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 .
Claims 1-12, 15-17, 19-22 and 45-48 are pending
Claims 7-12 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/27/2023.
Claims 1-6, 15-17, 19-22 and 45-48 are under consideration.
Rejections Maintained
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1-6, 15-17, 19-22 and 45-48 are rejected under 35 U.S.C. 103 as being unpatentable over Naito (Naito, et al., US 2016/0333112-A1; Published 11/17/2016, of record) in view of Atlas of Genetics and Cytogenetic in Oncology and Haematology (“Atlas”, article on ErBB2; Published 05/01/2011; URL: https://atlasgeneticsoncology.org/gene/162/erbb2-%28v-erb-b2-erythroblastic-leukemia-viral-oncogene-homolog-2-neuro-glioblastoma-derived-oncogene-homolog-%28avian%29%29 ; Accessed 1/8/2024, of record) and Hotta (Hotta, et al., J Thoracic Oncol. 2017 13(2):273, of record) and as evidenced by NCI (NCI et al., MedGen UID 475639 02/18/2018; URL: https://www.ncbi.nlm.nih.gov/medgen/475639 ; Accessed 1/12/2024, of record).
Naito teaches on the subject of anti-HER2 ADCs (Naito, Abstract). Regarding the structural limitations of claim 1, Naito teaches that ADC # 46 of Naito is an exact structural match for the structure of claim 1 with the antibody of the ADC being trastuzumab (Naito, ¶ 703-706). Regarding the sequence limitations of claims 16 and 17, SEQ ID NO: 1 of Naito is a 100% match for instant SEQ ID NO: 1 and SEQ ID NO: 2 of Naito is a 100% match for instant SEQ ID NO: 2 and that SEQ ID NOs: 1 and 2 correspond to the HC and LC sequences of trastuzumab, respectively (Naito, ¶ 0109). Note that Naito also teaches that the inventive ADCs are internalized following antigen binding (Naito, ¶ 0003). Regarding the DAR limitations of claim 19, Naito teaches that the inventive ADCs have a DAR between 3 and 8 (Naito, Claim 3). Regarding the cancer limitations of claims 14-15 and the dosing limitations of claims 20-21, Naito teaches that ADC #46 was tested vs the NSCLC line Calu-3 (Naito, ¶ 0742) at doses ranging from 1000 nM to 0.064 nM (same as 0.01 to 158 mg/kg) (Naito, ¶ 0747) and ADC #46 was found to inhibit these NSCLC cells with an IC50 of less than 1 nM (1 nM is around 0.158 mg/kg) (Naito, ¶ 0752). Regarding the dosing interval limitations of claim 22, Naito teaches that the inventive composition is administered at a dosing interval from 2 to 4 weeks (Naito, ¶ 0160). Regarding the metastatic limitation of claim 15, Naito teaches that the inventive ADCs are administered to suppress the growth of HER2 expressing metastatic cancer cells (Naito, ¶ 0375).
Naito does not teach a method of treating metastatic NSCLC, wherein said NSCLC comprises cells identified to have the Y772_A775Dup mutation to HER2, said method comprising administration of the ADC of Naito, having a DAR between 7.5 and 8, at a dose of 5.4 or 6.4 mg/kg administered every three weeks.
Atlas of Genetics and Cytogenetic in Oncology and Haematology (hereinafter “Atlas”) teaches that HER2 comprises an extracellular domain, a transmembrane domain and an intracellular tyrosine kinase domain (Atlas, p 2, ¶ 5). Atlas teaches that trastuzumab binds the extracellular domain of HER2 (Atlas, p 2, ¶5). Atlas also teaches the following structure for HER2, with amino acids 731-906 of the HER2 being in the intracellular tyrosine kinase domain (Atlas, p 1, Fig. 1):
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Fig. 1 of Atlas. The loci for the Y772_A775Dup mutation and the trastuzumab binding site on HER2 (Note: Arrows and red text added by examiner).
