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 Amendment filed June 5, 2026 in response to the Office Action of March 5, 2026, is acknowledged and has been entered. Claims 31-43, 45, 50-54, 57, 60-68, 71, and 73-75 are pending. Claims 31, 43, 53 and 54 are amended. Claims 33-36, 60, and 74 remain withdrawn as drawn to non-elected species. Claims 31, 32, 37-43, 45, 50-54, 57, 61-68, 71, 73, and 75 are currently being examined as drawn to the elected species of:
A. an alteration in a HER2 gene or gene product, wherein the alteration is a substitution at position 310 of a HER2 polypeptide;
B. wherein the report further comprises an indication of the presence in the sample of the HER2 alteration and/or an identification of nucleotide values of the HER2 alteration;
C. one agent that inhibits a HER2 gene product;
D. the HER2-specific kinase inhibitor neratinib and rejoined species trastuzumab HER2 antibody; and
E. the subject has undergone a treatment with the non-HER2 therapeutic agent or therapeutic modality methotrexate.
NOTE: The terms HER2 and ERBB2 are used interchangeably in the office action.
New Rejection
(necessitated by amendments)
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.
2. Claims 31, 32, 37-43, 45, 50-54, 57, 61-68, 71, 73, and 75 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 31 recites the limitation: “(i) the identification of the micropapillary histology”. There is insufficient antecedent basis for this limitation in the claim because there is no previously recited method step of identifying the micropapillary histology. The dependent claims are rejected for encompassing the rejected limitation of claim 31.
Maintained Rejection
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.
3. Claims 31, 32, 37-43, 45, 50-54, 57, 61-68, 71, and 73 remain rejected under 35 U.S.C. 103 as being unpatentable over Herter-Sprie et al (Frontiers in Oncology, 2013, 3:1-10; published online February 12, 2013); in view of US Patent Application Publication 2015/0307947, Basu et al, claiming priority to January 2013; Bose et al (Cancer Discovery, 2013, 3:224-237, published online Dec. 7, 2012, IDS) and Supplementary Table 1; Banerji et al (Nature, June 2012, 486:405-409); Weigelt et al (Cancer Discovery, February 2013, 3:145-147); Greulich et al (PNAS, September 2012, 109:14476-14481, IDS); Laé et al (Annals of Oncology, 2010, 21:815-819, IDS), Huang et al (March 5, 2013, US and Canadian Academy of Pathology (USCAP) Meeting, Poster Session, [908], IDS) and Schneider et al (Journal of Urology, vol. 189, No. 4S, Supplement, May 5, 2013, p. e160, abstract 395).
Herter-Sprie et al teach the need to sequence human patient tumor DNA samples for mutations in ERBB2 (HER2) gene because of their impact on diagnostics and response to treatment. Cancer cells frequently show “addiction” to mutationally activated oncogenes such as ERBB2. Herter-Sprie et al teach there are two known pharmacological manipulations to target HER2 for therapy: antibody therapy against the extracellular domain (ECD) of the receptor and small molecule compounds against the intracellular tyrosine kinase domain. Herter-Sprie et al teach it is known that amplification of ERBB2 gene contributes to aberrant activation of ERBB2 but current sequence technologies have enabled efficient identification of activating molecular alterations of ERBB2. The emergence of sophisticated genomic technologies like next-generation sequencing enabled high-throughput detection of known and novel oncogenic mutations of ERBB2 in a variety of tumor types. The mutations in ERBB2 offer unique therapeutic opportunities to broader range of patients than previously anticipated by analysis of ERBB2 amplification alone (abstract; p. 1, col. 1-2). Herter-Sprie et al review known activating somatic mutations of ERBB2 in cancer including insertions, deletions, substitutions, and missense mutations in the ECD, domain II, or kinase domains. Herter-Sprie et al specifically teach S310F and S310Y mutations that are found in lung cancer, breast cancer, ovarian cancer, and a bladder cancer cell line that results in elevated C-terminal tail phosphorylation without receptor dimerization. (p. 2, col. 2 to p. 3, col. 2), wherein the bladder cancer cell line 5637 is derived from a patient with bladder carcinoma. Herter-Sprie et al teach targeting ERBB2 for human patients identified with activating ERBB2 mutations using known ECD-binding antibodies trastuzumab and pertuzumab, as well as known tyrosine kinase inhibitors such as lapatinib and neratinib. A tumor cell line expressing the S310 mutation was effectively inhibited upon trastuzumab treatment (p. 4, col. 1-2; Conclusion p. 6). It is noted that mutation S310F and S310Y fall into categories of an alteration that results in increased activity of HER2, and a substitution of a serine residue at position 310 of HER2 polypeptide to a phenylalanine or tyrosine residue or as an alteration in the ECD.
