however, that even if 100% of cells in the sample are stained, the H-score can be any number from 100 to 300. Indeed, if 100% of all cells are stained with just one dot, the H-score is 100, if 100% of cells are stained with 4 to 9 dots, the H-score is 200, and so on. Clearly, there is a combinatorial explosion of the number of ways in which any given H-score greater than 1 can be obtained.
On the other hand, computing the "%positive" value (also known in the art as a "TPS" value - Tumor Percentage Score) requires merely counting the cells in a sample having at least one dot. There is only one way to obtain any given %positive score….
Thus, to establish a correlation between the %positive score and the H-score, a skilled
artisan would need to conduct an experiment that would measure the two scores for the same
sample of patients. There is no a priori expectation that such a correlation would exist, or, if it
does exist, that it would be a strong correlation (with a high correlation coefficient). For this reason, a skilled artisan would not know what value of an H-score would correspond to the
%positive value of 20.
Furthermore, even if a correlation between the two measures were experimentally established based on a sample of patients suffering from certain cancer, a skilled artisan would have no expectation that this correlation would hold for a different cancer.
Applicant’s arguments have been fully considered but they are not persuasive. Although the H-score is different from “% positive” value, as evidenced by the formula provided in the remarks: H-score = (%Bin-3 x 3) + (%Bin-2 x 2) + (%Bin-1 x 1) + (%Bin-0 x 0). To get the H-score, the “% positive” value is essentially obtained (%Bin-3 + %Bin-2 + %Bin-1. Klempner2018 explicitly teaches measuring DKK1 expression % positive value in cancer sample to determine DKK1 expression level (the last column, description of the top Figure). Klempner2018 teaches DKK1 expression in cells of cancer sample from a patient (H-score =78) (the last column, the top Figure). Because the quality of the Figure is too low, the DKK1 expression % positive value is difficult to determine. However, as set forth above, the predetermined % positive value for this patient is at least 26 (range between 26 to 78). Thus, even though Klempner2018 does not teach the whole claimed range “%positive value of 20 or above”, this patient (of H-score =78) reads on “the subject previously determined to have a DKK1 expression % positive value of 20 or above in a sample of the subject’s cancer”.
Regarding the argument that different cancer could have different correlations, it is noted that Klempner2018 is drawn on esophagogastric cancer (see Title of the Figure of the last column), which is the same cancer as instantly claimed.
Applicant further argues about unexpected benefit, as shown below:
2. A Cut off of% Positive Score of 20 Provides Unexpected Benefit
The expression levels of DKK1 surprisingly stratify patients suffering from certain
cancers into two groups: a group having an increased likelihood of responding, and a group not
having an increased likelihood of responding. The two groups are divided by a DKK1 expression1level of "20% positive."
The application as filed includes data supporting the unexpected stratification of patients
by the cutoff value of "% positive" of 20. Example 3, starting at para. [0219], describes a study
in which the DKK1 expression data was collected from 69 esophagogastric cancer (EGC)
patients receiving DKN-01 monotherapy or a combination of DKN-01 at 300 mg and a second
agent. (See para. [0219].) As a part of this analysis described in para. [0224], a sub-group of
patients (31 Gastric (G)/ gastroesophageal junction (GEJ) immunotherapy-naive (IO-patients)
patients) was analyzed using "% positive". With reference to FIG. 15, it was discovered that
patients having the DKK1 "% positive" values of 20 and above had longer PFS compared to
patients having the DKK1 "% positive" values of less than 20.
A significant and unexpected patient stratification was observed by selecting the claimed
cutoff values of the DKK1 expression. The claimed cutoff values demarcated a group of patients
(approximately one third of all patients, a tertile) that was discovered to have a statistically
significant improvement in the PFS.
Yet further rationale for choosing the "% positive" cutoff value of 20 can be seen based on the statistical analysis of the group of 31 patients described in Example 3 and para. [0224] of the PCT application. Applicant underscores that the following discussion pertains to the data described in the application as filed; only certain statistical analysis was conducted post-filing.
Applicant presents FIG. A, which is a scatter plot showing the distribution of "%
positive" values of the 31 patients discussed in para. [0224] by the type of response: partial response (PR), stable disease (SD), progressive disease (PD).
