DETAILED ACTION
The Examiner of your application in the USPTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Supervisory Patent Examiner Julie Wu.
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 1, 2, 3, 11, 16, 24, 34, 39, 73-75, 78, 85, 86, 97, 102, and 104-133 are pending and being examined on the merit.
Rejections Withdrawn
All previous rejections are withdrawn.
After reconsideration of the claims and prior art, previous indication of claims with allowable subject matter is withdrawn.
New Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 97, 102, 107-109, 112, and 131 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 97, 102, 112, and 131 recites the limitation "the mean fold change" in line 1. Claim 97 is dependent from claim 2, claims 102 and 131 are dependent from claim 85, and claim 112 is dependent from claim 1, and 2 and 86 do not recite the terms “mean fold change”. Thus, there is insufficient antecedent basis for this limitation in the claim.
Claims 107 and 108 are dependent from claim 1, and claim 109 is dependent from claim 1. Claim 1 requires that the dosage that is administered is about 6 µg/kg/day to about 15 µg/kg per day of a fusion protein of SEQ ID NO:1. Claims 107-109 requires that the dosage of claim 1 to be a fixed dose, which is a dose that is administered regardless of body weight. How can the dose of claim 1 be a fixed dose as required in claims 107-109 when the dose of claim 1 is dependent on body weight. Thus, the metes and bounds are unclear.
Claim Interpretation
Instant claimed “fusion protein of SEQ ID NO:1” is interpreted as a fusion protein comprising SEQ ID NO:1.
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 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 34
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 1-3, 11, 16, 78, 85, 86, 97, 102, 104-106, 110, 113-118 and 131, are rejected under 35 U.S.C. 103 as being unpatentable over Sun et al. (Cancer Research, 1 July 2017; 77 (13_Supplement): 4088, IDS entered July 6, 2022). NCT02799095 (published February 2, 2018, of record) as evidenced by Fardis (WO2022076952, due to extreme size of the full document, attachment is truncated to include only relevant information).
Sun et al. teaches ALKS 4230, an engineered fusion protein comprising circularly permutated interleukine-2 and the IL2 receptor (IL2R) alpha (IL2R[Symbol font/0x61]) that selectively activates the intermediate-affinity IL-2R, but not the high-affinity IL-2R (1st sentence).
Alignment of instant SEQ ID NO:1 with ALKS 4230 comprising SEQ ID NO:6 (nemvaleukin alfa or ALKS 4230) as disclosed in WO2022076952 (paragraphs 00147 and 00404):
BKY00984 standard; protein; 303 AA.
XX
AC BKY00984;
XX
DT 26-MAY-2022 (first entry)
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DE Nemvaleukin alpha protein sequence, SEQ ID 6.
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KW Fusion protein; IL2 protein; IL2A protein; Interleukin 2 alpha;
KW Interleukin-2 ligand; cell therapy; cytostatic;
KW non-small-cell lung cancer; respiratory-gen.; therapeutic.
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OS Homo sapiens.
OS Synthetic.
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CC PN WO2022076952-A1.
XX
CC PD 14-APR-2022.
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CC PF 15-OCT-2021; 2021WO-US055304.
XX
PR 06-OCT-2020; 2020US-0088282P.
PR 17-DEC-2020; 2020US-0127027P.
PR 05-FEB-2021; 2021US-0146402P.
PR 06-OCT-2021; 2021WO-US053841.
XX
CC PA (IOVA-) IOVANCE BIOTHERAPEUTICS INC.
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CC PI Fardis M, Finckenstein FG;
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DR WPI; 2022-509375/035.
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CC PT Treating non-small cell lung carcinoma (NSCLC) by administering
CC PT population of tumor infiltrating lymphocytes (TILs) (obtained by
CC PT multilesional sampling) to subject or patient having predetermined
CC PT absence of one or more driver mutations.
XX
CC PS Disclosure; SEQ ID NO 6; 595pp; English.