Herter-Sprie et al do not teach detecting both ERBB2 activating mutation, including S310F or S310Y, and lack of gene amplification or overexpression, in a patient with a micropapillary variant of bladder cancer, and selecting and treating the patient with trastuzumab or neratinib, although Herter-Sprie et al specifically teach and provide motivation to use current sequence technologies that enable efficient identification of activating molecular alterations of ERBB2 in order to identify such cancer patients for ERBB2 targeted therapy.
Herter-Sprie et al do not teach generating and providing a report indicating the selected treatment.
Herter-Sprie et al do not teach that patient has undergone treatment with non-HER2 therapeutic agent regimen comprising M-VAC (methotrexate, vinblastine, doxorubicin, cisplatin) regimen or that the regimen is discontinued after determining the presence of the ERBB2 activating mutation and the ERBB2-targeted therapy is then administered.
Basu et al teach methods and motivation to provide molecular profiling of cancer patients, such as sequencing tumor sample DNA for mutations particularly in the ERBB2/HER2 gene, in order to identify targets for drugs and the appropriate treatment for cancer patients (abstract; [7-8]; [74-75]; [39-41]; [107-111]; [131-132]; [255-257]; [260]; Table 2; [268]; [279]; claims 1, 2, 5, 8, 15-17, 91, and 95-97); wherein cancers for screening include bladder cancer or urinary carcinoma ([10]; [361]; [362]; [365]; claims 15-17); wherein sequencing includes mutational analysis of tumor cells with next-generation sequencing or utilizing known commercially available sequence analysis platforms ([25]; [28]; [74-75]; [193-195]; [204-217]); wherein treatment comprises HER2-targeting agents trastuzumab (HERCEPTIN®), pertuzumab, neratinib, and lapatinib ([282-283]; Table 6 on p. 72; Table 28 and 30); wherein the method comprises generating a report comprising results of the molecular profiling and a list of indicated treatments, wherein the report is computer generated, printed, or a computer file, accessible by web portal or transmitted over a network, including to users such as the patient, physicians, or third parties ([33-40; [324]; [340]; [345]; claims 131-146). Basu et al exemplify in Example 22 utilizing next-generation sequencing (NGS) for high throughput detection of oncogenic mutations in ERBB2 applied to several different solid tumor tissue samples from patients (including lung, breast, ovarian, and bladder), identified several mutations including known ERBB2-activating mutations in several cancer types, and identified a substitution mutation D769H in bladder cancer ([630-634]). Basu et al teach screening for ERBB2 mutations because ERBB2 is a major proliferative driver for several cancer types and it is known that ERBB2 gene amplification and protein overexpression are associated with sensitivity to HER2-targeted drugs. Basu et al teach that in some cancers, ERBB2 mutations may be more clinically relevant than ERBB2 amplification or protein expression ([630-631]). Basu et al determined that activating ERBB2 mutations can coexist with ERBB2 gene amplification or with other mutations in other key driver genes ([634]).
