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 .
1. Claims 1, 7-21, 25-35, 37-42, 46, 50-57, 61-66 are pending and being examined.
Specification
2. The disclosure is objected to because of the following informalities: The specification references “SEQ ID NO:7” several times. SEQ ID NO:7 is identified as a “000” dummy sequence in the sequence listing, therefore SEQ ID NO:7 does not represent an amino acid sequence for light chain variable region CDR2. See paragraph [0002] of the specification.
Examiner Suggestion: Change SEQ ID NO:7 to “AAS” throughout the specification.
Appropriate correction is required.
3. Claim 1 is objected to because of the following informalities: Claim 1 recites “SEQ ID NO:7” as an amino acid sequence representing LCDR2, however, SEQ ID NO:7 is identified as a “000” dummy sequence in the sequence listing. The specification at paragraph [0002] states SEQ ID NO:7 is AAS and the claims will be examined as such.
Examiner Suggestion: Delete “SEQ ID NO:7” in claim 1 and change to “AAS”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
4. Claims 14, 15, 18-20, 52-56 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.
Claim 14 depends from claim 10 and recites: “…wherein the administration of the PD-1 inhibitor leads to reduced use of analgesic therapy by the patient.” Claim 10 recites that the patient receives analgesic therapy prior to administration of the PD-1 inhibitor. The analgesic therapy was administered prior to the PD-1 inhibitor in the claimed method and there is no claim limitation stating that analgesic therapy was administered after PD-1 inhibitor or that the subject is on continuous analgesic therapy. Therefore, it is unclear what analgesic therapy has reduced use after administration of the PD-1 inhibitor.
Claim 15 depends from claim 10 and recites: “…further comprising reducing the amount of the analgesic therapy received by the patient by 20% or more within 1 year after administration of the PD-1 inhibitor.” Claim 10 recites that the patient receives analgesic therapy prior to administration of the PD-1 inhibitor. The analgesic therapy was administered prior to the PD-1 inhibitor in the claimed method and there is no claim limitation stating that analgesic therapy was administered after PD-1 inhibitor or that the subject is on continuous analgesic therapy. Therefore, it is unclear what analgesic therapy claim 15 is referring to that is being reduced within a year after administration of the PD-1 inhibitor.
Claim 18 depends from claim 1 and recites: “…wherein the administration of the PD-1 inhibitor concurrently leads to reduced analgesic use and at least 30% decrease in tumor cells or tumor size.” Claim 1 never recites using analgesics, therefore, it is unclear what “analgesic use” is reduced.
Claim 19 depends from claim 1 and recites: “…wherein the administration of the PD-1 inhibitor concurrently leads to reduced opioid use and at least 30% decrease in tumor cells or tumor size.” Claim 1 never recites using opioids, therefore, it is unclear what “opioid use” is reduced.
Claim 20 depends from claim 1 and recites: “…wherein the administration of the PD-1 inhibitor further reduces pain, reduces the need for analgesic therapy, promotes tumor regression, reduces tumor cell load, reduces tumor burden, prevents tumor recurrence in the patient, and/or increases patient survival.” The patient treated in claim 1 has basal cell carcinoma (BCC) and is not in remission, therefore, it is unclear how administration of the PD-1 inhibitor prevents tumor recurrence in the patient if the patient currently has BCC tumor that was not yet eliminated. Clarification is required.
Claim 52 depends from claim 46 and recites: “…wherein the amount of analgesic therapy received by the patient is reduced by at least 20% within 1 year after administration of the PD-1 inhibitor as compared to the amount of analgesic therapy received by the patient before administration of the PD-1 inhibitor.” Claim 46 recites that the patient is receiving analgesic therapy as a background medication prior to administration of the PD-1 inhibitor. The analgesic therapy was administered prior to the PD-1 inhibitor in the claimed method and there is no claim limitation stating that analgesic therapy was administered after PD-1 inhibitor or that the subject is on continuous analgesic therapy through PD-1 inhibitor treatment. Therefore, it is unclear what analgesic therapy claim 52 is referring to that is being reduced within a year after administration of the PD-1 inhibitor.
Claim 53 depends from claim 46 and recites: “…wherein the administration of the PD-1 inhibitor concurrently leads to reduced analgesic use and at least 30% decrease in tumor cells or tumor size”. Claim 46 recites that the patient is receiving analgesic therapy as a background medication prior to administration of the PD-1 inhibitor. The analgesic therapy was administered prior to the PD-1 inhibitor in the claimed method and there is no claim limitation stating that analgesic therapy was administered after PD-1 inhibitor or that the subject is on continuous analgesic therapy through PD-1 inhibitor treatment. Therefore, it is unclear what “analgesic use” is being reduced after the PD-1 inhibitor is administered.