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, Klempner2018 teaches that elevated tumor expression of DKK1 may correlated with better clinical outcome in a patient with esophagogastric cancer treated with DKN-01 + Pembrolizumab (§ Conclusions, bottom part of the last column), and measuring DKK1 expression % positive value in cancer sample to determine DKK1 expression level. Klempner2018 further teaches that a patient with a tumor DKK1 H-score of 78 responds to the combination treatment, however a patient with a tumor DKK1 H-score of 4 shows progressive disease under the same treatment (top part of the last column). Thus, one of ordinary skill in the art would have known and been motivated to treat esophagogastric cancer patients with high expression of DKK1 with a therapy including DKN-01. As set forth above, this patient (of predetermined H-score =78) reads on “the subject previously determined to have a DKK1 expression % positive value of 20 or above in a sample of the subject’s cancer”.
In addition, “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. MPEP 716.02(d).
In this case, the claimed antibodies are different from DKN-01 which is used in all the Examples and in the Remarks. Accordingly, the data is not commensurate in scope with the claimed invention and does not demonstrate the non-obviousness of the claimed invention.
Thus, Applicant’s arguments are not found persuasive for the reasons set forth above and the rejection is maintained for the reasons of record.
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.
U.S. Patent No. 11,267,876
Claims 1, 5-8, 11, 12, 15-23, 26, 27 and 57-59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11,267,876 B2 (hereinafter Pat. 876, corresponding to Appl. 16/345,191, of record) in view of NCT02013154-ver18 (Record History of 09/17/2018, of record), Klempner2018 (Klempner et al., EMSO 2018 Congress, Poster Display 660P, Publication Year: 2018, cited as CE in IDS of 12/03/2025), and De Lange (De Lange et al., Annals of Oncology 15: 484-488, Publication Year: 2004, of record).
The claims of Pat. 876 teaches:
1. A method of treating a subject suffering from a cancer, comprising the steps of: obtaining a sample of a cancer cell from the subject; determining that the subject has a constitutively activating mutation in a beta-catenin protein (SEQ ID NO: 2) in the sample; and administering to the subject determined to have the constitutively activating mutation in a beta-catenin protein (SEQ ID NO: 2) an effective amount of an anti-Dkk-1 antibody or antigen binding-fragment thereof, wherein the cancer is an esophageal cancer or a uterine cancer, and wherein the anti-Dkk-1 antibody or antigen binding-fragment thereof comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3 and the HCVR comprises CDRs HCDR1, HCDR2 and HCDR3, wherein LCDR1 has the amino sequence of SEQ ID NO: 6, LCDR2 has the amino sequence of SEQ ID NO: 7, LCDR3 has the amino sequence of SEQ ID NO: 8, HCDR1 has the amino sequence of SEQ ID NO: 9, HCDR2 has the amino sequence of SEQ ID NO: 10, and an HCDR3 has the amino sequence of SEQ ID NO: 11.
2. The method of claim 1, further including administering an effective amount of a chemotherapeutic agent.
3. The method of claim 2, wherein the chemotherapeutic agent is a taxane, paclitaxel, docetaxel, carbazitaxel, gemcitabine, carboplatin, cisplatin, oxaliplatin, fluorouracil, capecitabine, or tegafur, or any functional analog thereof.
4. The method of claim 1, wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 12 and the HCVR comprises the amino acid sequence of SEQ ID NO: 13. As shown below, this antibody reads on the antibody of instant claim 15.
Alignment of SEQ ID NO: 12 of Pat. 876 and SEQ ID NO: 7 of the instant application:
Query Match 100.0%; Score 564; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVLTQSPATLSLSPGERATLSCHASDSISNSLHWYQQKPGQAPRLLIYYGRQSIQGIPA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVLTQSPATLSLSPGERATLSCHASDSISNSLHWYQQKPGQAPRLLIYYGRQSIQGIPA 60
Qy 61 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQSESWPLHFGGGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQSESWPLHFGGGTKVEIK 107
Alignment of SEQ ID NO: 13 of Pat. 876 and SEQ ID NO: 8 of the instant application:
Query Match 100.0%; Score 637; Length 119;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATISGGGFGTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATISGGGFGTYY 60
Qy 61 PDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPGYHNYYFDIWGQGTTVTVSS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPGYHNYYFDIWGQGTTVTVSS 119
6. The method of claim 5, wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 16 and the HCVR comprises the amino acid sequence of SEQ ID NO: 17.
8. The method of claim 7, wherein the anti-Dkk-1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 22 and a light chain comprising the amino acid sequence of SEQ ID NO: 23. As evidenced by the specification of Pat. 876, DKN-01 has a heavy chain comprising SEQ ID NO: 22 and a light chain comprising SEQ ID NO: 23 (see col. 6, lines 44-53 of the specification). Taken together, the claims of Pat. 876 teach antibodies of instant claims 1, and 15-19.