Bose et al also identified breast cancer as having the HER2 activating mutations S310F or D769H, and identified the breast cancer having S310F as being HER2 gene amplification negative, associated with under-expression of HER2 protein (abstract; p. 225, col. 1-2; Figure 1A+B; Figure 2E+B; p. 228, col. 1-2). Bose lists six references detecting somatic HER2 mutations in breast cancers, including S310F mutation in HER2 negative cancers (Supplementary Table 1). Bose teaches the S310F HER2 mutation is likely a driver event in a patient’s cancer (p. 233, col. 1, Discussion). Bose et al demonstrated the HER2-activating mechanism of mutation D769H and demonstrated that cancer cells expressing the mutation were responsive to treatment with tyrosine kinase inhibitors targeting HER2 including neratinib and lapatinib (Figures 2, 4, and 5; p. 233, col. 1; Table 1). Bose et al teach testing the sensitivity of the somatic ERBB2 mutations to HER2-targeted drugs specifically for providing preclinical data for HER2 sequencing-directed clinical trials (p. 224, col. 2).
Banerji (cited by Bose et al in Supplementary Table 1) demonstrates successfully detecting HER2 somatic mutation S310F in breast tumor samples utilizing whole-genome sequencing or whole-exome sequencing, and determining that the tumor samples lacked HER2 amplification (p. 407, col. 1; p. 408, col. 2, Methods Summary; Supplementary Figure 9). Banerji teaches that simultaneous detection of the HER2 activating mutation S310F and lack of HER2 gene amplification supports the notion that the HER2 mutation has a driving role in those tumors (p. 407, col. 1).
Weigelt et al teach that conventionally, breast cancer patients are selected for, and treated with, anti-HER2 agents such as trastuzumab when their cancer is identified as HER2-amplified and HER2-overexpressing, however, Bose et al (above) discovered that there are cancers lacking HER2 amplification and overexpression that harbor activating HER2 mutations, and these HER2 mutations dictate the response to anti-HER2 drugs. Weigelt et al teach and suggest the need to sequence HER2 in cancers to assess the treatment of patients with HER2 mutant breast cancer using HER2-targeted agents. Weigelt et al teach one of the mutations detected is the S310F of the HER2 extracellular domain that is an activating mutation resulting in HER2 phosphorylation. Weigelt et al teach that the finding of Bose et al reveals the fact that despite lack of HER2 amplification and overexpression, a cancer can still be “addicted” to HER2 signaling due to HER2 activating mutations, therefore patients harboring these activating mutations may be overlooked for treatment with anti-HER2 agents if they lack HER amplification and overexpression. Weigelt et al teach that sequencing HER2 in tumors to identify HER2 activating mutations will expand the population of cancer patients that benefit from anti-HER2 therapy (p. 145, col. 1-2; p. 146, col. 1-2; Figure 1A and B; p. 147, col. 1-2).
Greulich et al teach and demonstrate that HER2 extracellular domain mutation S310F, as determined by sequencing, is oncogenic and is a HER2 activating mutation present in lung cancer, breast cancer, as well as a bladder cancer cell line (p. 14477, col. 1-2; Figure 1; p. 14478, col. 1-2; Table 1; p. 14479, col. 2). Greulich et al teach that the S310F mutation does not inhibit trastuzumab binding, and trastuzumab effectively inhibits survival of cancer cells expressing S310F mutation (p. 14479, col. 2). Greulich et al teach bladder cancer cells harboring the S310F mutation were effectively killed by agents that inhibit HER2 and MEK (p. 14479, col. 2; Figure 4). Greulich et al specifically suggest clinical utility of treating bladder cancer that comprises HER2 extracellular domain mutations by administration with anti-HER2 agents, alone or in combination with other agents (p. 14480, col. 2). Greulich et al teach trastuzumab and lapatinib are known inhibitors of HER2 used to treat cancer (p. 14476, col. 1) and demonstrate inhibition of cancer cells expressing S310F with HER2 inhibitors neratinib, afatinib, and trastuzumab (p. 14479, col. 1-2; Figure 4).
Lae et al teach it is known that urothelial bladder carcinoma can be driven by HER2. Lae et al teach measuring HER2 gene amplification and protein expression in urothelial bladder carcinoma and determined that many patients had HER2 protein overexpression in the absence of HER2 gene amplification. Lae et al teach the importance of measuring HER2 protein overexpression to select patients responsive to trastuzumab therapy. Lae et al teach that the M-VAC (methotrexate, vinblastine, doxorubicin, cisplatin) regimen for treating urothelial carcinoma is known (abstract, see entire paper and Table 1).