XX
CC The present invention relates to a method for treating non-small cell
CC lung carcinoma (NSCLC) by administering a population of tumor
CC infiltrating lymphocytes (TILs) to a subject or a patient having
CC predetermined absence of one or more driver mutations. The
XX
SQ Sequence 303 AA;
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Regarding claim 1, Sun teaches administering Sun teaches ALKS 4230 to treat cancer (lines 4-5). Sun teaches the results of pharmacodynamics (PD) of ALKS 4230 as well as its pharmacokinetics (PK) guided the selection of the starting dose for the ALKS 4230 first-in-human (FIH) clinical study based upon the Minimal Anticipated Biological Effect Level (MABEL) approach. Regarding claims 1, 2, 16, 78, 85, 86, 97 and 102, based on a MABEL dose of 0.1 µg/kg and projected MED of 0.7- 1.6 µg/kg, the proposed doses to be evaluated in the FIH Phase 1 study are 3 µg/kg, 10 µg/kg, or 30 µg/kg.
Regarding claims 3, 78, and 113-115, Sun teaches dosages of ALKS 4230 that leads to activation of NK cells, and memory CD8T cells (line 10). Sun teaches dosages of ALKS 4230 only slightly elevated IL-6, IL-8, and IFN-[Symbol font/0x67] (last sentence of the abstract).
Sun does not teach the dose of 3 µg/kg, 10 µg/kg, 30 µg/kg ALKS 4230 administered is per day.
Regarding claims 1, 16, 106, 117, and 118, NCT teaches a phase I clinical trial for treating solid tumors, including melanoma, comprised of intravenous administration of ALKS 4230 over 30 minutes each day for 5 consecutive days (same as at least two courses of treatment) for each cycle follow by a rest period (“Inclusion Criteria” and “Arms and Interventions”).
One of ordinary skill in the art before the effective filing date would have modify the dose of 3 µg/kg, 10 µg/kg, or 30 µg/kg ALKS 4230 that is administered to treat a solid tumor cancer in Sun with administering 3, 10, or 30 µg/kg per day to treat a solid tumor in NCT, because NCT is a phase I clinical trial for treating cancer comprised of intravenous infusion of ALKS 4230 is administered per day for 5 days. Regarding claims 3, 78, 104, 105, 113-116, and 131, administering 3, 10, or 30 µg/kg per day of ALKS 4230 to treat a solid tumor of Sun and NCT will necessarily increase circulating NK cells and CD8+ cells 2 folds over baseline, in the absence or relative greater than the increase in Treg cells, induce a partial response, and/or improve safety profile as compared to patients receiving a high dose of recombinant IL-2, lower risk of capillary leak syndrome, and/or induce a fold change in plasma IFN[Symbol font/0x67] level of 2 folds, because Sun and NCT teaches the claimed active method steps and Sun teaches administering minimal efficacious dose to achieve therapeutic effects. One of ordinary skill in the art before the effective filing date would have had a reasonable expectation of success for treating a solid tumor, including reoccurring cancer, comprised of administering 3, 10, or 30 µg/kg per day of ALKS 4230 as taught in Sun and NCT, because Sun discloses the dosages of ALKS 4230 that will give a circulating dose to achieve clinical outcomes, and NCT teaches a phase I clinical trial for ALKS 4230 that is administered each day for 5 days.
Claim(s) 24, 73-74, 111, 119-122 and 131are rejected under 35 U.S.C. 103 as being unpatentable over ). Sun et al. (Cancer Research, 1 July 2017; 77 (13_Supplement): 4088, IDS entered July 6, 2022). NCT02799095 (published February 2, 2018, of record) as evidenced by WO2022076952 as applied to claim 1 above, and further in view of Alvares (US2016/0175458, IDS entered on July 6, 2022) as evidenced by Nair et al. (J. Basic Clin Pharm, 2016, 7:27-31).
The teachings of Sun and NCT are described above.
NCT further teaches monitoring prognosis and cytokine levels up to last treatment cycle, assessed up to 24 months (page 2). NCT also teaches that the treatment time frame includes a first two treatment cycle, assessed up to 2 months (page 2).