Hotta teaches a clinical trial testing the ADC trastuzumab-DM1 on HER2-expressing cancers, including cancers having HER2 exon 20 mutations (Hotta, Abstract). Hotta teaches that known HER2 mutations can be detected by direct sequencing (Hotta, p 274, ¶ 6). Hotta teaches that the clinical trial comprised 5 patients having the HER2 mutation A775_G776insYMVA (Hotta, Table 1). As evidenced by NCI, the term A775_G776insYMVA (used by Hotta) and the term Y772_A775Dup (used in the instant Application) are synonyms and both terms refer to a mutation having MedGen UID of 475639 (NCI, p 2). Note; for the sake of clarity of the record, this mutation is referred to as Y772_A772dup, as used in the instant Application. Hotta teaches that one of the Y772_A775dup patients exhibited a partial response and 3 exhibited a stable disease state, this corresponds to 80% of patients having HER2 with the Y772_A775dup mutation exhibiting a stable disease or better (Hotta, Table 3). Applying arithmetic to Hotta’s numbers in Table 3, there were a total of 3 patients with wild type HER2 that exhibited a stable disease state out of 8 HER2 wild type patients total, which amounts to 37.5% stable disease or better rate for the wild type HER2 patients, which is lower than the 80% for the Y772_A775dup HER2 mutant patients (Hotta, Table 3). The partial response observed in the one Y772_A775dup HER2 mutant was the only partial response observed in the entire clinical trial and no complete responses were observed for any patient (Hotta, Table 3).
It would be prima facie obvious to apply the teachings of Atlas and Hotta to the teachings of Naito to arrive a method of treating metastatic NSCLC, said method comprising administration of the ADC of Naito, at a DAR between 7.5 and 8, at a dose of 5.4 or 6.4 mg/kg every three weeks, wherein said metastatic NSCLC cells include NSCLC cells that have been identified to contain the Y772_A775Dup mutation to HER2. The net result of this application would be a method of treating metastatic NSCLC, said method comprising administration of the ADC of Naito, at a DAR between 7.5 and 8, at a dose of 5.4 or 6.4 mg/kg every three weeks, wherein said metastatic NSCLC cells have been identified to have the Y772_A775Dup mutation to HER2. Naito teaches that the ADCs of Naito may be used in methods of treating NSCLC, including metastatic NSCLC. Naito also teaches that the ADC of Naito was able to inhibit growth of NSCLC cells in vitro with an IC50 less than 1 nM (1 nm is about 0.158 mg/kg). The teachings of Hotta demonstrate that cancer cells comprising the Y772_A775Dup mutation to HER2 are still responsive to trastuzumab-comprising ADCs. These data support the conclusion that the Y772_A775dup mutation to exon 20 should not affect the ability of the trastuzumab of the ADC to bind to its epitope on the extracellular domain of HER2. One of ordinary skill in the art would have a reasonable expectation of success administering the ADC of Naito to treat metastatic NSCLC possessing the Y772_A775Dup on HER2 because: 1) Naito teaches that an anti-HER2 ADC that is the same as the instant claimed ADC is used in methods of treating NSCLC, 2) Naito teaches that the ADC of Naito was able to suppress NSCLC cell growth in vitro with an IC50 of 0.158 mg/kg, 3) Atlas teaches that the location of the Y772_A775Dup mutation of HER2 and the location to which trastuzumab binds are in different domains of HER2, 4) Hotta teaches that cancer cells having the Y772_A775dup mutation on HER2 are still responsive to ADCs comprising trastuzumab.
Regarding the numerical limitations of claims 18-22 including: 1) a DAR that is between 7.5 and 8, 2) an administered dose of 5.4 or 6.4 mg/g and 3) a dosing interval of administration once every three weeks, all of these values are contained within a range of values already taught by Naito. It is prima facie obvious to one of ordinary skill in the art to modify the DAR range of 3-8, the dosage range between 0.01 and 158 mg/kg and the dosing interval range of two to three weeks of Naito to arrive at the claimed values of DAR between 7.5 and 8, a dose of 5.4 or 6.4 mg/kg and a dosing interval of three weeks via routine experimentation. The use of well-known and accepted techniques such as response surface modeling would even allow optimization of all the parameters at once while minimizing the number of experiments. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F. 2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) See MPEP 2144.05. Further with respect to optimal dosing regimens, it is not inventive to discover such regimens by routine experimentation when general conditions of a claim are disclosed in the prior art. See in re Aller, 220 F.2d 545, 456, 105 USPQ 233, 235 (CCPA 1955) and MPEP § 2144.05(11).
Response to Arguments
Applicant's arguments filed 2/9/2026 have been fully considered but they are not persuasive.