Huang et al teach it is known that micropapillary variants can be driven by HER2. Huang et al teach measuring HER2 protein expression by immunohistochemistry in micropapillary variants of urothelial carcinoma and confirmed that the majority of micropapillary carcinomas overexpress HER2 protein.
Schneider et al also teach it is known that micropapillary variants can be driven by HER2. Schneider et al teach measuring HER2 gene amplification and protein expression in micropapillary urothelial carcinoma to identify HER2 abnormalities relevant to treatment with HER2 targeting therapies, and teach that micropapillary urothelial carcinoma commonly overexpresses HER2 protein.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to sequence and detect HER2 activating mutations, including S310F, and detect lack of HER2 gene amplification/overexpression in a patient identified as having micropapillary variant of bladder cancer. One would have been motivated to because: (1) the cited art teaches the need to sequence HER2 and identify activating HER2 mutations in a variety of cancers in order to identify cancers for HER2-targeted therapy, including those with activating mutations that occur in the absence of amplification, serving as oncogenic drivers (as taught by Herter-Sprie et al, Banerji, Basu et al, Weigelt et al, Greulich et al); (2) Herter-Sprie et al teach sequencing for HER2 activating mutations allows for the identification of a broader range of patients outside those previously recognized by HER2 amplification; (3) the cited prior art recognizes that bladder cancer expresses HER2 activating mutations including S310F or D769H that are demonstrated to be effectively inhibited by HER2-targeting drugs (Herter-Sprie et al, Basu et al, Greulich et al); and (4) the cited prior art recognizes that urothelial bladder cancer and micropapillary variants can be HER2-driven (Lae et al, Huang et al, and Schneider et al). One of ordinary skill in the art would have a reasonable expectation of success sequencing for HER2-activating mutations and detecting lack of HER2 gene amplification in micropapillary variants because: (1) Herter-Sprie et al, Banerji, and Basu teach methods of next generation sequencing, whole genome sequencing, whole-exome sequencing, and commercially available sequencing platforms are successfully used, efficient, and known for high throughput sequencing of tumor tissues for detecting HER2 mutations in various cancer types; (2) HER2-activating somatic mutations are known and successfully sequenced and identified by the cited prior art including S310F or D769H identified in a bladder cancer cell line and patient bladder cancer tissue; and (3) Herter-Sprie et al, Banerji, Basu et al, and Weigelt et al teach methods detecting HER2 activating mutations and detecting lack of HER2 gene amplification are routinely used to characterize HER2 expression in a variety of tumors, and (4) Herter-Sprie et al, Banerji, Basu et al, and Weigelt et al teach and demonstrate HER2 activating mutations like S310F occur in the absence of HER2 gene amplification as a mechanism of HER2-driven cancer. Thus, the art provides both motivation and reasonable expectation of success to sequence HER2 activating mutations, including S310F, and detect lack of HER2 amplification in a variety of cancers, including bladder cancer that is already demonstrated to harbor HER2 activating mutations and can be HER2-driven.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat a subject identified as having micropapillary urothelial bladder cancer with a HER2-activating mutation, such as S310F, and lack of HER2 gene amplification/overexpression, by administration of an anti-HER2 antibody or kinase inhibitor, such as trastuzumab, lapatinib or neratinib. One would have been motivated to because the cited prior art teaches identifying cancer patients harboring HER2-activating mutations for the purpose of selecting them for HER2-targeted therapy (as taught by Herter-Sprie et al, Basu et al, Weigelt et al, Greulich et al) and the cited prior art teaches that effective HER2-targeted therapies are known including trastuzumab, lapatinib or neratinib. One of ordinary skill in the art would have a reasonable expectation of success treating micropapillary urothelial bladder cancer having a HER2-activating mutation, such as S310F, and lack of HER2 gene amplification/overexpression by administration of a HER2-targeting agent, such as trastuzumab, lapatinib, or neratinib, because the cited prior art established that cancer cells expressing S310 mutations are responsive to HER2 inhibitor neratinib, afatinib, and trastuzumab therapy (Herter-Sprie et al and Greulich et al).