Thus, the claims of Pat. 876 teach treating an esophageal cancer with an anti-DKK1 antibody (such as DKN-01 or antibody of claim 4) alone or in combination with additional therapeutic agent such as paclitaxel, gemcitabine or cisplatin. However, the claims of Pat. 876 do not teach the subject determined to have a DKK1 expression % positive value of 20 or above in a sample of the subject’s cancer, or the cancer is refractory or the subject is immunotherapy-naïve, or specific esophageal cancer recited, or triple combination of instant claims 26 and 27.
Klempner2018, NCT02013154-ver18 and De Lange teach as set forth above. In particular, Klempner2018 teaches that elevated tumor expression of DKK1 may correlated with better clinical outcome in a patient with esophagogastric cancer treated with DKN-01 + Pembrolizumab (§ Conclusions, bottom part of the last column). Klempner2018 teaches that a patient with a tumor DKK1 H-score of 78 responds to the combination treatment, however a patient with a tumor DKK1 H-score of 4 shows progressive disease under the same treatment (top part of the last column). As set forth above, the patient with a H-score 78 reads on “the subject previously determined to have a DKK1 expression % positive value of 20 or above in a sample of the subject’s cancer”. Klempner2018 and NCT02013154-ver18 treating various esophagogastric cancers with DKK1 antibody alone or in combination with paclitaxel or pembrolizumab; De Lange teaches combination of gemicitabine and cisplatin are effective for treating gastric cancers and can be combined with additional therapeutic agent.
It would have prima facie been obvious to one of ordinarily skilled in the art before the time the invention was filed to treat esophageal cancer with a constitutively activated beta-catenin protein with anti-DKK1 antibody e.g. DKN-01 as taught by Pat. 876 and to apply the method to the subject determined to have (a) a DKKI1 expression % positive value of above 20 (e.g. at least 26) in a sample of the subject's cancer because Kelmpner2018 teaches these patients show better response to the therapy comprising a DKK1 antibody (e.g. DKN-01). The motivation would have been to identify a suitable patient population for the combination therapy.
Regarding claims 8, 21-23 and 57-59, it would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat esophagogastric cancer patients with a determined DKK1 expression % positive value of above 20 for a DKK1-targeted therapy, as taught by the claims of Pat. 876, NCT02013154-ver18 and Kelmpner2018, and to apply the method to patients with Esophageal Cancer, Gastroesophageal Junction Cancer, or Gastric Adenocarcinoma refractory to anti-PD1/PD-L1 monoclonal antibody therapy, as taught by NCT02013154-ver18, because based on the teachings of Klempner2018 and NCT02013154-ver18, these patients show better response to the therapy and the treatment has been tested in a clinical trial. Given that all the components are well known in the art, as evidenced by the references, one of ordinary skill in the art would have had a reasonable expectation of success to reach the claimed method. The motivation would have been to apply the treatment to a suitable patient population.
Regarding claims 26 and 27, it would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use anti-DKK1 antibody alone or in combination with Pembrolizumab or paclitaxel in method of claim 1, as taught by the claims of Pat. 876, NCT02013154-ver18 and Klempner2018, and to develop a new combination: the claimed anti-DKK1 antibody + cisplatin + gemcitabine, because De Lange teaches cisplatin-gemcitabine are effective for treating gastric cancer, the combination shows manageable toxicity, cisplatin and gemcitabine show synergistic activity and can be combined with additional agents, Klempner2018 and NCT02013154-ver18 teaches DKK1 antibody is suitable for combination therapy, anti-DKK1 antibodies function through different mechanism, one of ordinary skill in the art would have had a reasonable expectation that the combination would be more effective for method of claim 1. The motivation would have been to develop a more effective cancer treatment and to expand the options for cancer treatment.
U.S. Patent No. 12,319,730
Claims 1, 5-8, 11, 12, 15-23, 26, 27 and 57-59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12,319,730 B2 (hereinafter Pat. 730, corresponding to Appl. 17/587,708, of record) in view of NCT02013154-ver18 (Record History of 09/17/2018, of record), Klempner2018 (Klempner et al., EMSO 2018 Congress, Poster Display 660P, Publication Year: 2018, cited as CE in IDS of 12/03/2025), and De Lange (De Lange et al., Annals of Oncology 15: 484-488, Publication Year: 2004, of record).
It is noted that Appl. 17/587,708 is a continuation of Appl. 16/345,191 (corresponding to Pat. 876), thus Pat. 730 and Pat. 876 share the same disclosure including the Sequence List.