The combined teachings of Sun and NCT do not teach administering multiple treatment cycle with a rest period of at least 9 days.
Alvarez teaches an IL-2/IL-2Rα single chain fusion body molecule comprises circularly permuted human IL-2 linked to the extracellular domain of IL-2Rα fusion protein linked to the CL-CH1-Fc domain (SEQ ID NO: 19) or the CH1-CL-Fc (SEQ ID NO: 20) of the IgG1 heavy chain (FIGS. 12A and 12B) (Page 21, Example 4, Paragraph 0183). SEQ ID NO:19 or 20 of Alvarez comprises an IL-2/IL-2Rα that is the same as instant SEQ ID NO:1 (see alignment).
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SEQ ID NO: 1 of instant application (Qy) and Alvarez SEQ ID NO:20 (Db)
Alvarez further teaches administering fusion proteins in a dosage ranges from 0.01 to 5 mg/kg (same as 10 µg/kg -5000 µg/kg) of the host body weight (paragraph 0160). Alvarez teaches that the treatment regimen entails administration once a week with multiple treatment cycles (paragraph 0160). Alvarez also teaches a treatment intervals between single dosages can be weekly or monthly (same as a rest period of at least “about” 9 days or “about” 16 days, respectively) (paragraph 0160). Alvarez further teaches intravenous administration of IL-2/IL-2Rα single chain protein comprising SEQ ID NO:19 to rats at a single dose of 1 mg/kg. As evidenced by Nair, 1 mg/kg in rat is the same as 162 µg/kg in humans (table 1; 1 mg/kg*0.189=0.162 mg/kg).
Regarding claims 24, 119-122 and 132-134, one of ordinary skill in the art before the effective filing date would have been motivated to modify the two treatment cycle in the method treating cancer comprised of administering 10 µg/kg of ALKS 4230 by Sun and NCT to have include a third treatment cycle with a rest period of a week (same as “at least about 9 days”) or month (same as “at least about 16 days”) prior to the start of the second treatment cycle as taught in Alvarez in order to aggressively treat cancer over a longer period of time. Further, through routine optimization, it is obvious to optimize the rest period in the method of treating cancer comprised of administering 10 µg/kg of ALKS 4230 by Sun and NCT to include a rest period of a week or month as taught in Alvarez. MPEP 2144.05 states "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." Regarding claim 111, it would be obvious that repeated treatment cycle will be administered to a patient if the cancer reoccurs, because Sun teaches treating aggressive cancer comprised of administering 10 µg/kg per day of ALKS 4230. One of ordinary skill in the art before the effective filing date would have had a reasonable expectation of success to form a method of treating cancer, including reoccurring cancer, comprised of administering 10 µg/kg/day of ALKS 4230 for one treatment cycle with a rest period of weekly or monthly, administering 10 µg/kg/day of ALKS 4230 for a second treatment cycle, because the combined teachings of Sun and NCT teaches two treatment cycle with a rest period, and Alvarez teaches that the rest period between treatment with a fusion protein of weekly or monthly.
Regarding claims 73-75, through routine optimization, one of ordinary skill in the art before the effective filing date would have been motivated to modify the treatment cycle of administering 10 µg/kg of ALKS 4230 by Sun and NCT once a day for 5 days, to administering a higher dose once weekly as taught in Alvarez, including a higher dose, including about 50 µg/kg once weekly in order to simplify the treatment regimen. Sun teaches the preferred pharmacokinetics of ALKS 4230 and Alvarez teaches a dosage range for administration of fusion proteins and a single human dose of 162 µg/kg of ALKS 4230 with an Fc domain. MPEP 2144.05 states "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." Regarding claim 75, administering 50 µg/kg weekly of ALKS 4230 to treat a solid tumor of Sun, NCT, and Alvarez will necessarily increase circulating NK cells in the absence of increasing circulating Tregs, because Sun teaches the pharmacokinetics of ALKS 4230 that will lead to such a phenotype. One of ordinary skill in the art before the effective filing date would have had a reasonable expectation of success through routine optimization to arrive form a method of treating cancer comprised of administering ALKS 4230 at a dose 50 µg/kg once weekly, because 50 µg/kg is within the dosage range taught by Alvarez and Sun teaches the preferred pharmacokinetics.