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to generate and provide or transmit a report on the results of the HER2 nucleic acid sequence profiling and selected treatment for a patient, and within about 21 days of obtaining the patient sample. One would have been motivated to and have a reasonable expectation of success to because Herter-Sprie et al and Basu et al teach the need to identify and treat cancer patients having HER2 mutations; and Basu et al teaches methods for generating reports summarizing the HER2 profiling result and selected treatment, for use in transmission to the patient, a physician, or third party to act upon. Based on the disclosure of the cited art for obtaining samples and utilizing known methods for sequencing mutations in the sample, it is well within the level of one skilled in the art to generate and provide a report within 21 days of testing.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed, one would be motivated and have a reasonable expectation of success to test and treat micropapillary urothelial carcinoma patients previously treated with or currently undergoing M-VAC therapy because it is an established therapeutic regimen for urothelial carcinoma patients. It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed, one would be motivated and have a reasonable expectation of success to end M-VAC therapy and administer HER2-targeted therapy to micropapillary urothelial carcinoma patients identified as having a HER2 activating mutation such as S310F or D769H, because the cited prior art provides motivation and reasonable expectation of success to treat cancer patients harboring HER2-activating mutations, such as S310F or D769H, with HER2-targeting agents trastuzumab, lapatinib or neratinib, for the reasons set forth above.
Response to Arguments
4. Applicants argue that the claims are not obvious over the cited references due to the amendments to claim 31 requiring identification of a treatment for micropapillary carcinoma of the urinary tract, bladder, or urothelial cells in the subject in response to: (i) identification of micropapillary histology, (ii) detection of the presence of the recited HER2 mutation, and (iii) detection of the lack of HER2 gene amplification or overexpression of a HER2 gene or gene product, wherein the identified treatment comprises one or more agents that inhibit a HER2 gene or gene product selected from the recited Markush grouping. Applicants argue the cited references do not render obvious generating a report indicating the identified treatment or administering the identified treatment to a subject having a micropapillary carcinoma of the urinary tract, bladder, or urothelial cells. Applicants argue the cited combination of references still fails to teach or suggest the claimed treatment pathway for the specifically claimed cohort, and the combination of references fails to provide a reasonable pathway from the identified profile to the recited therapy.
Applicants argue that none of the references, considered alone or in combination, teaches or suggests administering the recited treatment (one or more agents that inhibit a HER2 gene or gene product selected from the Markush grouping recited in claim 31) to this specific cohort (a subject having a micropapillary carcinoma of the urinary tract, bladder, or urothelial cells characterized by micropapillary histology, a HER2 mutation encoding a substitution at position 157 or 310 of a HER2 polypeptide, and the lack of HER2 gene amplification or overexpression of a HER2 gene or gene product). Applicants argue that claim 31 is not directed merely to screening for HER2 mutations or generally considering HER2-targeted therapy. Rather, claim 31 requires a specific combination (mutation/disease profile): (i) identifying a subject with a micropapillary carcinoma of the urinary tract, bladder, or urothelial cells; (ii) detecting a claimed HER2 mutation; (iii) detecting the lack of HER2 gene amplification or overexpression (e.g., negative IHC results); and, when all of these features are present, administering a HER2-directed treatment. Applicants argue that even assuming, arguendo, that it was known to screen for HER2 alterations across cancers, there is still no teaching or suggestion of how a person having ordinary skill in the art would arrive at or treat this particular patient subset.