Claim 54 depends from claim 46 and recites: “…wherein the administration of the PD-1 inhibitor concurrently leads to reduced opioid use and at least 30% decrease in tumor cells or tumor size”. Claims 46 and 54 do not recite administration of an opioid, therefore it is unclear what “opioid use” is being reduced.
Claim 55 depends from claim 46 and recites: “…wherein the administration of the PD-1 inhibitor concurrently leads to reduced cancer pain and at least 30% decrease in tumor cells or tumor size.” Claims 46 and 55 never recite the subject had cancer pain, therefore it is unclear what “cancer pain” is being reduced.
Claim 56 depends from claim 46 and recites: “…wherein the administration of the PD-1 inhibitor concurrently leads to reduced cancer pain, reduced opioid use, and a tumor response selected from the group consisting of stable disease (SD), partial response (PR) and complete response (CR), as determined using RECIST criteria.” Claims 46 and 56 never recite the subject had cancer pain or the method comprises opioid use, therefore it is unclear what “cancer pain” and “opioid use” is being reduced.
Claim Interpretation
5. Claim 1 recites: “A method of treating or inhibiting cancer pain”. This preamble is interpreted to encompass methods intended to inhibit any cancer pain that may arise in the future and inhibiting cancer pain that is not yet being experienced by the BCC patient treated.
Claim 46 recites: “A method of reducing use of analgesic therapy”. This preamble is interpreted to encompass methods intended to reduce use of analgesic therapy in the future that has not been administered or used yet.
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.
6. Claim(s) 1, 7, 8, 10-12, 20, 21, 25-35, 37-42, 46, 50, 57, 61-66 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US Patent Application Publication 2017/0327567, Skokos et al, published 2017.
Skokos teaches a method of treating a patient comprising:
(a) selecting a patient with basal cell carcinoma (BCC),
(a) administering to the patient a therapeutically effective amount of anti-PD-1 antibody REGN2810, also known as cemiplimab, comprising SEQ ID NO:1 and 2 identical to instant SEQ ID NOs:1 and 2 comprising CDR SEQ ID NOs:3-8, and comprising SEQ ID NOs:9 and 10 (see sequence alignments below) ([10]; [18]; [45-46]; [48]; [50]; [57]; [59]; [81]; [97-100]; [138]; [203-207]; [222]; [225]; Table 9; [372]; Example 8; [375-377]; [380]; Example 12; [464-479]; Fig. 14; claims 1-37); and
(b) administering an additional therapeutic agent selected from an anti-inflammatory drug such as corticosteroids, non-steroidal anti-inflammatory drugs (NSAID), a PD-L1 inhibitor, anti-LAG-3 antibody, chemotherapy, and combinations thereof ([67]; [74-77]; [87]; [107-111]; [195-199]; [287]; [293]; [300]; claim 23);
wherein the anti-PD-1 antibody is administered to the patient at the same time, before, or after administration of additional therapeutic agent, or wherein the anti-PD-1 antibody and therapeutic agent are administered as a co-formulation ([67]);
wherein the patient treated has cancer pain or bone pain ([42]);
wherein the BCC is metastatic or locally advanced ([10]; Fig. 14; [36]; [59]; [224]; Example 7; Example 12; claim 22);
wherein the anti-PD-1 antibody is administered at a dose of 1 mg/kg to 20 mg/kg of the patient’s body weight, 3 mg/kg, 10 mg/kg, or administered at about 200 mg, 250 mg, or 350 mg ([11]; [48]; [60]; [119-127]; [132-135]; [141-144]; [228]; [292-294]; Table 9; Table 12; Example 8);
wherein the anti-PD-1 antibody is administered as one or more doses, administered every week, every 2 weeks, every 3 weeks, or every 4 weeks ([14-15]; [48]; [50]; [59]; [60]; [119-127]; [151]; [160]; [226-227]; Example 7; [287]);
wherein the anti-PD-1 antibody is administered intravenously or subcutaneously ([200]; [292-294]; claim 28),
wherein patient is intolerant to or progresses after treatment with a hedgehog pathway inhibitor ([10]; [59]; [225]; Table 9; Example 12; [465-467]);
wherein treatment results in tumor regression, inhibits tumor growth, prevents tumor recurrence, and increases overall survival ([50]; [80]; [132]; [156]; [371]; Table 12); and
wherein treatment of BCC with anti-PD-1 antibody REGN2810 resulted in 36.7% reduction in tumor size and partial response (PR) as determined by RECIST criteria (Table 12).