Applicant begins arguing the 35 USC § 103 rejection articulated above by citing portions of the MPEP on the subject of reasonable expectation of success (MPEP § 2143.02) as well as the subject of unexpected results rebutting a prima facie case of obviousness (MPEP § 716.02(a)(II)). Applicant then points out that the Naito reference does not teach methods of treating metastatic NSCLC Applicant then argues Naito’s silence on HER2 mutated cancer means any indication of whether one of skill in the art would reasonably expect to treat HER2 mutated NSCLC or whether the high ORR achieved by the claimed invention is unexpected would have to come from the secondary art applied. Applicant again attacks the Hotta reference, citing Hotta’s list of study limitations (Hotta, p 278), pointing out that Hotta notes the study of Hotta being “small” and that the study did NOT suggest any relationship between HER2 mutation and efficacy. Applicant cites the 5-fold improvement over the Hotta reference that the instant claimed invention demonstrates (Specification, ¶ 0127; Table 1), which Applicant alleges constitute unexpected results sufficient to rebut the prima facie case of obviousness. Applicant bases this on the sheer magnitude of the ORR for the claimed invention vs Hotta.
These arguments are not persuasive for several reasons. First, the primary art being modified is Naito and not Hotta. The Hotta reference, together with the ProteinAtlas reference, was offered to explain why one of skill in the art would have a reasonable expectation of success administering the ADC of Naito to a person having NSCLC with the Y772_A775Dup mutation. As Applicant correctly noted, Naito is silent on HER2 mutations and all motivation to administer the ADC of Naito must come from the secondary art. In order for an ADC to properly function, the antibody component of the ADC must be able to specifically bind its antigen (in this case HER2) and mediate endocytosis/internalization after binding. Since Naito is silent on HER2 mutants, one of skill in the art would turn to the prior art. The ProteinAtlas reference shows that the Y772_A775Dup mutation and the trastuzumab binding site are on the opposite sides of the cell membrane. One of skill in the art would take that information and likely conclude that the mutation is unlikely to affect the ability of trastuzumab to bind HER2 mutant and mediate internalization because the two loci are sufficiently far away. The Hotta reference adds to the conclusion that the Y772_A775Dup mutation would be unlikely to affect trastuzumab’s ability to bind HER2 (mutant in this case) and mediate internalization because Hotta observed that the trastuzumab-comprising ADC of Hotta performed about as well in HER2 mutated NSCLC as it did vs wild type HER2. This, like the teachings of ProteinAtlas, would steer one of skill in the art to conclude that that the mutation is unlikely to affect the ability of trastuzumab to bind HER2 mutant and facilitate internalization because Hotta did not observe any results that would lead one to conclude the mutation affects the ability of trastuzumab to bind HER2 and mediate internalization. Taken together, ProteinAtlas and Hotta provide a person of skill in the art sufficient motivation to administer the ADC of Naito to a NSCLC having Y772_A775Dup-mutated HER2 with a reasonable expectation of success because both references support the conclusion that the Y772_A775Dup would be unlikely to affect trastuzumab binding/internalization and the ADC of Naito is a trastuzumab-comprising ADC.
Please note: detailed comparisons of clinical results from the instant claimed invention vs the clinical results from the Hotta reference do not address the rejection at hand because the ADC administered in the collective method taught by Naito, ProteinAtlas and Hotta as discussed above is the ADC of Naito, not the ADC of Hotta that is administered. If, for the sake of argument, Applicant had data showing that administering the instant claimed ADC (which is structurally identical to the ADC of Naito) to NSCLC using the instant claimed method produces unexpected, superior results compared to other methods of administering this same ADC to NSCLC patients, those data could rebut the instant prima facie case of obviousness (MPEP § 716.02).
Applicant also argues that data offered to rebut the prima facie case of obviousness are sufficiently commensurate with the scope of the instant claims it is offered to support, citing MPEP § 2145. Applicant cites Exhibit A, showing HER2 mutations in the lung are grouped into three subgroups: 1) extracellular domain, 2) kinase domain and 3) transmembrane domain. Applicant then presents Figure 3 and notes that the present specification demonstrates efficacy of the claimed NSCLC treatment in each of the three domains. Applicant argues that, although these three domains represent distinct mutation locations within HER2, the demonstrated efficacy at each site support the understanding that the claimed subject matter exhibits efficacy for any HER2 mutation.
Regarding this set of arguments, instant claim 2 is directed to 87 different mutations of HER2 and instant claim 1 is directed to any possible mutation. Figure 3 of the Specification contains data from 8 E20 mutations, two transmembrane mutations and one extracellular mutation. There simply are not enough data to be representative of the massive genera being claimed. Additionally, there is not sufficient data to show efficacy for any HER2 mutation. A hypothetical HER2 mutant where all of the epitopic contact residues have been replaced with glycine would likely fare very poorly in the clinic but is still encompassed by claim 1.
Applicant also argues, going off the argument articulated 2 paragraphs above, that one of skill in the art would not have a reasonable expectation of success applying the teachings of Hotta and ProteinAtlas as motivation to administer the ADC of Naito to a patient having the Y772_A775Dup mutation in HER2 because none of the references applied disclose diversity of efficacy with respect to specific mutation or mechanism of action of ADC drug.
In response, the only mutation relevant to the rejection above is the Y772_A775Dup and both Hotta and ProteinAtlas together provide strong evidence that no lack of efficacy should be observed when the ADC of Naito is administered for Y772_A775Dup-mutated HER2 vs wild type HER2.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6, 15-17, 19-22 and 45-48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10,155,821 B2 in view of (Naito, et al., US 2016/0333112-A1; Published 11/17/2016, of record) and Atlas of Genetics and Cytogenetic in Oncology and Haematology (“Atlas”, article on ErBB2; Published 05/01/2011; URL: https://atlasgeneticsoncology.org/gene/162/erbb2-%28v-erb-b2-erythroblastic-leukemia-viral-oncogene-homolog-2-neuro-glioblastoma-derived-oncogene-homolog-%28avian%29%29 ; Accessed 1/8/2024) and Hotta (Hotta, et al., J Thoracic Oncol. 2017 13(2):273, of record) and as evidenced by NCI (NCI et al., MedGen UID 475639 02/18/2018; URL: https://www.ncbi.nlm.nih.gov/medgen/475639 ; Accessed 1/12/2024, of record).
Regarding the structure limitations of instant claim 1, patented claim 1 is directed to an ADC that is structurally identical to the structure of instant claim 1 and is bound to an anti-HER2 antibody. Regarding the sequence limitations of claims 16-17, SEQ ID NOs: 1 and 2 of patented claims 6-8 are 100% matches for instant SEQ ID NOs: 1 and 2, respectively and correspond to the anti-HER2 antibody trastuzumab. Regarding the DAR limitations of claim 19, patented claim 3 is directed to a DAR between 3 and 8.
The ‘821 patent does not teach that the ADC of the ‘821 patent is administered in a method of treating metastatic NSCLC, wherein said NSCLC comprises cells known to have the Y772_A775Dup mutation in HER2 and wherein the ADC has a DAR between 7.5 and 8 and is administered at 5.4 or 6.4 mg/kg every three weeks.
Naito teaches on the subject of anti-HER2 ADCs (Naito, Abstract). Naito teaches that ADC # 46 of Naito is an exact structural match for the structure of the ADC of the ‘821 patent, with the antibody of the ADC being trastuzumab (Naito, ¶ 703-706). Note that Naito also teaches that the ADCs of Naito are internalized following antigen binding (Naito, ¶ 0003). Regarding the cancer limitations of claims 13-15 and the dosing limitations of claims 20-21, Naito teaches that ADC #46 of Naito was tested vs the NSCLC line Calu-3 (Naito, ¶ 0742) at doses ranging from 1000 nM to 0.064 nM (same as 0.01 to 158 mg/kg) (Naito, ¶ 0747) and ADC #46 was found to inhibit these NSCLC cells with an IC50 of less than 1 nM (1 nM is around 0.158 mg/kg) (Naito, ¶ 0752). Regarding the dosing interval limitations of claim 22, Naito teaches that the composition of Naito is administered at a dosing interval from 2 to 4 weeks (Naito, ¶ 0160). Regarding the metastatic limitation of claim 15, Naito teaches that the ADCs of Naito are administered to suppress the growth of HER2 expressing metastatic cancer cells (Naito, ¶ 0375).
