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. The Election filed July 21, 2026, in response to the Office Action of April 21, 2026, is acknowledged and has been entered. Applicants elected without traverse Group I and the species of:
A. PD-L1 antibody comprising CDR SEQ ID NOs:3-8 (atezolizumab); and
B. method further administering a taxane.
Claims 1, 2, 30, 31, 44, 47-49, 55, 58, 59, 62, 63, 69, 70, 78, 79, 84, 85, and 114 are now pending and examined as drawn to the elected species.
Specification
2. The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. Examiner suggests a title relevant to the claimed invention of treatment of HLA-C1 positive NSCLC with a PD-1 axis binding antagonist.
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.
3. Claims 44, 47, and 59 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 44 recites the limitation "the benefit". There is insufficient antecedent basis for this limitation in the claim. Claim 47 is rejected for encompassing the rejected limitation of claim 44.
Claim 59 recites the limitation "the VL". There is insufficient antecedent basis for this limitation in the claim.
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.
4. Claim(s) 1, 30, 44, 47-49, 55, 69, 70, 78, and 79 are rejected under 35 U.S.C. 103 as being unpatentable over Socinski et al (J Clinical Oncology, 2018, 36:9002); in view of Wisniewski et al (Human Immunology, 2012, 73:927-931); Chowell et al (Science, 2018, 359:582-587); and Omar et al (Immunology, 2011, 133:94-104).
Socinski teaches treating NSCLC patients by administering atezolizumab, carboplatin, and paclitaxel that resulted in significant overall survival benefit compared to therapy lacking atezolizumab, regardless of HLA-C genotype. Socinski teaches the treatment was first line (1L) therapy in non-squamous NSCLC patients, some with metastases (Background; Table). Socinski teaches the treatment regimen comprises atezolizumab 1200 mg + carboplatin AUC 6 + paclitaxel 200 mg/m2 (Arm A), or atezolizumab 1200 mg + carboplatin AUC 6 + paclitaxel 200 mg/m2 + bevacizumab 15 mg/kg (Arm B), each regimen administered intravenously (IV) on Day 1 of each 21 day cycle (q3w) for 4-6 cycles (Background).
Socinski does not teach treating NSCLC patients determined to comprise at least one copy of HLA-C1 (claim 1) and that HLA-C1 was detected by PCR-based assay (claim 30).
Wisniewski teaches a method of treating NSCLC in a patient whose genome has been determined to comprise at least one copy of HLA-C1, the method comprising administering to the patient an effective amount of chemotherapy (Figure 1; Table 1; section 2.1); wherein patients comprising HLA-C1 were 6 times more likely to respond to treatment than other genotypes and survived longer (abstract; Figure 1 and 2; p. 929, col. 1-2). HLA-C1 genotype was determined by PCR-based assay (section 2.2).
Chowell teaches NSCLC patients having heterozygosity of HLA class I A, B, and C genotypes (i.e., including patients having at least 1 HLA-C copy) are more likely to respond to immune checkpoint blockade therapy including anti-PD-1/PD-L1 antibody therapy than patients homozygous for HLA class I genotypes, and had significantly improved overall survival (abstract; Figure 1).
Omar teaches NSCLC patients commonly comprise at least one copy of HLA-C1 as well as CD158b (KIR2DL2/3) (abstract; Figure 1 and 2). Omar determined HLA-C1 genotype by PCR-based assay (p. 96, col. 2, “HLA typing”).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was effectively filed to include NSCLC patients determined to have at least one copy of HLA-C1 by PCR-based assay in the NSCLC population treated by Socinski. One would have been motivated to, and have a reasonable expectation of success to because: (1) Socinski demonstrates NSCLC patients treated with atezolizumab (anti-PD-L1 antibody) + carboplatin + paclitaxel had significantly improved overall survival response as compared to patients treated without atezolizumab regardless of their HLA-C1 status; (2) Wisniewski and Omar demonstrate that NSCLC patients commonly comprise and express HLA-C1 genotype, as determined by PCR-based assay, and are in need of treatment; (3) Wisniewski demonstrate that NSCLC patients expressing HLA-C1 have significantly improved overall survival and treatment response to chemotherapy than other genotypes; and (4) Chowell demonstrates that NSCLC patients having at least one HLA-C genotype in a heterozygous HLA setting respond significantly better to immune checkpoint therapy comprising PD-1/PD-L1 inhibiting antibody and have improved survival compared to patients homozygous for the other genotypes.