Regarding claim 1, given the method taught by Skokos administers the same claimed anti-PD-1 antibody to the same claimed BCC patient population, the method of Skokos is expected to produce the same claimed result of inhibiting pain.
Regarding claim 46, given the method taught by Skokos administers the same claimed analgesic therapy prior to the same claimed anti-PD-1 antibody, and to the same claimed cancer patient population, the method of Skokos is expected to produce the same claimed result of reducing use of analgesic therapy.
Instant SEQ ID NO:9 RG2810 heavy chain aligned with Skokos SEQ ID NO:9:
US-15-593-897-9
Filing date in PALM: 2017-05-12
Sequence 9, US/15593897
Publication No. US20170327567A1
GENERAL INFORMATION
APPLICANT: Regeneron Pharmaceuticals, Inc.
TITLE OF INVENTION: Combination of anti-PD-1 antibodies and
TITLE OF INVENTION: radiation to treat cancer
FILE REFERENCE: 40848.0059USU1
CURRENT APPLICATION NUMBER: US/15/593,897
CURRENT FILING DATE: 2017-05-12
PRIOR APPLICATION NUMBER: US 62/335743
PRIOR FILING DATE: 2016-05-13
PRIOR APPLICATION NUMBER: US 62/340142
PRIOR FILING DATE: 2017-05-23
PRIOR APPLICATION NUMBER: US 62/348546
PRIOR FILING DATE: 2016-06-10
PRIOR APPLICATION NUMBER: US 62/350305
PRIOR FILING DATE: 2017-06-15
PRIOR APPLICATION NUMBER: US 62/364920
PRIOR FILING DATE: 2016-07-21
PRIOR APPLICATION NUMBER: US 62/374020
PRIOR FILING DATE: 2016-08-12
PRIOR APPLICATION NUMBER: US 62/451274
PRIOR FILING DATE: 2017-01-27
NUMBER OF SEQ ID NOS: 10
SEQ ID NO 9
LENGTH: 444
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: R2810 HC
ALIGNMENT:
Query Match 100.0%; Score 2371; Length 444;
Best Local Similarity 100.0%;
Matches 444; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQAPGKGLEWVSGISGGGRDTYF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQAPGKGLEWVSGISGGGRDTYF 60
Qy 61 ADSVKGRFTISRDNSKNTLYLQMNSLKGEDTAVYYCVKWGNIYFDYWGQGTLVTVSSAST 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNSKNTLYLQMNSLKGEDTAVYYCVKWGNIYFDYWGQGTLVTVSSAST 120
Qy 121 KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY 180
Qy 181 SLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLF 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLF 240
Qy 241 PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV 300
Qy 301 SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV 360
Qy 361 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF 420
Qy 421 SCSVMHEALHNHYTQKSLSLSLGK 444
||||||||||||||||||||||||
Db 421 SCSVMHEALHNHYTQKSLSLSLGK 444
Instant SEQ ID NO:10 RG2810 light chain aligned with Skokos SEQ ID NO:10:
US-15-593-897-10
Filing date in PALM: 2017-05-12
Sequence 10, US/15593897
Publication No. US20170327567A1
GENERAL INFORMATION
APPLICANT: Regeneron Pharmaceuticals, Inc.
TITLE OF INVENTION: Combination of anti-PD-1 antibodies and
TITLE OF INVENTION: radiation to treat cancer
FILE REFERENCE: 40848.0059USU1
CURRENT APPLICATION NUMBER: US/15/593,897
CURRENT FILING DATE: 2017-05-12
PRIOR APPLICATION NUMBER: US 62/335743
PRIOR FILING DATE: 2016-05-13
PRIOR APPLICATION NUMBER: US 62/340142
PRIOR FILING DATE: 2017-05-23
PRIOR APPLICATION NUMBER: US 62/348546
PRIOR FILING DATE: 2016-06-10
PRIOR APPLICATION NUMBER: US 62/350305
PRIOR FILING DATE: 2017-06-15
PRIOR APPLICATION NUMBER: US 62/364920
PRIOR FILING DATE: 2016-07-21
PRIOR APPLICATION NUMBER: US 62/374020
PRIOR FILING DATE: 2016-08-12
PRIOR APPLICATION NUMBER: US 62/451274
PRIOR FILING DATE: 2017-01-27
NUMBER OF SEQ ID NOS: 10
SEQ ID NO 10
LENGTH: 214
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: R2810 LC
ALIGNMENT:
Query Match 100.0%; Score 1112; Length 214;
Best Local Similarity 100.0%;
Matches 214; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDSITITCRASLSINTFLNWYQQKPGKAPNLLIYAASSLHGGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDSITITCRASLSINTFLNWYQQKPGKAPNLLIYAASSLHGGVPS 60
Qy 61 RFSGSGSGTDFTLTIRTLQPEDFATYYCQQSSNTPFTFGPGTVVDFRRTVAAPSVFIFPP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTIRTLQPEDFATYYCQQSSNTPFTFGPGTVVDFRRTVAAPSVFIFPP 120
Qy 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
Qy 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
||||||||||||||||||||||||||||||||||
Db 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
7. Claim(s) 1, 7, 8, 10-12, 20, 21, 25-35, 37-42, 46, 50, 57, 61-66 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US Patent 12,473,364; Fury et al, claiming priority to 2018.
