DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Interpretation
For claims 9 and 15, attention is drawn to paragraph [0052] which states “As used herein, an "olinvacimab variant" means a monoclonal antibody which
comprises heavy chain and light chain sequences that are substantially identical to those in olinvacimab, except for having three, two or one conservative amino acid substitutions at positions that are located outside of the light chain CDRs and six, five, four, three, two or one conservative amino acid substitutions that are located outside of the heavy chain CDRs,…. In other words, olinvacimab and a olinvacimab variant comprise identical CDR sequences, but differ from each other due to having a conservative amino acid substitution at no more than three or six other positions in their full length light and heavy chain sequences, respectively.” Similarly in [0053], a “pembrolizumab variant” is structurally defined the same way. Tables 3 and 4 define the sequences of pembrolizumab and olinvacimab, respectively.
Specification
All references to location in the specification are in reference to the clean substitute specification filed 7/14/2023.
The disclosure is objected to because of the following informalities: Paragraph [0015] references color drawings, however, it does not appear any color drawings were filed. In [0083] “γ4” is underlined in two instances.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 23 and 24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 23 and 24 recites the limitation "pembrolizumab” and “olinvacimab". There is insufficient antecedent basis for this limitation in the claims. Alternatively, if it was intended that pembrolizumab and olinvacimab were administered in addition to the PD-1 antagonist and VEGFR2 antagonist of claim 1, then the claims are indefinite and require clarification that pembrolizumab and olinvacimab (or variant thereof) are additionally administered.
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.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 3, 4,6-8, 13-15 and 17-22 is/are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over KR 10201800132401 (Yoo, published 12/12/2018, English machine translation included as Office action appendix) as admitted in the instant specification in [0077] and Table 3.
Yoo teaches a method of treating cancer by administering a combination of an anti-PD-1 antibody which is pembrolizumab (Keytruda®) and an anti-VEGFR antibody comprising the light and heavy chain CDR1-3 of SEQ ID NO:1-6, respectively, and variable light and variable heavy chain regions (VL and VH) of SEQ ID NO: 6 and 8, respectively ([0001] and [0013] of translation). A pharmaceutical composition comprising an anti-VEGFR antagonist antibody, i.e., that inhibits angiogenesis, and PD-1 antagonist antibody, i.e., that binds to PD-1 and inhibits the activity of PD-1, including blocking binding of PD-L1, wherein the combination has an amplified anticancer effect compared to either alone is taught ([0005], [0012], [0013], [0015]-[0018] of translation). Treatment of mouse models of lung and colon cancer with a combination of an anti-PD-1 and anti-VEGFR-2 antibody showed tumor size was significantly reduced compared to either antibody alone ([0023] of translation). The mice had not previously been treated with anti-PD-1 or anti-PD-L1 therapy. Those examples used a combination of an anti-mouse PD-1 antagonist antibody and anti-VEGR antibody “TTAC-0001” ([0046], [0060], Table in [0047] and [0061] of the translation). The two antibodies may be formulated together in the same vessel and for simultaneous administration ([0025]-[0026] of translation). The cancer to be treated may be breast cancer ([0024] of translation).
Yoo is silent with respect to the heavy and light chain sequences of the anti-VEGFR2 antibody TTAC-0001 which comprises the VL and VH of SEQ ID NO:6 and 8 and does not disclose the sequence of anti-PD-1 antibody pembrolizumab. As can be seen from the Sequence Listing of Yoo, the anti-VEGFR-2 antibody comprising respective CDRs of SEQ ID NO:1-6 and VL/VH of SEQ ID NO:6/8 are identical to the olinvacimab CDRs of respective instant SEQ ID NO:17-22, and VL and VH of SEQ ID NO:15 and 16, respectively. The instant specification in [0077] states that anti-VEGFR2 antibody olinvacimab is also called TTAC-0001 and comprises the respective light and heavy chain sequences of SEQ ID NO:13 and 14. Therefore, TTAC-0001 (olinvacimab) inherently comprises those light and heavy chain sequences. Instant Table 3 shows the sequences of pembrolizumab heavy and light chain CDR1-3, variable regions and complete heavy and light chain sequences. These sequences are inherent to the pembrolizumab antibody. Because the function of the antibody is inherent due to its structure, e.g., that pembrolizumab binds human PD-1 and blocks the binding of human PD-L1 and of human PD-L2 to human PD-1.
Alternatively, it would have been obvious to use the method of Yoo wherein the anti-PD-1 antibody was pembrolizumab instead of the anti-mouse PD-1 antagonist antibody wherein either the animal cancer model had human PD-1-expressing cells or wherein the animal was a human. Substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art before the effective filing date of the invention.