Given: (1) all the cited prior art recognize the need to treat NSCLC patients, (2) the cited prior art recognizes that the NSCLC patient population commonly comprises at least one copy of HLA-C1; and (3) the cited prior art demonstrates the significant benefits of adding atezolizumab to chemotherapy treatment regimen for NSCLC patients, and benefits of treating patients comprising at least one copy of HLA-C1; it is well within the level of the ordinary skilled artisan to include NSCLC patients determined to comprise at least one copy of HLA-C1 in the method of Socinski, and to predictably and successfully treat NSCLC and significantly improve their overall survival.
5. Claim(s) 2 is rejected under 35 U.S.C. 103 as being unpatentable over Socinski et al (J Clinical Oncology, 2018, 36:9002); Wisniewski et al (Human Immunology, 2012, 73:927-931); Chowell et al (Science, 2018, 359:582-587); and Omar et al (Immunology, 2011, 133:94-104); as applied to claims 1, 30, 44, 47-49, 55, 69, 70, 78, and 79 above, and further in view of Creelan (Cancer Control, 2014, 21:80-89).
Socinski, Wisniewski, Chowell, and Omar (the combined references) teach a method for treating NSCLC in a patient determined to comprise at least one copy of HLA-C1, by administering a treatment regimen comprising atezolizumab as set forth above.
The combined references do not teach the NSCLC patient genome additionally comprises at least one copy of KIR2DL3.
As stated above, Omar teaches NSCLC patients commonly comprise at least one copy of HLA-C1 as well as CD158b (KIR2DL2/3) (abstract; Figure 1 and 2).
Wisniewski additionally teaches “Virtually all people possess KIR2DL2 and/or KIR2DL3 receptors which react with C1 epitope of HLA-C molecules” (Discussion section 4).
Creelan also teaches it is known that KIR2DL3 is the NK receptor for HLA-C1 ligand. Creelan teaches (p. 85, col. 2 at top) that: “the less suppressive KIR2DL3 phenotype is correlated with better response to treatment and more favorable survival in NSCLC.”
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was effectively filed to include NSCLC patients determined to have at least one copy of KIR2DL3 with at least one copy of HLA-C1 in the method of treatment taught by the combined references. One would have been motivated to, and have a reasonable expectation of success to because: (1) the cited prior art recognize that NSCLC patients are in need of treatment; (2) Omar, Wisniewski, and Creelan teach it is known that nearly everyone and NSCLC patients commonly comprise least one copy of KIR2DL3; and (3) Creelan teaches it is known that KIR2DL3 is the NK receptor for HLA-C1 ligand, and KIR2DL3 is the most desirable KIR to express in NSCLC because it is the least immune-suppressive KIR phenotype, and is correlated with better response to treatment and more favorable survival in NSCLC.
6. Claim(s) 58, 59, 62, and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Socinski et al (J Clinical Oncology, 2018, 36:9002); Wisniewski et al (Human Immunology, 2012, 73:927-931); Chowell et al (Science, 2018, 359:582-587); and Omar et al (Immunology, 2011, 133:94-104); as applied to claims 1, 30, 44, 47-49, 55, 69, 70, 78, and 79 above, and further in view of WO 2019/035939, Chang et al.
Socinski, Wisniewski, Chowell, and Omar (the combined references) teach a method for treating NSCLC in a patient determined to comprise at least one copy of HLA-C1, by administering a treatment regimen comprising atezolizumab intravenously administered every 3 weeks at 1200 mg as set forth above.
The combined references do not teach the CDR, VH, and VL sequences of atezolizumab.