Atlas teaches that HER2 comprises an extracellular domain, a transmembrane domain and an intracellular tyrosine kinase domain (Atlas, p 2, ¶ 5). Atlas teaches that trastuzumab binds the extracellular domain of HER2 (Atlas, p 2, ¶5). Atlas also teaches the following structure for HER2, with amino acids 731-906 of the HER2 being in the intracellular tyrosine kinase domain (Atlas, p 1, Fig. 1):
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Fig. 1 of Atlas. The loci for the Y772_A775Dup mutation and the trastuzumab binding site on HER2 (Note: Arrows and red text added by examiner).
Hotta teaches of a clinical trial testing the ADC trastuzumab-DM1 on HER2-expressing cancers, including cancers having HER2 exon 20 mutations (Hotta, Abstract). Hotta teaches that known HER2 mutations can be detected by direct sequencing (Hotta, p 274, ¶ 6). Hotta teaches that the clinical trial comprised 5 patients having the HER2 mutation A775_G776insYMVA (Hotta, Table 1). As evidenced by NCI, the term A775_G776insYMVA (used by Hotta) and the term Y772_A775Dup (used in the instant Application) are synonyms and both terms refer to a mutation having MedGen UID of 475639 (NCI, p 2). Note; for the sake of clarity of the record, this mutation be referred to as Y772_A772dup, as used in the instant Application. Hotta teaches that one of the Y772_A775dup patients exhibited a partial response and 3 exhibited a stable disease state, this corresponds to 80% of patients having HER2 with the Y772_A775dup mutation exhibiting a stable disease or better (Hotta, Table 3). Applying arithmetic to Hotta’s numbers in Table 3, there were a total of 3 patients with wild type HER2 that exhibited a stable disease state out of 8 HER2 wild type patients total, which amounts to 37.5% stable disease or better rate for the wild type HER2 patients, which is lower than the 80% for the Y772_A775dup HER2 mutant patients (Hotta, Table 3). The partial response observed in the one Y772_A775dup HER2 mutant was the only partial response observed in the entire clinical trial and no complete responses were observed for any patient (Hotta, Table 3).
It would be prima facie obvious to apply the teachings of Naito, Atlas and Hotta to the teachings of the ‘821 patent to arrive a method of treating metastatic NSCLC, said method comprising administration of the ADC of the ‘821 patent, at a DAR between 7.5 and 8, at a dose of 5.4 or 6.4 mg/kg every three weeks, wherein said metastatic NSCLC cells include NSCLC cells that have been identified to contain the Y772_A775Dup mutation to HER2. The net result of this application would be a method of treating metastatic NSCLC, said method comprising administration of the ADC of the ‘821 patent, at a DAR between 7.5 and 8, at a dose of 5.4 or 6.4 mg/kg every three weeks, wherein said metastatic NSCLC cells have been identified to have the Y772_A775Dup mutation to HER2. Naito teaches that the ADCs of the ‘821 patent may be used in methods of treating NSCLC, including metastatic NSCLC. Naito also teaches that the ADC of the ‘821 patent was able to inhibit growth of NSCLC cells in vitro with an IC50 less than 1 nM (1 nm is about 0.158 mg/kg). The teachings of Hotta demonstrate patients having the Y772_A775dup mutation to HER2 are still responsive to trastuzumab-comprising ADCs. These data support the conclusion that the Y772_A775dup mutation to exon 20 should not affect the ability of the trastuzumab of the ADC to bind to its epitope on the extracellular domain of HER2. One of ordinary skill in the art would have a reasonable expectation of success administering the ADC of the ‘821 patent to treat metastatic NSCLC possessing the Y772_A775Dup on HER2 because: 1) Naito teaches that an anti-HER2 ADC that is the same as the instant claimed ADC and the ADC of the ‘821 patent is used in methods of treating NSCLC, 2) Naito teaches that the ADC of the ‘821 patent was able to suppress NSCLC cell growth in vitro with an IC50 of 0.158 mg/kg, 3) Atlas teaches that the location of the Y772_A775Dup mutation of HER2 and the location to which trastuzumab binds are in different domains of HER2, 4) Hotta teaches that cancer cells having the Y772_A775dup mutation on HER2 are still responsive to ADCs comprising trastuzumab.