The applied reference has a common Applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Fury teaches a method of treating a cancer patient, the method comprising:
(a) selecting a patient with basal cell carcinoma (BCC) and
(b) administering to the patient a therapeutically effective amount of anti-PD-1 antibody cemiplimab (REGN2810) that comprises heavy chain SEQ ID NO:9 and light chain SEQ ID NO:10 that are 100% identical to instant SEQ ID NOs:9 and 10, respectively (cols. 1-2;10; 13-14; claims 1-31);
the method further comprising administering an additional therapeutic agent such as NSAID, steroid, chemotherapy, anti-PD-L1 antibody, anti-LAG3 antibody, and more (col. 9; claim 23);
wherein the additional therapy is administered before or after the anti-PD-1 antibody or in combination with the antibody (claims 24-25; col. 8-9);
wherein the anti-PD-1 antibody is administered more than one time, such as every 2, 3, or 4 weeks (cols. 8, 18-20);
wherein the anti-PD-1 antibody is administered at 1, 3, or 10 mg/kg of the patient’s weight or at a dose between 200, 250, or 350 mg (col. 20-21);
wherein the anti-PD-1 antibody is administered intralesionally or subcutaneously (col. 10; col. 17, lines 65-67);
wherein the BCC is metastatic (col. 6-7);
wherein the patient has progressed on HHI therapy (col. 2); and
wherein the method results in delayed tumor growth, prevents tumor recurrence, increases survival, results in complete or partial response, leads to at least 30% or more decrease in tumor cells or tumor size (col. 10; col. 28; claim 19).
Fury further teaches and exemplifies administering acetaminophen prior to administration of anti-PD-1 antibody REGN2810 (col. 26-27).
Regarding claim 1, given the method taught by Fury administers the same claimed anti-PD-1 antibody to the same claimed BCC patient population, the method of Fury is expected to produce the same claimed result of inhibiting cancer pain.
Regarding claim 46, given the method taught by Fury administers the same claimed analgesic acetaminophen prior to the same claimed anti-PD-1 antibody, and to the same claimed cancer patient population, the method of Fury is expected to produce the same claimed result of reducing use of analgesic therapy.
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.
8. Claim(s) 1, 7, 8, 10-21, 25-35, 37-42, 46, 50-57, 61-66 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2017/0327567, Skokos et al, published 2017; in view of Black et al (The American Surgeon; Vol. 79, Issue 6, June 2103; p. E221 only); Warthan et al (Journal of the American Academy of Dermatology, 2004, 50, issue 3, Supplement, P129); Goto et al (Current Treatment Options in Oncology, 2019, 20:34, pages 1-10; IDS); WO 2018/209329, Ji et al, published November 2018; Wang et al (Journal of Cancer Institute, July 2020; 130:3603-3620; IDS); and Graff et al (Annals of Oncology, 2016, 27(Supplement 6):vi243-vi265; IDS).
Skokos teaches and exemplifies successfully treating a metastatic BCC patient comprising administering anti-PD-1 antibody REGN2810, as set forth above. Skokos further teaches patients identified in need of treatment have cancer pain or bone pain, as set forth above.
Skokos does not teach:
the specific metastatic BCC patient treated in their method had pain and that the method resulted in reduced pain or inhibited the pain (claims 1, 17, 55, 56),
the method resulted in reduced pain by about 20% or more within 1 year of administering the anti-PD-1 antibody (claim 16);
the method further comprises administering opioids to the BCC patients to reduce cancer pain (claim 13),
administering opioids prior to the anti-PD-1 antibody (claims 10, 46), and
reducing the use of opioids after anti-PD-1 antibody cemiplimab administration (14, 18, 19, 52-54, 56).
Black teaches it is known that BCC can metastasize and result in cancer bone pain (p. E221, col. 2, last paragraph).