The claims of Pat. 730 teach:
1. A method of treating a human subject suffering from a cancer, comprising the steps of: determining that the subject has a constitutively activating mutation in a beta-catenin protein (SEQ ID NO: 2) in a sample of cancer cells; and administering to the subject determined to have the constitutively activating mutation in a beta-catenin protein (SEQ ID NO: 2) in the sample of cancer cells an effective amount of an anti-Dkk-1 antibody or antigen binding-fragment thereof, wherein the cancer is an esophageal cancer, …, and wherein the anti-Dkk-1 antibody or antigen binding-fragment thereof comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3 and the HCVR comprises CDRs HCDR1, HCDR2 and HCDR3, wherein LCDR1 has the amino acid sequence of SEQ ID NO: 6, LCDR2 has the amino acid sequence of SEQ ID NO: 7, LCDR3 has the amino acid sequence of SEQ ID NO: 8, HCDR1 has the amino acid sequence of SEQ ID NO: 9, HCDR2 has the amino acid sequence of SEQ ID NO: 10, and HCDR3 has the amino acid sequence of SEQ ID NO: 11. It is noted based on paragraphs [0025] and [0026] of instant publication US 2022/0381786 A1, the claimed esophagogastric cancer (elected species) would encompass all esophageal cancer and gastric (stomach) cancers.
2. The method of claim 1, further including administering an effective amount of a chemotherapeutic agent.
3. The method of claim 2, wherein the chemotherapeutic agent is a taxane, paclitaxel, docetaxel, carbazitaxel, gemcitabine, carboplatin, cisplatin, oxaliplatin, fluorouracil, capecitabine, or tegafur, or any functional analog thereof. Thus, the claims of Pat. 730 teaches combination of anti-DKK1 antibody with paclitaxel, or gemcitabine, or cisplatin.
4. The method of claim 1, wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 12 and the HCVR comprises the amino acid sequence of SEQ ID NO: 13. As set forth above, this antibody reads on the antibody of instant claim 15.
6. The method of Claim 5, wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 16 and the HCVR comprises the amino acid sequence of SEQ ID NO: 17.
8. The method of Claim 7, wherein the anti-Dkk-1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 22 and a light chain comprising the amino acid sequence of SEQ ID NO: 23. Taken together, the claims of Pat. 730 teach antibodies of instant claims 1, and 15-19.
Thus, the claims of Appl. 730 teach treating an esophageal cancer with an anti-DKK1 antibody (such as DKN-01 or antibody of claim 7) alone or in combination with additional therapeutic agent such as paclitaxel, gemcitabine or cisplatin.
However, the claims of Pat. 730 do not teach the subject determined to have a DKK1 expression % positive value of 20 or above in a sample of the subject’s cancer, or the cancer is refractory or the subject is immunotherapy-naïve, or specific esophageal cancer recited, or triple combination of instant claims 26 and 27.
Klempner2018, NCT02013154-ver18 and De Lange teach as set forth above. In particular, Klempner2018 teaches that elevated tumor expression of DKK1 may correlated with better clinical outcome in a patient with esophagogastric cancer treated with DKN-01 + Pembrolizumab (§ Conclusions, bottom part of the last column). Klempner2018 teaches that a patient with a tumor DKK1 H-score of 78 responds to the combination treatment, however a patient with a tumor DKK1 H-score of 4 shows progressive disease under the same treatment (top part of the last column). As set forth above, the patient with a H-score 78 reads on “the subject previously determined to have a DKK1 expression % positive value of 20 or above in a sample of the subject’s cancer”. Klempner2018 and NCT02013154-ver18 treating various esophagogastric cancers with DKK1 antibody alone or in combination with paclitaxel or pembrolizumab; De Lange teaches combination of gemicitabine and cisplatin are effective for treating gastric cancers and can be combined with additional therapeutic agent.
It would have prima facie been obvious to one of ordinarily skilled in the art before the time the invention was filed to treat esophageal cancer with a constitutively activated beta-catenin protein with anti-DKK1 antibody e.g. DKN-01 as taught by Pat. 730 and to apply the method to the subject determined to have (a) a DKKI1 expression % positive value of above 20 in a sample of the subject's cancer because Kelmpner2018 teaches these patients show better response to the therapy comprising a DKK1 antibody (e.g. DKN-01, or antibody of claim 4 of Pat. 730). The motivation would have been to identify a suitable patient population for the combination therapy.