Claim 34, 125, and 126 are rejected under 35 U.S.C. 103 as being unpatentable over Sun et al. (Cancer Research, 1 July 2017; 77 (13_Supplement): 4088, IDS entered July 6, 2022). NCT02799095 (published February 2, 2018, of record) and Alvares (US2016/0175458, IDS entered on July 6, 2022) as evidenced by Fardis (WO2022076952) and Nair et al. (J. Basic Clin Pharm, 2016, 7:27-31) as applied to claim 1 above, and further in view of Losey et al. (Cancer Res 1 July 2017; 77 (13_Supplement): 591, IDS entered on July 6, 2022).
The teaching of Sun, NCT, and Alvares are described above.
The combined teachings of Sun, NCT, and Alvares do not teach furthering administering an anti-PD1 antibody. However, these deficiencies are made up in Losey.
Losey teaches a method of treating cancer comprised of administering ALKS 4230 in combination with an anti-PD-1 antibodies (abstract). Losey teaches that anti-PD-1 antibody treatment enhances the ability of ALKS 4230 to inhibit tumor growth and survival (next to the last sentence). Losey further teaches that a clinical trial testing the effectiveness of ALKS 4230 with a checkpoint inhibitor for treating cancer (last two sentences).
One of ordinary skill in the art before the effective filing date would have been motivated to combine the method of treating cancer comprised of administering 10 µg/kg/day of ALKS 4230 with a rest period of a month followed by a second course of treatment comprised of administering 10 µg/kg/day of ALKS 4230 of Sun, NCT, and Alvarez, with the method treating cancer comprised of further administering an anti-PD1 antibody with ALKS 4230 as taught in Losey in order to more aggressively and effectively inhibit tumor growth and survival. The combined teachings of Sun, NCT, and Alvarez teaches a method of treating cancer comprised of administering 10 µg/kg/day ALKS 4230 for 5 days with a rest period of a month followed by a second course of treatment comprised of administering 10 µg/kg/day of ALKS 4230 for 5 days, and Losey teaches that combining ALKS 4230 with anti-PD1 is more effective at inhibiting tumor growth and ALKS 4230 alone. One of ordinary skill in the art before the effective filing date would have had a reasonable expectation of success for combing the methods of Sun and NCT, with Losey to form a method of treating cancer comprised of administering 10 µg/kg/day of ALKS 4230 for 5 days with a rest period of a month 9 followed by a second course of treatment comprised of administering 10 µg/kg/day of ALKS 4230 for 5 days, to include an anti-PD1 antibody, because Losey has shown that anti-PD1 treatment enhances the anti-tumor effects of ALKS 4230.
Claim 39, 125-129 are rejected under 35 U.S.C. 103 as being unpatentable over Sun et al. (Cancer Research, 1 July 2017; 77 (13_Supplement): 4088, IDS entered July 6, 2022). NCT02799095 (published February 2, 2018, of record) and Alvares (US2016/0175458, IDS entered on July 6, 2022) as evidenced by Fardis (WO2022076952) as applied to claim 1 and 34 above, and further in view of Freshwater (Journal for ImmunoTherapy of Cancer, 2017, 5:43, pages 1-9).
The combined teachings of Sun, NCT, Alvarez, and Losey are described above.
The combined teachings of Sun, NCT, Alvarez, and Losey do not teach that the PD-1 antibody that is administered in the combination treatment is pembrolizumab, wherein pembrolizumab is administered during the first cycle and second cycle of ALKS 4230 treatment. However, this deficiency is made up in Freshwater.
Freshwater teaches that pembrolizumab is a PD-1 antibody that is high affective at treating a variety of cancers (page 2, see “background”). Freshwater teaches that 200 mg of pembrolizumab is an effective flat dose (abstract; figure 1).