Warthan teaches it is known BCC can metastasize to the bone and cause cancer bone pain.
Goto teaches BCC and squamous cell carcinoma (SCC) are two types of non-melanoma skin cancers (p. 2, col. 2). Goto teaches SCC also metastasizes to the bone and pain commonly occurs in such patients (p. 1; Table 1; Figure 1; p. 3). For bone pain due to metastasis, pharmacotherapy with opioid agents is the most basic treatment (p. 1). There is a close relationship between pain and bone or skin metastasis in advanced skin cancer (p. 4). Pain is the most common symptom for patients with skin cancer. Also, 43% of patients with unresectable skin cancer have bone metastasis, which can become one of the sources of pain. Pharmacotherapy using opioid is the most basic method for controlling pain (p. 5, “Pain”). Goto teaches that high dose opioid for controlling pain due to bone and skin metastases may be linked to drowsiness and delirium. Goto suggests opioid-induced cognitive dysfunction should be minimized by opioid rotation and use of non-opioid agents (p. 7).
Ji teaches cancer can metastasize to the bone causing bone cancer pain and dramatically impairing the quality of life in cancer patients ([5]; [127]). Ji teaches that current treatments for pain are only partially effective and cause significant side effects, particularly addiction to opioids, and there is an urgent need for effective and safe pain medicine ([4]; Summary of the Invention [1]). Ji teaches and demonstrates the administration of anti-PD1 antibody to cancer subjects to block PD-1 can function successfully in reducing cancer bone pain as well as protecting against destructive osteoclast activation associated with bone pain ([9]; Figures 24, 26, and 27; [34]; [36-37]; [62-65]; [69]; [71-76]; Example 11; claims 10-12).
Wang teaches and demonstrates essentially the same thing as Ji. Wang teaches cancer pain is experienced by 70% of patients with advanced stage cancer, and more than 80% of this pain is attributed to metastatic cancer-induced bone pain. Bone metastasis from late-stage cancers may form osteolytic bone lesions, leading to pathological fractures and marked cancer bone pain. Current treatment for cancer pain, including opioids, have limited analgesic efficacy. A revolutionary approach in cancer immunotherapy targets immune checkpoint inhibitors, including PD-1. Anti-PD-1 treatment has shown success in treating cancers. Checkpoint pathways are implicated in the formation of osteoclasts and PD-1 deficiency leads to a reduction of osteoclastogenesis without altering the number of osteoblasts (Introduction; p. 3603). The experiments of Wang demonstrates that repeated anti-PD-1 antibody (nivolumab) injections produced sustained beneficial effects for relieving cancer pain and protecting bone destruction (p. 3604, col. 1). Anti-PD-1 antibody nivolumab successfully protects against bone destruction in a mouse model after cancer cell inoculation, wherein 29.4% of untreated mice had bone fractures and 0% of mice treated with nivolumab had bone fractures (p. 3604, col. 2; Figure 1 and 3). Nivolumab successfully produces sustained cancer pain or bone cancer pain relief in a mouse model after cancer cell inoculation. Repeated IV nivolumab injections effectively reduced formation of osteoclasts in tumor-bearing mice (p. 3606; Figures 2 and 4; p. 3609, col. 2; p. 3613, col. 2). Nivolumab reduces destructive osteoclast activation in mouse bone cancer (p. 3611, col. 1). Wang provides Figure 10 that illustrates the mechanism of action for anti-PD-1 antibody inhibiting bone pain. Wang et al teach (p. 3615):
“Patients with bone metastasis have high risk of bone cancer pain. Thus, demonstrating the effect of nivolumab in preclinical models will guide future clinical trials in preventing and treating bone fractures and bone cancer pain. Because the half-life of nivolumab is much longer in humans than mice (2 weeks vs. 3 days), nivolumab could be more effective in protecting bone destruction and alleviating bone cancer pain in humans. Our finding also suggests nivolumab treatment does not disrupt normal bone structure in cancer-free animals. Thus, abnormal PD-L1 expression in BM microenvironment could be a prerequisite for this immunotherapy to be effective. Furthermore, our results indicate that posttreatment with nivolumab, starting 5 days after tumor inoculation, is still efficacious in decreasing bone destruction and cancer pain, despite better effects of prophylactic treatment. In addition to lung cancers, bone metastasis also occurs in late-stage breast, thyroid, and bladder cancers as well as other cancers, and osteolytic bone lesions are very common in these cancers, leading to pathological fractures and severe bone cancer pain (4). It is noteworthy that improving life quality in terminal cancer patients is as important as extending survival. Thus, our discovery of protecting bone fractures and alleviating bone cancer pain with anti–PD-1 immunotherapy is innovative and highly feasible. Actually, several clinical studies have shown that anti–PD-1 treatment might reduce cancer pain and improve quality of life in patients with advanced non–small-cell lung cancer and advanced head and neck cancer (43, 44). Case reports also indicate that nivolumab treatment can alleviate cancer pain in head and neck cancer patients with spinal bone metastasis and in renal cell carcinoma patients with multiple bone metastasis (45, 46). In particular, Ansari et al. showed a marked improvement in pain score, with a reduction from 8/10 to 3/10 (46).”