Regarding claims 8, 21-23 and 57-59, it would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat esophagogastric cancer patients with a determined DKK1 expression % positive value of above 20 for a DKK1-targeted therapy, as taught by the claims of Pat. 730, NCT02013154-ver18 and Kelmpner2018, and to apply the method to patients with Esophageal Cancer, Gastroesophageal Junction Cancer, or Gastric Adenocarcinoma refractory to anti-PD1/PD-L1 monoclonal antibody therapy, as taught by NCT02013154-ver18, because based on the teachings of Klempner2018 and NCT02013154-ver18, these patients show better response to the therapy and the treatment has been tested in a clinical trial. Given that all the components are well known in the art, as evidenced by the references, one of ordinary skill in the art would have had a reasonable expectation of success to reach the claimed method. The motivation would have been to apply the treatment to a suitable patient population.
Regarding claims 26 and 27, it would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use anti-DKK1 antibody alone or in combination with Pembrolizumab or paclitaxel in method of claim 1, as taught by the claims of Pat. 730, NCT02013154-ver18 and Klempner2018, and to develop a new combination: the claimed anti-DKK1 antibody + cisplatin + gemcitabine, because De Lange teaches cisplatin-gemcitabine are effective for treating gastric cancer, the combination shows manageable toxicity, cisplatin and gemcitabine show synergistic activity and can be combined with additional agents, Klempner2018 and NCT02013154-ver18 teaches DKK1 antibody is suitable for combination therapy, anti-DKK1 antibodies function through different mechanism, one of ordinary skill in the art would have had a reasonable expectation that the combination would be more effective for method of claim 1. The motivation would have been to develop a more effective cancer treatment and to expand the options for cancer treatment.
Response to Arguments
For the Double Patenting rejection, Applicant first argues:
Applicant's Claim 1 differs from the claims of the underlying patents in that the present claims do require that the subject be previously determined to have a DKK1 expression% positive value of 20 or above, and do not require a constitutively active beta-catenin protein. Nothing in the claims of either U.S. Patent No. 11,267,876 or U.S. Patent No. 12,319,730 provides any reason that would have led a skilled artisan to make this modification with a reasonable expectation of success. The Office Action too does not provide any such reason, relying solely on an alleged overlap of the subject matter. As USB makes clear, a mere overlap of subject matter is insufficient to sustain an ODP rejection.
Applicant’s arguments have been fully considered but they are not persuasive. Although both Pat. 876 and Pat. 730 require a constitutively active beta-catenin protein for esophageal cancer, given the Broadest Reasonable Interpretation, the instant claims encompass esophageal cancer subjects of Pat. 876 and Pat. 730. Thus, the scope of instant claims overlaps with the scope of Pat. 876 and Pat. 730. Regarding the limitation “the subject previously determined to have a DKK1 expression % positive value of 20 or above”, Klempner2018 teaches that elevated tumor expression of DKK1 may correlated with better clinical outcome in a patient with esophagogastric cancer treated with DKN-01 + Pembrolizumab. Klempner2018 teaches that a patient with a tumor DKK1 H-score of 78 (who reads on “the subject previously determined to have a DKK1 expression % positive value of 20 or above in a sample of the subject’s cancer”) responds to the combination treatment, however a patient with a tumor DKK1 H-score of 4 shows progressive disease under the same treatment (top part of the last column). Based on the additional teachings of Klempner2018, NCT02013154-ver18 and De Lange, one of ordinary skill in the art would have treated the subject previously have high %positive value (e.g. at least 26) with reasonable success because subjects with high DKK1 expression would be more likely to respond to the DKK1 targeting treatment.
Applicant further argues:
The cited claims of U.S. Patent No. 11,267,876 or U.S. Patent No. 12,319,730 do not direct a person of ordinary skill in the art to disregard the requirement that the patient have a constitutively active beta-catenin protein and to select for treatment a patient previously determined to have an % positive score of the DKK1 expression of 20 or above. In fact, measuring the DKK1 expression is not even disclosed in the underlying patents.
Furthermore, evidence of an unexpected predictive power of the % positive score of 20 supports finding of non-obviousness of the claimed subject matter over the cited claims of the underlying patents, just as it supports finding of non-obviousness over the cited references.
Applicant’s arguments have been fully considered but they are not persuasive. Although the claims of Pat. 876 or Pat. 730 do not teach a patient previously determined to have an % positive score of the DKK1 expression of 20 or above, Klempner2018, NCT02013154-ver18 and De Lange teach treating subject with a previously determined to have an % positive value of the DKK1 expression of 20 or above, as set forth in the 103 rejection. Thus, combining these references with the claims of Pat. 876 or Pat. 730 would further teach treating subject with a previously determined to have an % positive value of the DKK1 expression of 20 or above.
Regarding the unexpected benefits, Applicant is reiterating the arguments set forth above. Thus for the reasons set forth above the rejection is maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CHENG LU/Examiner, Art Unit 1642
/PETER J REDDIG/Primary Examiner, Art Unit 1646
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