Claim(s) 1, 3, 4, 6-8, 13-15 and 17-23, 25 and 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over KR 10201800132401 (Yoo, published 12/12/2018, English machine translation included as Office action appendix) as applied to claims 1, 3, 4, 6-8, 13-15 and 17-22 above, and further in view of ClinicalTrial.gov ID NCT03720431 (version 3, 2019-01-17), ClinicalTrials.gov ID NCT01660360 (ver. 3, 2014-01-27) and as admitted in the instant specification in [0077] and Table 3.
Yoo teaches a method of treating cancer by administering a combination of an anti-PD-1 antibody which is pembrolizumab (Keytruda®,) and an anti-VEGFR antibody comprising the light and heavy chain CDR1-3 of SEQ ID NO:1-6, respectively, and variable light and variable heavy chain regions (VL and VH) of SEQ ID NO: 6 and 8, respectively ([0001] and [0013] of translation). A pharmaceutical composition comprising an anti-VEGFR antagonist antibody, i.e., that inhibits angiogenesis, and PD-1 antagonist antibody, i.e., that binds to PD-1 and inhibits the activity of PD-1, including blocking binding of PD-L1, wherein the combination has an amplified anticancer effect compared to either alone is taught ([0005], [0012], [0013], [0015]-[0018] of translation). Treatment of mouse models of lung and colon cancer with a combination of an anti-PD-1 and anti-VEGFR-2 antibody showed tumor size was significantly reduced compared to either antibody alone ([0023] of translation). Those examples used a combination of an anti-mouse PD-1 antagonist antibody and anti-VEGR antibody “TTAC-0001” (a.k.a. tanibirumab) ([0046], [0060], Table in [0047] and [0061] of the translation). It is stated ([0029] of translation), “The pharmaceutical composition of the present invention may vary depending on the patient's age, sex, and weight, and specifically, depending on the degree of disease development of a subject with cancer, the composition of the present invention may be administered once or several times daily at a dose of 0.1 to 100 mg/kg. Additionally, the dosage may be increased or decreased depending on the route of administration, the severity of the disease, gender, weight, age, and especially the degree of cancer the patient has.” The two antibodies may be formulated together in the same vessel and for simultaneous administration ([0025]-[0026] of translation). Administration may be intravenous ([0028]). The cancer to be treated may be breast cancer ([0024] of translation). Yoo is silent with respect to the heavy and light chain sequences of the anti-VEGFR2 antibody TTAC-0001 which comprises the VL and VH of SEQ ID NO:6 and 8 and does not disclose the sequence of anti-PD-1 antibody pembrolizumab. Yoo does not teach a dosage and frequency of administration for pembrolizumab or olinvacimab or treatment specifically of triple negative breast cancer.
ClinicalTrial.gov ID NCT03720431(v.3) teaches a phase Ib clinical trial administering TTAC-0001 and pembrolizumab in metastatic triple-negative breast cancer patients (Official Title). Pembrolizumab is administered on day 1 every 3 weeks with TTAC-001 administered in a dose of either 12, 16 or 8 mg/kg on day 1 every week (Arms). Patients having received prior therapy with anti-PD-1 or anti-PD-L1 agent are excluded (#28 of Eligibility:Criteria).
ClinicalTrial.gov ID NCT01660360(v.3) teaches a phase I clinical trial administering tanibirumab, a VEGFR-2 antibody, to patients with advanced or metastatic cancer (Official Title). It is administered at one of 7 doses, including 16 mg/kg by intravenous infusion, on day 1 of every week (Study Description: Detailed Description, and Arms).
As can be seen from the Sequence Listing of Yoo, the anti-VEGFR-2 antibody comprising respective CDRs of SEQ ID NO:1-6 and VL/VH of SEQ ID NO:6/8 are identical to the olinvacimab CDRs of respective instant SEQ ID NO:17-22, and VL and VH of SEQ ID NO:15 and 16, respectively. Further, Yoo discloses TTAC-0001 is also called tanibirumab ([0013]). The instant specification in [0077] states that anti-VEGFR2 antibody olinvacimab is also called TTAC-0001 and comprises the light and heavy chain sequences of SEQ ID NO:13 and 14, respective. Therefore, TTAC-0001 (olinvacimab) inherently comprises those light and heavy chain sequences. Instant Table 3 shows the pembrolizumab heavy and light chain CDR1-3, variable region and complete heavy and light chain sequences. These sequences are inherent to the pembrolizumab antibody.