Chang teaches known PD-L1 antibodies for the treatment of cancers, including NSCLC, including atezolizumab and discloses the known sequences of atezolizumab as comprising VH SEQ ID NO:175 and VL SEQ ID NO:179 ([62]; [73]; [224]) that comprise 100% of the instantly claimed CDRs, VH, and VL sequences instantly claimed (see sequence alignments below).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was effectively filed to administer a PD-L1 antibody comprising the instantly claimed sequences in the method of the combined references. One would have been motivated to and have a reasonable expectation of success to, because: (1) the combined references teach and demonstrate the success of treating NSCLC by the addition of anti-PD-L1 atezolizumab to treatment regimens; and (2) Chang teaches the VH and VL sequences of atezolizumab are publicly known.
Instant VH SEQ ID NO:9 aligned with WO 2019035939 atezolizumab VH SEQ ID NO:175:
RESULT 2
BGC31575
(NOTE: this sequence has 1 duplicate in the database searched.
See complete list at the end of this report)
ID BGC31575 standard; protein; 119 AA.
XX
AC BGC31575;
XX
DT 04-APR-2019 (first entry)
XX
DE Anti-PD-L1 antibody (atezolizumab) heavy chain variable region, SEQ 175.
XX
KW Atezolizumab; B7 homolog 1; B7-H1; CD274 protein; PD-L1 protein;
KW PDCD1 ligand 1; PDCD1L1 protein; PDCD1LG1 protein;
KW Programmed cell death 1 ligand 1; Programmed death ligand 1; antibody;
KW antibody therapy; cancer; cell death; cytostatic;
KW heavy chain variable region; prophylactic to disease; therapeutic.
XX
OS Unidentified.
XX
CC PN WO2019035939-A1.
XX
CC PD 21-FEB-2019.
XX
CC PF 16-AUG-2018; 2018WO-US000212.
XX
PR 16-AUG-2017; 2017US-0546297P.
PR 16-AUG-2017; 2017US-0546300P.
PR 30-AUG-2017; 2017US-0552152P.
PR 07-SEP-2017; 2017US-0555114P.
XX
CC PA (DRAG-) DRAGONFLY THERAPEUTICS INC.
XX
CC PI Chang GP, Cheung AF, Du J, Grinberg A, Haney W, Sethi DK;
CC PI Wagtmann N, Lunde BM, Prinz B;
XX
DR WPI; 2019-185715/18.
XX
CC PT Protein comprises first antigen-binding site that binds NKG2D, second
CC PT antigen-binding site that binds epidermal growth factor receptor, human
CC PT leukocyte antigen-E , C-C chemokine receptor type 4 and antibody Fc
CC PT domain.
XX
CC PS Claim 58; SEQ ID NO 175; 125pp; English.
XX
CC The present invention relates to a novel protein comprising an amino acid
CC sequence selected from SEQ ID NO: 264-269 (see BGC31664-BGC31669). The
CC protein comprises a first antigen-binding site that binds to a NKG2D
CC protein, a second antigen-binding site that binds to a protein selected
CC from an epidermal growth factor receptor (EGFR), a HLA-E, a C-C chemokine
CC receptor type 4 (CCR4) or a programmed cell death 1 ligand 1 (PD-L1) and
CC an antibody Fc domain or a portion thereof sufficient to bind a CD16
CC protein or a third antigen-binding site that binds to the CD16 protein.
CC The first antigen-binding site and the second antigen-binding site
CC comprises a heavy chain variable domain and a light chain variable
CC domain. The invention further claims: (1) a formulation comprising the
CC protein and a pharmaceutically acceptable carrier; (2) a cell comprising
CC one or more nucleic acids expressing the protein; (3) a method for
CC enhancing tumor cell death; and (4) a method for treating cancer. The
CC protein of the present invention can be used in a pharmaceutical
CC composition for preventing and treating cancer. The present sequence
CC represents an anti-PD-L1 antibody (atezolizumab) heavy chain variable
CC region, where the antibody can be used for preparing the protein of the
CC present invention capable of treating cancer.