Buchbinder teaches that pembrolizumab is an FDA approved PD-1 antibody (page 1, right column, 1st paragraph). Buchbinder teaches administration of IL-2 prior to and following PD-1 treatment (page 2, see “Patients”).
One of ordinary skill in the art before the effective filing date would have been motivated to use 200 mg pembrolizumab of Freshwater as the anti-PD-1 antibody in the method of treating cancer comprised of administering 10 µg/kg/day of ALKS 4230 with an anti-PD1 antibody of Sun, NCT, Alvarez, and Losey. Buccbiner teaches that pembrolizumab is an FDA approved PD-1 antibody that has been studied with IL-2 treatment. Further, through routine optimization, it would be obvious to administer pembrolizumab with ALKS 4230 during the first and second cycle of treatment. One of ordinary skill in the art before the effective filing date would have had a reasonable expectation of success for using 200 mg pembrolizumab of Freshwater as the anti-PD-1 antibody in the method of treating cancer of Sun, NCT, Alvarez and Losey to form a method of treating cancer comprised of administering 10 µg/kg/day of ALKS 4230 for 5 days with a rest period of a month 9 followed by a second course of treatment comprised of administering 10 µg/kg/day of ALKS 4230 for 5 days, wherein 200 mg pembrolizumab is administered with ALKS 4230 during the first course and second course of treatment, because Freshwater teaches that pembrolizumab is an effective anti-PD1 antibody for treating a variety of cancer.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 2, 3, 11, 24, 34, 39, 73-75, 78, 85-86, 97, 102, 104-105, 107-133 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11246906B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
Patented claims are directed to a method of treating cancer in a patient, including a solid cancer (claim 4), comprised of administering subcutaneously administering to the patient a dose of a fusion protein of SEQ ID NO:1 (same as instant SEQ ID NO:1) a periodic dosing is once every about 3 days to once every about 60 days, wherein the dose is administered every 3 or 21 days; and/or the dose is about 0.1 mgs to about 30 mgs or 1µg/kg to about 500 µg/kg of the fusion protein of SEQ ID NO: 1 or a corresponding fixed dose based on an about 60 to about 70 kg adult or based on an about 12 kg to about 50 kg or more child (claim 1). Thus, the patented method has a resting period of 7 days, 14 days, or 21 days. Regarding claims 3, 75, 102, and 104, the patented claims further states that the method results in a greater increase in circulating CD8+ T cells in the patient as compared to daily subcutaneous administration, optionally wherein: the increase in circulating CD8+ T cells in the patient is at least 2-fold over baseline; the ratio of increase of CD8+ T cells in the patient is greater than the ratio of increase in to CD4+ T regulatory cells (Tregs); and/or the ratio of increase in circulating CD8+ cells in the patient is greater than the ratio of increase in circulating CD4+ Treg cells (claims 1 and 3). Patented claimed method requires that the 200 mg of pembrolizumab is administered on the first day of treatment with the fusion protein comprising SEQ ID NO:1 and every week or once every three weeks (claims 6-10).
Claims 1, 2, 3, 11, 24, 34, 39, 73-75, 78, 85-86, 97, 102, 104-105, 107-133 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-48 of U.S. Patent No. 11980652B2. Although the claims at issue are not identical, they are not patentably distinct from each other because they are not patentably distinct from each other.