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant application to have treated a cancer with pembrolizumab, 200 mg administered on day 1 every 3 weeks, and olinvacimab, 16 mg/kg on day 1 every week, by intravenous infusion as taught by NCT03720431 for the treatment of metastatic triple-negative breast cancer and in view of Yoo teaching intravenous administration of the combination of the two antibodies and NCT01660360 teaching intravenous infusion of olinvacimab (tanibirumab) for treatment of a variety of advanced and metastatic cancers. There would have been a reasonable expectation of success because the combination was in use in a clinical trial and Yoo showed superior antitumor activity in both a lung and a colon cancer mouse model with a combination of the anti-PD-1 and anti-VEGFR-2 antibodies. It further would have been obvious wherein the patient being treated had not before been previously treated with an anti-PD-1 or anti-PD-L1 therapy consistent with the eligibility criteria of NCT03720431.
Claim(s) 1, 3, 4, 6-8, 13-15 and 17-26 is/are rejected under 35 U.S.C. 103 as being unpatentable over KR 10201800132401 (Yoo, published 12/12/2018, English machine translation included as Office action appendix) as applied to claims 1, 3, 4, 6-8, 13-15 and 17-21 above, and further in view of ClinicalTrial.gov ID NCT03720431 (version 3, 2019-01-17), ClinicalTrials.gov ID NCT01660360 (ver. 3, 2014-01-27) and Stenger (https://ascopost.com/issues/july-25-2020/pembrolizumab-for-adult-and-pediatric-patients-with-tumor-mutational-burden-high-solid-tumors/, 2020-07-25) and as admitted in the instant specification in [0077] and Table 3.
Yoo teaches a method of treating cancer by administering a combination of an anti-PD-1 antibody which is pembrolizumab (Keytruda®,) and an anti-VEGFR antibody comprising the light and heavy chain CDR1-3 of SEQ ID NO:1-6, respectively, and variable light and variable heavy chain regions (VL and VH) of SEQ ID NO: 6 and 8, respectively ([0001] and [0013] of translation). A pharmaceutical composition comprising an anti-VEGFR antagonist antibody, i.e., that inhibits angiogenesis, and PD-1 antagonist antibody, i.e., that binds to PD-1 and inhibits the activity of PD-1, including blocking binding of PD-L1, wherein the combination has an amplified anticancer effect compared to either alone is taught ([0005], [0012], [0013], [0015]-[0018] of translation). Treatment of mouse models of lung and colon cancer with a combination of an anti-PD-1 and anti-VEGFR-2 antibody showed tumor size was significantly reduced compared to either antibody alone ([0023] of translation). Those examples used a combination of an anti-mouse PD-1 antagonist antibody and anti-VEGR antibody “TTAC-0001” (a.k.a. tanibirumab) and ([0046], [0060], Table in [0047] and [0061] of the translation). It is stated ([0029] of translation), “The pharmaceutical composition of the present invention may vary depending on the patient's age, sex, and weight, and specifically, depending on the degree of disease development of a subject with cancer, the composition of the present invention may be administered once or several times daily at a dose of 0.1 to 100 mg/kg. Additionally, the dosage may be increased or decreased depending on the route of administration, the severity of the disease, gender, weight, age, and especially the degree of cancer the patient has.” The two antibodies may be formulated together in the same vessel and for simultaneous administration ([0025]-[0026] of translation). Administration may be intravenous ([0028]). The cancer to be treated may be breast cancer ([0024] of translation). Yoo is silent with respect to the heavy and light chain sequences of the anti-VEGFR2 antibody TTAC-0001 which comprising the VL and VH of SEQ ID NO:6 and 8 and does not disclose the sequence of anti-PD-1 antibody pembrolizumab. Yoo does not teach a dosage and frequency of administration for pembrolizumab or olinvacimab or treatment specifically of triple negative breast cancer.
ClinicalTrial.gov ID NCT03720431(v.3) teaches a phase Ib clinical trial administering TTAC-0001 and pembrolizumab in metastatic triple-negative breast cancer patients (Official Title). Pembrolizumab is administered on day 1 every 3 weeks with TTAC-001 administered in a dose of either 12, 16 or 8 mg/kg on day 1 every week (Arms). Patients having received prior therapy with anti-PD-1 or anti-PD-L1 agent are excluded (#28 of Eligibility:Criteria)
ClinicalTrial.gov ID NCT01660360(v.3) teaches a phase I clinical trial administering tanibirumab, a VEGFR-2 antibody, to patients with advanced or metastatic cancer (Official Title). It is administered at one of 7 doses, including 16 mg/kg by intravenous infusion, on day 1 of every week (Study Description: Detailed Description, and Arms).