Regarding the numerical limitations of claims 18-22 including: 1) a DAR that is between 7.5 and 8, 2) an administered dose of 5.4 or 6.4 mg/g and 3) a dosing interval of administration once every three weeks, all of these values are contained within a range of values already taught by Naito and the ‘821 patent. That is to say, Naito teaches: 1) doses between 1000 nM to 0.064 nM (same as 0.01 to 158 mg/kg) (with IC50 being less than 1 nM (same as 0.158 mg/kg) and 2) a dosing interval between two and three weeks. The ‘821 patent teaches a DAR between 3 and 8. It is prima facie obvious to one of ordinary skill in the art to start with the DAR range of 3-8, the dosage range between 0.01 and 158 mg/kg and the dosing interval range of two to three weeks and arrive at the claimed values of DAR between 7.5 and 8, a dose of 5.4 or 6.4 mg/kg and a dosing interval of three weeks via routine experimentation. The use of well-known and accepted techniques such as response surface modeling would even allow optimization of all the parameters at once while minimizing the number of experiments. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 MPEP 2144.05. Further with respect to optimal dosing regimens, it is not inventive to discover such regimens by routine experimentation when general conditions of a claim are disclosed in the prior art. See in re Aller, 220 F.2d 545, 456, 105 USPQ 233, 235 (CCPA 1955) and MPEP § 2144.05(11).
Response to Arguments
Applicant provides no arguments unique to this rejection other than stating that the reference patent does not remedy the alleged deficiencies of Naito, Hotta and ProteinAtlas.
Claims 1-6, 15-17, 19-22 and 45-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37, 40-43, 45-51, 57-60, 62, 64-65, 72 and 75-82 of copending Application No. 16,334,008 (Published as US 2019/0330368A1 on 10/31/2019, of record) in view of (Naito, et al., US 2016/0333112-A1; Published 11/17/2016, of record) and Atlas of Genetics and Cytogenetic in Oncology and Haematology (“Atlas”, article on ErBB2; Published 05/01/2011; URL: https://atlasgeneticsoncology.org/gene/162/erbb2-%28v-erb-b2-erythroblastic-leukemia-viral-oncogene-homolog-2-neuro-glioblastoma-derived-oncogene-homolog-%28avian%29%29 ; Accessed 1/8/2024, of record) and Hotta (Hotta, et al., J Thoracic Oncol. 2017 13(2):273, of record) and as evidenced by NCI (NCI et al., MedGen UID 475639 02/18/2018; URL: https://www.ncbi.nlm.nih.gov/medgen/475639 ; Accessed 1/12/2024, of record).
Regarding the structure limitations of instant claim 1, copending claim 37 is directed to an ADC that is structurally identical to the structure of instant claim 1 and is bound to an anti-HER2 antibody. Regarding the sequence limitations of claims 16-17, SEQ ID NOs: 1 and 2 of copending claims 50-51 are 100% matches for instant SEQ ID NOs: 1 and 2, respectively and correspond to the anti-HER2 antibody trastuzumab. Regarding the DAR limitations of claim 19, copending claim 49 is directed to a DAR of 7.5 to 8. Regarding the dosage limitations of claim 21, copending claim 80 is directed to a dosage of 6.4 mg/kg. Regarding the dosage limitations of claim 46, copending claim 79 is directed to a dosage of 5.4 mg/kg. Regarding the dosage interval limitations of instant claim 22, copending claim 57 is directed to administration every 3 weeks.
The ‘008 application does not teach that the ADC of the ‘008 application is administered in a method of treating metastatic NSCLC, said NSCLC comprising cells known to have the Y772_A775Dup mutation in HER2.
Naito teaches on the subject of anti-HER2 ADCs (Naito, Abstract). Naito teaches that ADC # 46 of Naito is an exact structural match for the structure of the ADC of the ‘008 application, with the antibody of the ADC being trastuzumab (Naito, ¶ 703-706). Note that Naito also teaches that the ADCs of Naito are internalized following antigen binding (Naito, ¶ 0003). Naito teaches that ADC #46 of Naito was tested vs the NSCLC line Calu-3 (Naito, ¶ 0742) and was found to inhibit these NSCLC cells with an IC50 of less than 1 nM (1 nM is around 0.158 mg/kg) (Naito, ¶ 0752). Regarding the metastatic limitation of claim 15, Naito teaches that the ADCs of Naito are administered to suppress the growth of HER2 expressing metastatic cancer cells (Naito, ¶ 0375).