XX
SQ Sequence 119 AA;
Query Match 100.0%; Score 644; Length 119;
Best Local Similarity 100.0%;
Matches 118; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYY 60
Qy 61 ADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS 118
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS 118
Instant VL SEQ ID NO:10 aligned with WO 2019035939 atezolizumab VL SEQ ID NO:179:
BGC31579
ID BGC31579 standard; protein; 108 AA.
XX
AC BGC31579;
XX
DT 04-APR-2019 (first entry)
XX
DE Anti-PD-L1 antibody (atezolizumab) light chain variable region, SEQ 179.
XX
KW Atezolizumab; B7 homolog 1; B7-H1; CD274 protein; PD-L1 protein;
KW PDCD1 ligand 1; PDCD1L1 protein; PDCD1LG1 protein;
KW Programmed cell death 1 ligand 1; Programmed death ligand 1; antibody;
KW antibody therapy; cancer; cell death; cytostatic;
KW light chain variable region; prophylactic to disease; therapeutic.
XX
OS Unidentified.
XX
CC PN WO2019035939-A1.
XX
CC PD 21-FEB-2019.
XX
CC PF 16-AUG-2018; 2018WO-US000212.
XX
PR 16-AUG-2017; 2017US-0546297P.
PR 16-AUG-2017; 2017US-0546300P.
PR 30-AUG-2017; 2017US-0552152P.
PR 07-SEP-2017; 2017US-0555114P.
XX
CC PA (DRAG-) DRAGONFLY THERAPEUTICS INC.
XX
CC PI Chang GP, Cheung AF, Du J, Grinberg A, Haney W, Sethi DK;
CC PI Wagtmann N, Lunde BM, Prinz B;
XX
DR WPI; 2019-185715/18.
XX
CC PT Protein comprises first antigen-binding site that binds NKG2D, second
CC PT antigen-binding site that binds epidermal growth factor receptor, human
CC PT leukocyte antigen-E , C-C chemokine receptor type 4 and antibody Fc
CC PT domain.
XX
CC PS Claim 58; SEQ ID NO 179; 125pp; English.
XX
CC The present invention relates to a novel protein comprising an amino acid
CC sequence selected from SEQ ID NO: 264-269 (see BGC31664-BGC31669). The
CC protein comprises a first antigen-binding site that binds to a NKG2D
CC protein, a second antigen-binding site that binds to a protein selected
CC from an epidermal growth factor receptor (EGFR), a HLA-E, a C-C chemokine
CC receptor type 4 (CCR4) or a programmed cell death 1 ligand 1 (PD-L1) and
CC an antibody Fc domain or a portion thereof sufficient to bind a CD16
CC protein or a third antigen-binding site that binds to the CD16 protein.
CC The first antigen-binding site and the second antigen-binding site
CC comprises a heavy chain variable domain and a light chain variable
CC domain. The invention further claims: (1) a formulation comprising the
CC protein and a pharmaceutically acceptable carrier; (2) a cell comprising
CC one or more nucleic acids expressing the protein; (3) a method for
CC enhancing tumor cell death; and (4) a method for treating cancer. The
CC protein of the present invention can be used in a pharmaceutical
CC composition for preventing and treating cancer. The present sequence
CC represents an anti-PD-L1 antibody (atezolizumab) light chain variable
CC region, where the antibody can be used for preparing the protein of the
CC present invention capable of treating cancer.
XX
SQ Sequence 108 AA;
ALIGNMENT:
Query Match 100.0%; Score 559; Length 108;
Best Local Similarity 100.0%;
Matches 108; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR 108
||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR 108
7. Claim(s) 31 and 114 are rejected under 35 U.S.C. 103 as being unpatentable over Socinski et al (J Clinical Oncology, 2018, 36:9002); Wisniewski et al (Human Immunology, 2012, 73:927-931); Chowell et al (Science, 2018, 359:582-587); and Omar et al (Immunology, 2011, 133:94-104); as applied to claims 1, 30, 44, 47-49, 55, 69, 70, 78, and 79 above, and further in view of Gao et al (HLA. 2018; 91:539-541).