Patented claims are directed to a method of treating cancer in a patient, including a solid cancer (claim 4), comprised of administering subcutaneously administering to the patient a dose of a fusion protein of SEQ ID NO: 1 (same as instant SEQ ID NO:1) a periodic dosing is once every about 3 days to once every about 60 days, wherein the dose is administered every 7 days, once every 14 days or once every 21 days; and/or the dose is about 0.1 mgs to about 30 mgs of the fusion protein of SEQ ID NO: 1 (claim 22-24) or 1µg/kg to about 500 µg/kg (claim 25), or a corresponding fixed dose based on an about 60 to about 70 kg adult or based on an about 12 kg to about 50 kg or more child (claim 26). Thus, the patented method has a resting period of 7 days, 14 days, or 21 days. Regarding claims 3, 75, 104, and 102, ‘451 teaches that administration of the fusion protein comprising SEQ ID NO:1 results in a greater increase in circulating CD8+ T cells in the patient as compared to daily subcutaneous administration, optionally wherein: the increase in circulating CD8+ T cells in the patient is at least 2-fold over baseline; the ratio of increase of CD8+ T cells in the patient is greater than the ratio of increase in to CD4+ T regulatory cells (Tregs); and/or the ratio of increase in circulating CD8+ cells in the patient is greater than the ratio of increase in circulating CD4+ Treg cells (claim 7). The patented method further claims administering 200 mg of pembrolizumab on the first day of treatment with the fusion protein comprising SEQ ID NO:1 and every week or once every three weeks (claims 43-58).
Claims 1, 2, 3, 11, 16, 34, 74, 75, 78, 85, 86, 97, 102, 104-106, 110-118, and 123-131 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,248,050. Although the claims at issue are not identical, they are not patentably distinct from each other because they are not patentably distinct from each other.
Regarding instant claims 1, 2, 11, 16, 34, 85, both sets of claims are drawn to a method of treating cancer comprised of administering a fusion protein comprising SEQ ID NO:1, which is the same as instant fusion protein comprising SEQ ID NO:1 and 200mg of pembrolizumab, wherein pembrolizumab is administered intravenously (claim 3), wherein fusion protein comprising SEQ ID NO:1 is intravenously administered at a dose of 10 µg/kg of the intravenously for 5 consecutive days (1, 5, 6 & 8. Regarding instant claim 78, patented claims 11-12 are directed to method of treating cancer comprised of administering 3 µg/kg/day. Regarding claims 3, 78, 104, 105, 113-116, and 131, administering 3, 10, or 14.5 µg/kg per day of a fusion protein comprising SEQ ID NO:1 to treat cancer will necessarily increase circulating NK cells and CD8+ cells 2 folds over baseline, in the absence or relative greater than the increase in Treg cells, induce a partial response, and/or improve safety profile as compared to patients receiving a high dose of recombinant IL-2, lower risk of capillary leak syndrome, and/or induce a fold change in plasma IFN[Symbol font/0x67] level of 2 folds, because the patented claims are directed to the same instant claimed method steps. Regarding claim 130, patented claim 13 teaches that the method further teaches that the 200 mg pembrolizumab is administered during the first course and second course of treatment.
Claims 1, 2, 3, 11, 24, 34, 39, 73-75, 78, 85-86, 97, 102, 104-105, and 107-133 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11945870B2. Although the claims at issue are not identical, they are not patentably distinct from each other because they are not patentably distinct from each other.
Regarding instant claims 1, 2, 11, 16, 34, 85, patented claims are drawn to a method of treating cancer, including carcinoma or breast cancer (claim 17), comprised of administering a fusion protein comprising SEQ ID NO:1, which is the same as instant fusion protein comprising SEQ ID NO:1 and 200mg of pembrolizumab, wherein pembrolizumab is administered intravenously (claims 5, and 7), wherein the fusion protein comprising SEQ ID NO:1 is intravenously administered at a dose of 3 µg/kg, 10 µg/kg, 15 µg/kg per day for 5 consecutive days (claims 1, 6 & 8) or every week (same as a rest period of 7 days), or every two weeks (same rest period of 14 days), or every three weeks (same as rest period of 21 days). Patented claims 10-11 further claimed that the method further teaches that the 200 mg pembrolizumab is administered during the first course and second course of treatment. Regarding instant claims 3, 78, 104, 105, 113-116, and 131, administering 3, 10, or 15 µg/kg per day of a fusion protein comprising SEQ ID NO:1 to treat cancer will necessarily increase circulating NK cells and CD8+ cells 2 folds over baseline, in the absence or relative greater than the increase in Treg cells, induce a partial response, and/or improve safety profile as compared to patients receiving a high dose of recombinant IL-2, lower risk of capillary leak syndrome, and/or induce a fold change in plasma IFN[Symbol font/0x67] level of 2 folds, because the patented claims are directed to the same instant claimed method steps. Regarding claim 130, patented method further comprises administering 200 mg pembrolizumab during the first course and second course of treatment (claim 13).