Atlas teaches that HER2 comprises an extracellular domain, a transmembrane domain and an intracellular tyrosine kinase domain (Atlas, p 2, ¶ 5). Atlas teaches that trastuzumab binds the extracellular domain of HER2 (Atlas, p 2, ¶5). Atlas also teaches the following structure for HER2, with amino acids 731-906 of the HER2 being in the intracellular tyrosine kinase domain (Atlas, p 1, Fig. 1):
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Fig. 1 of Atlas. The loci for the Y772_A775Dup mutation and the trastuzumab binding site on HER2 (Note: Arrows and red text added by examiner).
Hotta teaches of a clinical trial testing the ADC trastuzumab-DM1 on HER2-expressing cancers, including cancers having HER2 exon 20 mutations (Hotta, Abstract). Hotta teaches that known HER2 mutations can be detected by direct sequencing (Hotta, p 274, ¶ 6). Hotta teaches that the clinical trial comprised 5 patients having the HER2 mutation A775_G776insYMVA (Hotta, Table 1). As evidenced by NCI, the term A775_G776insYMVA (used by Hotta) and the term Y772_A775Dup (used in the instant Application) are synonyms and both terms refer to a mutation having MedGen UID of 475639 (NCI, p 2). Note; for the sake of clarity of the record, this mutation be referred to as Y772_A772dup, as used in the instant Application. Hotta teaches that one of the Y772_A775dup patients exhibited a partial response and 3 exhibited a stable disease state, this corresponds to 80% of patients having HER2 with the Y772_A775dup mutation exhibiting a stable disease or better (Hotta, Table 3). Applying arithmetic to Hotta’s numbers in Table 3, there were a total of 3 patients with wild type HER2 that exhibited a stable disease state out of 8 HER2 wild type patients total, which amounts to 37.5% stable disease or better rate for the wild type HER2 patients, which is lower than the 80% for the Y772_A775dup HER2 mutant patients (Hotta, Table 3). The partial response observed in the one Y772_A775dup HER2 mutant was the only partial response observed in the entire clinical trial and no complete responses were observed for any patient (Hotta, Table 3).
It would be prima facie obvious to apply the teachings of Naito, Atlas and Hotta to the teachings of the ‘008 application to arrive a method of treating metastatic NSCLC, said method comprising administration of the ADC of the ‘008 application, at a DAR between 7.5 and 8, at a dose of 5.4 or 6.4 mg/kg every three weeks, wherein said metastatic NSCLC cells include NSCLC cells that have been identified to contain the Y772_A775Dup mutation to HER2. The net result of this application would be a method of treating metastatic NSCLC, said method comprising administration of the ADC of the ‘008 application, at a DAR between 7.5 and 8, at a dose of 5.4 or 6.4 mg/kg every three weeks, wherein said metastatic NSCLC cells have been identified to have the Y772_A775Dup mutation to HER2. Naito teaches that the ADCs of the ‘008 application may be used in methods of treating NSCLC, including metastatic NSCLC. Naito also teaches that the ADC of the ‘008 application was able to inhibit growth of NSCLC cells in vitro with an IC50 less than 1 nM (1 nm is about 0.158 mg/kg). The teachings of Hotta demonstrate that Y772_A775dup mutant HER2 patients are still responsive to trastuzumab-comprising ADCs. These data support the conclusion that the Y772_A775dup mutation to exon 20 should not affect the ability of the trastuzumab of the ADC to bind to its epitope on the extracellular domain of HER2. One of ordinary skill in the art would have a reasonable expectation of success administering the ADC of the ‘008 application to treat metastatic NSCLC possessing the Y772_A775Dup on HER2 because: 1) Naito teaches that an anti-HER2 ADC that is the same as the instant claimed ADC and the ADC of the ‘008 application is used in methods of treating NSCLC, 2) Naito teaches that the ADC of the ‘008 application was able to suppress NSCLC cell growth in vitro with an IC50 of 0.158 mg/kg, 3) Atlas teaches that the location of the Y772_A775Dup mutation of HER2 and the location to which trastuzumab binds are in different domains of HER2, 4) Hotta teaches that cancer cells comprising the Y772_A775dup mutation to HER2 are still responsive to ADCs comprising trastuzumab.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant grouped the responses to this rejection with those of the NSDP rejection in view of the ‘821 patent.
Conclusion
Claims 1-6, 15-17, 19-22 and 45-48 are rejected.
No claims are allowed.
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/SYDNEY VAN DRUFF/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643