Socinski, Wisniewski, Chowell, and Omar (the combined references) teach a method for treating NSCLC in a patient determined to comprise at least one copy of HLA-C1, by administering a treatment regimen comprising atezolizumab as set forth above.
The combined references do not teach the HLA-C1 was determined using next-generation sequencing comprising germline whole-genome sequencing comprising fragmenting a DNA sample from the patient, adding adapters to the fragmented DNA to produce one or more libraries, and sequencing the one or more libraries.
Gao teaches and successfully demonstrate methods of identifying HLA-C1 genotype in an individual by extracting DNA from a biological sample, full length genomic sequencing of HLA allele, fragmenting DNA, adapter ligation, indexing polymerase chain reaction (PCR) with next generation sequencing, and data analysis, all carried our using commercially available kits, reagents, and software (see entire paper and Figure 1).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was effectively filed to utilize the sequencing methods of Gao to determine the NSCLC patient comprises at least one HLA-C1 copy in the method of the combined references. One would have been motivated to and have a reasonable expectation of success to because: (1) the combined references teach determining the HLA-C1 status of an NSCLC human patient; and (2) Gao teaches known methods and commercially available kits and software for successfully determining the HLA-C1 status of a human individual.
8. Claim(s) 84 and 85 are rejected under 35 U.S.C. 103 as being unpatentable over Socinski et al (J Clinical Oncology, 2018, 36:9002); Wisniewski et al (Human Immunology, 2012, 73:927-931); Chowell et al (Science, 2018, 359:582-587); and Omar et al (Immunology, 2011, 133:94-104); as applied to claims 1, 30, 44, 47-49, 55, 69, 70, 78, and 79 above, and further in view of “Socinski II” (Annals of Oncology, 2018, Vol. 29, Supp 8; viii750-viii751, abstract LBA65); and Jotte et al (Journal of Thoracic Oncology, Vol. 15, No. 8; p. 1351-1360; online April 14, 2020).
Socinski, Wisniewski, Chowell, and Omar (the combined references) teach a method for treating non-squamous NSCLC in a patient determined to comprise at least one copy of HLA-C1, by administering a treatment regimen comprising atezolizumab as set forth above.
The combined references do not teach treating squamous NSCLC and at the dose/regimen of instant claim 85.
Socinski II teaches Impower131 clinical study comprising a method of treating advanced/metastatic squamous cell NSCLC patients by administering atezolizumab 1200 mg q3w + carboplatin AUC 6 q3w + paclitaxel 200 mg/m2 q3w (Arm A), or administering atezolizumab 1200 mg q3w + carboplatin AUC 6 q3w + nab-paclitaxel 100 mg/m2 q3w (Arm B) for 4-6 cycles. Interim analysis demonstrated improved PFS in Arm B versus patients treated without atezolizumab.
Jotte teaches Impower131 clinical study comprising a method of treating advanced/metastatic squamous cell NSCLC patients by administering atezolizumab 1200 mg IV Day 1 of 21-day cycle + carboplatin AUC 6 mg/ml/min IV Day 1 of 21-day cycle + either paclitaxel 200 mg/m2 IV or 175 mg/m2 IV on Day 1 of 21-day cycle, or nab-paclitaxel 100 mg/m2 IV Days 1, 8, and 15 of each 21-day cycle. (p. 1353, col. 1, first paragraph). Jotte teaches adding atezolizumab to platinum-based chemotherapy significantly improved PFS in patients with first-line squamous NSCLC (Conclusion, p. 1352).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was effectively filed to include squamous NSCLC in the NSCLC patient population treated in the method of the combined references. One would have been motivated to, and have a reasonable expectation of success to because: (1) The cited combined references teach the success for the therapeutic regimen comprising atezolizumab for treating non-squamous NSCLC patients, significantly improving overall survival compared to regimens lacking ateolizumab; and (2) Socinski II and Jotte demonstrate the atezolizumab treatment regimen is also successful for treating squamous NSCLC patients, significantly improving PFS compared to regimens lacking atezolizumab.
9. Conclusion: No claim is allowed.
10. 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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