Graff demonstrates treating metastatic cancer patients with anti-PD-1 antibody pembrolizumab resulted in significant anti-tumor clinical activity and two responders were able to discontinue opioid analgesic after reporting resolution of cancer-related pain (Methods).
Treating cancer pain:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat cancer pain in the method of Skokos, particularly for metastatic/unresectable locally advanced BCC, and to reduce pain by about 20% or more within 1 year after administering anti-PD-1 antibody. One would have been motivated because: (1) Skokos recognizes that their patient populations can have metastatic bone pain and the need to improve quality of life by lowering pain; (2) Black and Warthan recognize that this patient population can have metastasis to bone and metastatic bone pain and is need of pain treatment; (3) Goto recognizes skin cancer metastasis results in bone pain and is in need of treatment; and (4) Ji and Wang teach treatment of bone pain caused by cancer metastasis to bone is common, and teach anti-PD-1 antibody immunotherapy can be an effective and safe therapy for reducing pain associated with cancer metastasis to bone. One of ordinary skill in the art would have a reasonable expectation of success to reduce cancer pain in the method of Skokos because: (1) Skokos demonstrates anti-PD-1 antibody cemiplimab (REGN2810) successfully treats metastatic BCC; (2) Ji and Wang teach anti-PD-1 antibody immunotherapy can be an effective and safe therapy for reducing pain associated with cancer metastasis to bone; (3) Ji and Wang successfully demonstrate anti-PD1 antibody reduces pain and bone destruction; (4) Wang teaches the known mechanism of action for anti-PD-1 antibody reducing bone pain; (5) Wang teaches there are numerous case reports of cancer pain from metastasis being alleviated with anti-PD-1 antibody therapy; and (6) Graff demonstrates successfully eliminating cancer pain in metastatic cancer patients after being on anti-PD-1 antibody treatment.
Additionally administering opioids:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer an opioid to the metastatic cancer patients or metastatic/unresectable locally advanced BCC patient population treated in the method of Skokos to treat pain. One would have been motivated to because: (1) Skokos, Black, and Warthan recognize that such patient populations can have metastasis and bone pain and the need to improve quality of life by lowering pain; (2) Goto recognizes that metastatic bone pain is treated by opioids; (3) Ji and Wang also teach treatment of bone pain caused by cancer metastasis to bone is common and treated with opioids. One of ordinary skill in the art would have a reasonable expectation of success to administer an opioid to the cancer patients in the method of Skokos before or after the PD-1 antibody because Goto, Ji, Wang, and Graff all teach or demonstrate opioids are commonly administered to treat cancer pain or bone pain associated with metastatic cancers and metastatic/unresectable locally advanced skin cancer.
Reducing opioid use during cemiplimab treatment
One of ordinary skill in the art would have been motivated to, and have a reasonable expectation of success to, reduce the use of opioids over any time range for metastatic/unresectable locally advanced BCC patients being treated with anti-PD-1 antibody cemiplimab because: (1) Skokos teaches and demonstrates successful treatment of this patient population with anti-PD-1 antibody cemiplimab; (2) Goto recognizes skin cancer patients commonly have metastatic bone pain that is treated by opioids and teach the need to minimize opioid use due to undesirable side effects; (3) Ji and Wang also teach treatment of bone pain caused by cancer metastasis to bone is common and treated with opioids, teach the need to reduce the use of opioids due to their limited analgesic efficacy and significant side effects, and teach anti-PD-1 antibody immunotherapy can be an effective and safe therapy for reducing pain associated with cancer metastasis to bone; (4) Ji and Wang successfully demonstrate anti-PD1 antibody reduces pain and bone destruction; (5) Wang teaches the known mechanism of action for anti-PD-1 antibody reducing bone pain; (6) Wang teaches there are numerous case reports of cancer pain from metastasis being alleviated with anti-PD-1 antibody therapy; and (7) Graff demonstrates metastatic cancer patients reducing the use of opioids to 0% and eliminating pain after being on anti-PD-1 antibody treatment. Given: (1) the known use of opioids for treating cancer bone pain in metastatic/unresectable locally advanced cancer patients in the cited art, (2) the known need to reduce the use of opioids for treating cancer bone pain and to find safer more effective alternatives, (3) the known successful treatment of metastatic/unresectable locally advanced BCC patients with anti-PD-1 antibody cemiplimab; (4) the known success and mechanism of anti-PD-1 antibodies for the treatment of cancer bone pain from metastasis, one of skill in the art could have reduced the use of opioids to at least 20% within a year and reduced pain by about 20% or more in a year in a population of metastatic/unresectable locally advanced BCC patients being treated with anti-PD-1 antibody cemiplimab with a reasonable expectation of success.