Stenger teaches that pembrolizumab received accelerated FDA approval for adult and pediatric patients with unresectable or metastatic tumor mutation burden-high solid tumors (second paragraph). Pembrolizumab is an anti-PD-1 monoclonal antibody that blocks binding to PD-L1 and PD-L2 ligands, thereby removing inhibition of an antitumor response (“How It Works”). It was approved for not only administration of 200 mg/3 weeks, but also 400 mg/6 weeks by intravenous infusion (“How It Is Used”).
As can be seen from the Sequence Listing of Yoo, the anti-VEGFR-2 antibody comprising respective CDRs of SEQ ID NO:1-6 and VL/VH of SEQ ID NO:6/8 are identical to the olinvacimab CDRs of respective instant SEQ ID NO:17-22, and VL and VH of SEQ ID NO:15 and 16, respectively. Further, Yoo discloses TTAC-0001 is also called tanibirumab ([0013]). The instant specification in [0077] states that anti-VEGFR2 antibody olinvacimab is also called TTAC-0001 and comprises the light and heavy chain sequences of SEQ ID NO:13 and 14, respectively. Therefore, TTAC-0001 (olinvacimab) inherently comprises those light and heavy chain sequences. Instant Table 3 shows the pembrolizumab heavy and light chain CDR1-3, variable region and complete heavy and light chain sequences. These sequences are inherent to the pembrolizumab antibody.
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant application to have treated a cancer with pembrolizumab, 200 mg administered on day 1 every 3 weeks or 400 mg administered on day 1 every 6 weeks, and olinvacimab, 16 mg/kg on day 1 every week, by intravenous infusion as taught by NCT03720431 for the treatment of metastatic triple-negative breast cancer and in view of Yoo teaching intravenous administration of the combination of the two antibodies, as well as NCT01660360 teaching intravenous infusion of olinvacimab (tranibirumab) for treatment of a variety of advanced and metastatic cancers and Stenger teaching FDA approval of pembrolizumab dosage of 400 mg/6 weeks. There would have been a reasonable expectation of success because the combination was in use in a clinical trial and Yoo showed that in both a lung and a colon cancer mouse model the combination of the two related antibodies was more effective than either alone. Further Yoo taught that dosage depends on severity of the disease, gender, weight, age, and especially the degree of cancer the patient has. Therefore, it would have been obvious to have optimized the dosage for both antibodies. It further would have been obvious wherein the patient being treated had not before been previously treated anti-PD-1 or anti-PD-L1 therapy consistent with the eligibility criteria of NCT03720431.
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
LI et al. (Cancer Res. Vol. 26, No. 7, pp. 1712-1724, Dec. 2019, Abstract and Materials and Methods, cited in the IDS filed 3/1/2023) teaches combining an anti-PD-1 antibody (SHR-1210 [later named pembrolizumab]) and different doses of VEGFR2-targeting agents (antibody DC101 or tyrosine kinas inhibitor apatinib) in syngeneic breast cancer mouse models. The efficacy of combined anti-angiogenic and anti-PD-1 therapy was further evaluated in patients with advanced triple-negative breast cancer (TNBC). Blockade of VEGFR2 sensitized breast tumors to PD-1 blockade in a dose-dependent manner and the VEGFR antagonism led to immune cell infiltration secretion of osteopontin (OPN), which subsequently induced tumor cell production of TGF-β, which in turn upregulates PD-1 expression on immune cells. In patients with advanced TNBC, combined treatment with low-dose anti-VEGFR2 inhibitor and anti-PD-1 demonstrated excellent tolerability and efficacy. Higher OPN and TGF-β expressions correlated with improved treatment responses. Li et al. supports the reasonable expectation of antitumor activity by combining an antagonist of PD-1 and VEGFR for the treatment of TNBC.
Herbst et al. (Ann. Oncol. 27(Suppl 6):vI574, Abstract LBA38 Oct. 2016) teaches efficacy of treatment of a variety of cancers (Methods) in a phase 1 clinical trial with both ramucirumab (R, an anti-VEGFR-2 antibody) plus pembrolizumab (P, 200 mg on day 1 every 3 weeks). For non-small cell lung cancer (NSCLC), it is concluded, “R + P generated no new safety signals and demonstrated promising clinical activity in pts with previously treated advanced NSCLC, including PD-L1 neg pts.” Herbest also provides a reasonable expectation of cancer treatment using a VEGFR-2 and PD-1 antagonist antibody and motivation for that use.
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
January 27, 2026