Claims 1, 2, 3, 11, 24, 34, 39, 73-75, 78, 85-86, 97, 102, 104-105, and 107-133 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim over claims 1, 4, 6, 10, 14-16, 18, 23-29, 31 and 33-36 of copending Application No. 18660534 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Both the copending claims and the instant claims are directed to a method of treating cancer, including renal cell carcinoma, comprised of administering a 1 µg/kg-500 µg/kg of a fusion protein comprising SEQ ID NO:1 (same as instant SEQ ID NO:1) with a periodic dosing of every 3 days to about every 60 days (same as resting period) (claims 1, 6, and 10). The copending methods further comprises intravenous administering 200 mg of pembrolizumab every week to every 3 weeks, wherein pembrolizumab is administered simultaneously or subsequence to the administration of the fusion protein comprising SEQ ID NO:1 (claim 27-29, and 31).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 2, 3, 11, 24, 34, 39, 73-75, 78, 85-86, 97, 102, 104-105, and 107-133 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim over claims 1, 2, 4-7, 11, 12, 14, 18-21, 29-31, 35 and 36 of copending Application No. 18623537 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims are directed to a method of treating platinum-resistant ovarian cancer comprised of intravenous (claim 9) administration of a fusion protein comprising SEQ ID NO:1 (same as instant SEQ ID NO:1) and a checkpoint inhibitor, including 200 mg pembrolizumab (claims 5 and 18), wherein the fusion protein is administered at a dose of 6 µg/kg , 10 µg/kg or 14.5 µg/kg (claim 11) and checkpoint inhibitors are administered at the same time or sequentially (claims 1 and 21). The copending claims claimed that pembrolizumab is administered to the patient once every 3 weeks (claim 20). The copending claims claimed that the fusion protein comprising SEQ ID NO:1 is administered intravenously at a dose of 6 µg/kg for 5 days, every 3 weeks (same as a rest period of 21 days), and pembrolizumab is administered intravenously at a dose of 200 mg every 3 weeks. Regarding instant claims 3, 78, 104, 105, 113-116, and 131, administering 6, 10, or 15 µg/kg per day of a fusion protein comprising SEQ ID NO:1 to treat cancer will necessarily increase circulating NK cells and CD8+ cells 2 folds over baseline, in the absence or relative greater than the increase in Treg cells, induce a partial response, and/or improve safety profile as compared to patients receiving a high dose of recombinant IL-2, lower risk of capillary leak syndrome, and/or induce a fold change in plasma IFN[Symbol font/0x67] level of 2 folds, because the patented claims are directed to the same instant claimed method steps.
Claims 16 and 106 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-58 of U.S. Patent No. 11980652 as applied to claim 1 above, and further in view of NCT02799095 (published February 2, 2018, of record).
The patented claims are described above.
The patented claims are not directed to intravenous administration of the fusion protein.
The teachings of NCI are described above.
One of ordinary skill in the art before the effective filing date would have the method of treating cancer comprised of subcutaneous administration of the fusion protein comprising SEQ ID NO:1 to include intravenous administration of NCT in order to have a method with more flexibility on the administration of the fusion protein comprising SEQ ID NO:1. The patented claims are directed to a method of treating cancer comprised of administering a fusion protein comprising SEQ ID NO:1. NCT teaches that the fusion protein comprising can be administered intravenously. One of ordinary skill in the art before the effective filing date would have had a reasonable expectation of success for treating a solid tumor, comprised of intravenous administration of a fusion protein comprising SEQ ID NO:1, because NCT teaches intravenous administration of SEQ ID NO:1 to treat cancer.
