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 December 3, 2025 in response to the Office Action of June 4, 2025 is acknowledged and has been entered.
Claims 1, 12, 15, 16, 18, 21-23, 26 and 27 have been amended.
Claims 13, 14, 24 and 25 have been cancelled.
Claims 1, 5-8, 11, 12, 15-23, 26, 27 and 57-59 are pending and under consideration.
The declaration under 37 CFR 1.130(a) filed on December 3, 2025 by Michael Kagey is sufficient to make Klempner reference (Klempner et al, Journal of Clinical Oncology, volume 38, Number 4 suppl., Publication Date: 02/04/2020) excepted from prior art. Klempner reference has listed ten authors: Samuel J. Klempner, Johanna C. Bendell, Victoria Meucci Villaflor, Laura LaNiel Tenner, Stacey Stein, Girish S. Naik, Cynthia A. Sirard, Michael Kagey, Marya F. Chaney, and John H. Strickler. Based on the Declaration of Michael Kagey, the seven coauthors Samuel J. Klempner, Johanna C. Bendell, Victoria Meucci Villaflor, Laura LaNiel Tenner, Stacey Stein, Marya F. Chaney, and John H. Strickler are not co-inventors of the subject matter disclosed and claimed in the present application because he had no role in the conception of the subject matter disclosed and claimed in the present application. The remaining three authors: Girish S. Naik, Cynthia A. Sirard, Michael Kagey are co-inventors of the present application. In view of the Declaration, the current 102, 103 and double patenting rejections are withdrawn.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, CC, CD, CE and CF, 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).
New Claim Objections
Claim 1 is objected to because of the following informalities: “is selected from an esophagogastric cancer” should be “is an esophagogastric cancer”, because only one option is listed. Appropriate correction is required.
Claim 7 is objected to because of the following informalities: “wherein the patient” should be “wherein the subject” for consistence. Appropriate correction is required.
NEW REJECTIONS
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 5 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 5, which depends on claim 1, recites “wherein the cancer is selected from an esophageal cancer, a gastro-esophageal junction cancer, a gastric cancer, an epithelial endometrial cancer, an epithelial ovarian cancer, or a cholangiocarcinoma”. However, the amended claim 1 is limited to an esophagogastric cancer and an epithelial endometrial cancer, an epithelial ovarian cancer, or a cholangiocarcinoma is not an esophagogastric cancer. Thus, claim 5 fails to include all the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 16 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 16, which depends on claim 1, recites “wherein the LCVR and HCVR comprise amino acid sequences selected from the group consisting of: (i) …; (ii) a LCVR comprising the amino acid sequence of SEQ ID NO: 11 and a HCVR comprising the amino acid sequence of SEQ ID NO: 12; (iii) a LCVR comprising the amino acid sequence of SEQ ID NO: 13 and a HCVR comprising the amino acid sequence of SEQ ID NO: 10; and (iv) a LCVR comprising the amino acid sequence of SEQ ID NO: 14 and a HCVR comprising the amino acid sequence of SEQ ID NO: 10”. However, SEQ ID NO: 11, SEQ ID NO: 13 and SEQ ID NO: 14 do not comprise LCDRs 1-3 of SEQ ID NOs: 1-2-3 as recited by the amended claim 1; SEQ ID NO: 12 does not comprise HCDRs 1-3 of SEQ ID NOs: 4-5-6 as recited by the amended claim 1. Thus, claim 16 options (ii) to (iv) fail to include all the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 17 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 17, which depends on claim 1 indirectly, recites “wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 11 and the HCVR comprises the amino acid sequence of SEQ ID NO: 12”. However, as set forth above, SEQ ID NO: 11 does not comprise LCDRs 1-3 of SEQ ID NOs: 1-2-3 as recited by the amended claim 1; SEQ ID NO: 12 does not comprise HCDRs 1-3 of SEQ ID NOs: 4-5-6 as recited by the amended claim 1. Thus, claim 17 fails to include all the limitations of claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 18 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 18, which depends on claim 1, recites “wherein the DKK1 antibody comprises a heavy chain and a light chain amino acid sequence selected from the group consisting of a) …, b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 and a light chain comprising the amino acid sequence of SEQ ID NO: 18, c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, and d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain comprising the amino acid sequence of SEQ ID NO: 21”. However, SEQ ID NO: 18, SEQ ID NO: 20 and SEQ ID NO: 21 do not comprise LCDRs 1-3 of SEQ ID NOs: 1-2-3 as recited by the amended claim 1; SEQ ID NO: 17 does not comprise HCDRs 1-3 of SEQ ID NOs: 4-5-6 as recited by the amended claim 1. Thus, claim 18 options (b) to (d) fail to include all the limitations of claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 19 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 19, which depends on claim 1 indirectly, recites “wherein the DKK1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 and a light chain comprising the amino acid sequence of SEQ ID NO: 18”. However, as set forth above, SEQ ID NO: 18 does not comprise LCDRs 1-3 of SEQ ID NOs: 1-2-3 as recited by the amended claim 1; SEQ ID NO: 17 does not comprise HCDRs 1-3 of SEQ ID NOs: 4-5-6 as recited by the amended claim 1. Thus, claim 19 fails to include all the limitations of claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 legible on the poster of Klempner2018 filed by Applicant on December 3, 2025 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). Based on the H-score calculation method described in the Figure, H-score of 78 would have a DKK1 expression % positive value above 20, because a DKK1 expression % positive value of 20 could have had a H-score no more than 60. 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 cover a DKK1 expression % positive value of at least 26 (is all staining are strong, H-score of 78 would translate to a % positive value of 26) or above, which overlap with the range as instantly claimed.
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 at 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 % positive value of at least 26 or 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 H-score of 78 (which corresponding a % positive value of at least 26 or above) 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).
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.
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) in view of NCT02013154-ver18 (Record History of 09/17/2018, Klempner (Klempner et al, Journal of Clinical Oncology, volume 38, Number 4 suppl., Publication Date: 02/04/2020, of record), and De Lange (De Lange et al., Annals of Oncology 15: 484-488, Publication Year: 2004).
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). Based on the H-score calculation method described in the Figure, H-score of 78 would have a DKK1 expression % positive value above 20, because a DKK1 expression % positive value of 20 could have had a H-score no more than 60. 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 at 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 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) in view of NCT02013154-ver18 (Record History of 09/17/2018, Klempner (Klempner et al, Journal of Clinical Oncology, volume 38, Number 4 suppl., Publication Date: 02/04/2020, of record), and De Lange (De Lange et al., Annals of Oncology 15: 484-488, Publication Year: 2004).
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). Based on the H-score calculation method described in the Figure, H-score of 78 would have a DKK1 expression % positive value above 20, because a DKK1 expression % positive value of 20 could have had a H-score no more than 60. 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 at 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 rejections over Pat. 876, or Pat. 730, applicant argues that the patients being treated has a constitutively activated beta-catenin protein. Applicant’s arguments have been considered, but have not been found persuasive, because the instant claims encompass treating all esophageal cancer. Thus, the instant claims include esophageal cancer patients who has a constitutively activated beta-catenin protein. The patient scope of Pat. 876 or Pat. 730 overlaps with the patient scope of the instant claims. Based on the teachings of references, one of the ordinary skill in the art would have expected that a DKK-1 targeted therapy would be more effective to patients with high DKK1 expression. Based on the teaching of references, one of ordinary skill in the art would have a reasonable expectation of success to reach the claimed invention, as set forth above.
Conclusion
No claims are allowed.
All other objections and rejections set forth in the previous Office Action of June 4, 2025 are hereby withdrawn in view of the claim amendments and Applicant’s arguments.
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.
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/CHENG LU/ Examiner, Art Unit 1642
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