9. Claim(s) 9 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2017/0327567, Skokos et al, published 2017; Black et al (The American Surgeon; Vol. 79, Issue 6, June 2103; p. E221 only); Warthan et al (Journal of the American Academy of Dermatology, 2004, 50, issue 3, Supplement, P129); Goto et al (Current Treatment Options in Oncology, 2019, 20:34, pages 1-10); WO 2018/209329, Ji et al, published November 2018; Wang et al (Journal of Cancer Institute, July 2020; 130:3603-3620); and Graff et al (Annals of Oncology, 2016, 27(Supplement 6):vi243-vi265); as applied to claims 1, 7, 8, 10-21, 25-35, 37-42, 46, 50-57, 61-66 above, and further in view of Skokos.
Skokos; Black; Warthan; Goto; Ji; Wang; and Graff (the combined references) teach a method for treating or inhibiting cancer pain in a BCC patient by administering anti-PD-1 antibody REGN2810, as set forth above.
The combined references do not exemplify the method results in the quality of life of the patient improved or maintained from baseline as measured by EORTC, QLQ-C30, and SKINDEX.
Skokos further teaches measuring quality of life of the BCC patient by EORTC, QLQ-C30, and SKINDEX-16 ([476]; [466]). Skokos further teaches:
[0478] It is expected that consistent with phase 1 results (see Examples 7 and 8 herein) administration of REGN2810 will lead to tumor regression in patients with advanced basal cell carcinoma who showed progression of disease upon treatment with a Hedgehog pathway inhibitor (HHI) or were intolerant of prior HHI therapy. Patients show complete response, partial response or stable disease upon treatment with REGN2810.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was effectively filed for the method of the combined references to result in the quality of life of the BCC patient improved or maintained from baseline as measured by EORTC, QLQ-C30, and SKINDEX. One would have been motivated to, and have a reasonable expectation of success to, because Skokos teaches assessing quality of life after treatment by measuring EORTC, QLQ-C30, and SKINDEX and teaches they expected successful treatment based on the success of their phase 1 results.
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).
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10. Claims 1, 10, 11, 12, 20, 21, 25-35, 37, 38, 41, 46, 50, 57, 61, and 65 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S. Patent No. 12,473,364. Although the claims at issue are not identical, they are not patentably distinct from each other because the US Patent claims a method of administering the same drugs to a patient population comprising an overlapping population of patients instantly claimed, thereby rendering obvious the instantly claimed method. The US Patent claims:
1. A method of treating or inhibiting the growth of a tumor, comprising:
(a) selecting a patient with a skin cancer; and
(b) intralesionally administering to the tumor of the patient one or more doses of a pharmaceutical composition comprising a therapeutically effective amount of a programmed death 1 (PD-1) inhibitor, wherein the PD-1 inhibitor is an antibody or antigen-binding fragment thereof that specifically binds PD-1 and comprises three complementarity determining regions (CDRs) (HCDR1, HCDR2, and HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and three CDRs (LCDR1, LCDR2, and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2 wherein the skin cancer is cutaneous squamous cell carcinoma (CSCC) or basal cell carcinoma (BCC).
2. The method according to claim 1, wherein the skin cancer is CSCC.
3. The method according to claim 1, wherein the skin cancer is recurrent resectable CSCC.
4. The method according to claim 1, wherein the patient has had prior treatment for the cancer.
5. The method according to claim 4, wherein the prior treatment comprises surgery, radiation, chemotherapy, treatment with a PD-1 inhibitor, and/or other anti-tumor therapy.
6. The method according to claim 1, wherein the patient is at risk of recurrence.
7. The method according to claim 1, wherein the patient has a prior history of recurrence after surgery.
8. The method according to claim 1, wherein each dose of the PD-1 inhibitor comprises one or more intralesional injections of the pharmaceutical composition into the tumor.
9. The method according to claim 8, wherein at least two intralesional injections are administered into different locations of the tumor.