Claims 1, 2, 3, 11, 16, 24, 34, 73-75, 78, 85, 86, 97, 102-105-110-124, 125, and 131-133 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-16 of U.S. Patent No. 11945870B2 in view of Sun et al. (Cancer Research, 1 July 2017; 77 (13_Supplement): 4088, IDS entered July 6, 2022). NCT02799095 (published February 2, 2018, of record) and Alvares (US2016/0175458, IDS entered on July 6, 2022) as evidenced by Fardis (WO2022076952) and Nair et al. (J. Basic Clin Pharm, 2016, 7:27-31).
Patented claims are directed to a method of treating cancer comprised of intravenous (claim 3) administering a fusion protein comprising SEQ ID NO:1 (same as instant SEQ ID NO:1 and ALK4230) and Lenvatinib (same as a therapeutic agent of instant claim 34 or cytotoxic agent of instant claim 125) (claims 1-3). Patented claims claimed that said method will result in no increase in CD4+ Tregs cells or conventional CD4+ T cells (claims 9-11), it will increase CD8+ T cells and dendritic cells in tumors and decrease of tumor associated macrophages , greater expression of genes associated with cytotoxic function (claims 10 and 12).
Patented claimed method is silent on the dose and treatment cycle for the fusion protein comprising SEQ ID NO:1. However, these deficiencies are made up in Sun, NCI, and Alares.
The teachings of Sun are described above.
The teachings of NCI are described above.
The teachings of Alvares are described above.
One of ordinary skill in the art before the effective filing date would have modify the patented method of treating comprised of administering a fusion comprising SEQ ID NO:1 (same as ALKS 4230) and Lenvatinib, to have a dose cycle of administering 3 µg/kg per day, 10 µg/kg per day, or 30 µg/kg per day ALKS 4230 every day for five days of Sun and NCT, to have include a second or third treatment cycle with a rest period of a week (same as “at least about 9 days”) or month (same as “at least about 16 days”) prior to the start of the second treatment cycle as taught in Alvarez in order to aggressively treat cancer over a longer period of time. Sun teaches administration of 3 µg/kg per day, 10 µg/kg per day, or 30 µg/kg per day ALKS 4230 results in preferred pharmacological profiles, NCT is a phase I clinical trial for treating cancer comprised of intravenous infusion of ALKS 4230 is administered per day for 5 days and at least two treatment cycles, and Alvares teaches a rest period of a week or a month between treatment cycle for fusion proteins. One of ordinary skill in the art before the effective filing date would have had a reasonable expectation of success for treating cancer, including reoccurring cancer, comprised of administering Lenvatinib and 3, 10, or 30 µg/kg per day of ALKS 4230 for five days, a rest period of a week or month, prior to a second cycle or third cycle, because Sun discloses the dosages of ALKS 4230 that will give a circulating dose to achieve clinical outcomes, and NCT teaches a phase I clinical trial for ALKS 4230 that is administered each day for 5 days, and Alvares teaches a rest period of a week or a month between treatment cycle for fusion proteins.
Regarding claims 73-75, through routine optimization, one of ordinary skill in the art before the effective filing date would have been motivated to modify the treatment cycle of administering ALKS 4230 to include a higher dose, including about 50 µg/kg once weekly in order to simplify the treatment regimen. Sun teaches the preferred pharmacokinetics of ALKS 4230 and Alvarez teaches a dosage range for administration of fusion proteins and a single human dose of 162 µg/kg of ALKS 4230 with an Fc domain. MPEP 2144.05 states "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." One of ordinary skill in the art before the effective filing date would have had a reasonable expectation of success through routine optimization to arrive form a method of treating cancer comprised of administering ALKS 4230 at a dose 50 µg/kg once weekly, because 50 µg/kg is within the dosage range taught by Alvarez and Sun teaches the preferred pharmacokinetics.
Conclusion
No claims allowed.
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/JULIE WU/ Supervisory Patent Examiner, Art Unit 1643