10. The method according to claim 8, wherein two to five intralesional injections are administered into two to five locations of the tumor.
11. The method according to claim 8, wherein at least one intralesional injection is administered into the upper half of the tumor.
12. The method according to claim 8, wherein at least one intralesional injection is administered into skin overlying the tumor.
13. The method according to claim 8, wherein at least one intralesional injection is administered into a superior periphery of the tumor, adjacent an interface with normal-appearing skin.
14. The method according to claim 1, wherein the tumor has a surface diameter of at least 1 cm.
15. The method according to claim 1, wherein the tumor has a surface diameter of no more than 2 cm.
16. The method according to claim 1, wherein each dose is administered once a day, once in two days, once in three days, once in four days, once in five days, once in six days, once a week or twice a week.
17. The method according to claim 1, wherein each dose comprises 5 mg to 200 mg of the PD-1 inhibitor.
18. The method according to claim 1, wherein each dose comprises 5 mg, 15 mg, or 44 mg of the PD-1 inhibitor.
19. The method according to claim 1, wherein the administration of the PD-1 inhibitor promotes tumor regression, reduces tumor cell load, reduces tumor burden, and/or prevents tumor recurrence in the patient.
20. The method according to claim 1, wherein the intralesional administration of the PD-1 inhibitor promotes at least about 10% more tumor regression than intravenous administration of the PD-1 inhibitor.
21. The method according to claim 1, wherein the intralesional administration of the PD-1 inhibitor leads to lower incidence of adverse events, less severity of adverse events, and/or less toxicity than intravenous administration of the PD-1 inhibitor.
22. The method according to claim 1, further comprising surgically removing the tumor after step (b).
23. The method according to claim 1, further comprising administering a second therapeutic agent or therapy selected from surgery, radiation, chemotherapy, a corticosteroid, an anti-inflammatory drug, and/or combinations thereof.
24. The method of claim 23, wherein the PD-1 inhibitor is administered before a second therapeutic agent or therapy.
25. The method of claim 23, wherein the PD-1 inhibitor is administered after a second therapeutic agent or therapy.
26. The method according to claim 1, wherein: HCDR1 has an amino acid sequence of SEQ ID NO: 3; HCDR2 has an amino acid sequence of SEQ ID NO: 4; HCDR3 has an amino acid sequence of SEQ ID NO: 5; LCDR1 has an amino acid sequence of SEQ ID NO: 6; LCDR2 has an amino acid sequence of SEQ ID NO: 7; and LCDR3 has an amino acid sequence of SEQ ID NO: 8.
27. The method according to claim 26, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a HCVR/LCVR sequence pair of SEQ ID NOs: 1/2.
28. The method according to claim 27, wherein the anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain has an amino acid sequence of SEQ ID NO: 9.
29. The method according to claim 27, wherein the anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the light chain has an amino acid sequence of SEQ ID NO: 10.
30. The method according to claim 27, wherein the anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain has an amino acid sequence of SEQ ID NO: 9 and the light chain has an amino acid sequence of SEQ ID NO: 10.
31. The method according to claim 1, wherein the PD-1 inhibitor is cemiplimab or a bioequivalent thereof.
It is noted that the US Patent defines “anti-inflammatory drug” as comprising a corticosteroid or a non-steroidal anti-inflammatory (NSAID) (col. 9, lines .33-35).
Regarding instant claim 1, given the claimed method of the US Patent administers the same claimed anti-PD-1 antibody to the same claimed BCC patient population, the method of the US Patent is expected to produce the same claimed result of inhibiting cancer pain.
Regarding instant claim 46, given the claimed method of the US Patent administers the same claimed additional therapeutic (steroid or anti-inflammatory NSAID) prior to the same claimed anti-PD-1 antibody, and to the same claimed cancer patient population, the method of the US Patent is expected to produce the same claimed result of reducing use of analgesic therapy.
11. Conclusion: No claim is allowed. It is noted that US Patent 12,473,364, Fury, is applied as prior to the claims as stated above, wherein the method disclosed by Fury would produce the same results of inhibiting any cancer pain that may arise in the future, however, Fury does not teach or suggest the BCC patients already have cancer pain and does not teach or suggest treating existing cancer pain by administering the anti-PD-1 antibody. Fury also does not teach or suggest analgesic therapy use or doses were reduced after treating cancer patients with the anti-PD-1 antibody. Fury is focused on intralesional administration of the anti-PD-1 antibody, doses of anti-PD-1 antibody associated with the intralesional administration, and the advantages associated with intralesional administration over intravenous or systemic administration of anti-PD-1 antibody.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642
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