Applicants argue that Basu, Bose, Banerji, Weigelt, Greulich, Laé, Huang, and Schneider fail to remedy the deficiencies of Herter-Sprie because, even if other of the cited references disclose assay for detecting HER2 mutations and overexpression, they do not teach or suggest doing so in the recited cohort of patients and then administering a HER2-directed treatment as recited in claim 31 when a HER2 mutation but not gene amplification/overexpression is present. Applicants argue that Basu fails to teach or suggest identifying the specific genomic profile for micropapillary urothelial carcinoma recited in claim 31 in order to treat with a HER2-directed therapy. It only teaches that DNA sequencing and IHC/expression sequencing can be accomplished simultaneously. However, the amended claims are not directed to how the genomic/histological profile is obtained, but rather what results must be present to indicate treatment with a HER2-directed therapy. Applicants argue that Bose discloses identifying HER2 mutations in HER2 overexpression/amplification-negative breast cancer; it fails to teach or suggest also looking for HER2 mutations in micropapillary urothelial carcinoma that is HER2 overexpression/amplification-negative and then treating those patients with HER2-directed therapy. Applicants argue that Banerji is also breast cancer-specific, and thus the skilled person aiming to identify treatments for micropapillary carcinoma of the urinary tract, bladder, or urothelial cells would have no reason to consider its teachings. Applicants argue that Weigelt is also breast cancer-specific and fails to teach or suggest identifying treatments for micropapillary carcinoma of the urinary tract, bladder, or urothelial cells or considering such an indication for HER2-directed therapy. Applicants argue that Greulich reports preclinical findings from lung, breast, and bladder cancer cell lines but does not disclose the claimed patient population having the specific genomic and histological features recited in claim 31. Applicants argue that Laé fails to teach or suggest identifying the recited HER2 mutations or the lack of HER2 gene amplification/overexpression in micropapillary carcinoma of the urinary tract, bladder, or urothelial cells. Applicants argue that Huang and Schneider merely teach assaying HER2 gene amplification/overexpression and fail to teach or suggest treating with a HER2-directed therapy even when HER2 gene amplification/overexpression is negative.
Applicants argue that the Examiner's rationale for combining all of the cited references depends on impermissible hindsight based on the instant application because only in hindsight would it have been obvious to look for micropapillary histology, the recited HER2 mutations, and lack of HER2 gene amplification/overexpression in these particular subtypes of cancer. Many of the references suggest divergent screening and/or treatment options without a specific indication to pursue the specific features recited in claim 31. Applicants argue that Greulich reports that abrogation of survival of a bladder cancer cell line harboring ERBB2 S310F required combination ERBB2 and MEK inhibition, not treatment solely with agents targeting HER2 (page 14477, left column, first paragraph; page 14479, right column, 2ⁿᵈ full paragraph; and Figure 4F). Applicants argue that this undercuts any assertion that Greulich would have led a POSITA to administer the claimed HER2-directed treatment regimen to the claimed cohort. Applicants argue that Bose also suggests that HER2 mutations in breast cancer exhibit variable drug responses, including resistance to some of the types of therapies recited in claim 31 (page 6, 2ⁿᵈ paragraph). Applicants argue that Bose's statement that there is variable drug response in HER2-mutated tumors undermines any claim that a POSITA would have had a reasonable expectation that the claimed cohort should be treated with the recited HER2-directed therapy based on the cited combination. Applicants argue that there is no reason a priori to focus on the specific features recited in claim 31 based on the cited references instead of other treatments they suggest, other than hindsight reasoning based on the pending claims.
Applicants argue there is no reasonable expectation of identifying or treating the specific patient cohort recited in claim 31 based on the cited references. Applicants argue that one of ordinary skill in the art at the time the instant application was filed would not have had a reasonable expectation of success in identifying carcinoma of the urinary tract, bladder, or urothelial cells with micropapillary histology, the recited HER2 mutations, and lack of HER2 gene amplification/overexpression based on the combination of Herter-Sprie, Basu, Bose, Banerji, Weigelt, Greulich, Laé, Huang, and Schneider. Applicants argue that at best, the combination of references suggests extending HER2 sequencing to other cancers. Applicants argue that Examiner has stated that "Applicants have not persuasively argued that the screening methods for detecting the claimed HER2 mutation and lack of gene amplification would not also predictably and successfully function to detect the same HER2 mutation and lack of amplification on micropapillary carcinomas of the urinary tract, bladder, or urothelial cells" (Office Action, page 19).
However, Applicants reiterate arguments that the amended claims are not directed to how the genomic/histological profile is obtained, but rather what features are present in an individual patient's cancer to indicate treatment with a HER2-directed therapy. In other words, whether or not one could sequence or test for a particular biomarker, in this case HER2 mutations and gene overexpression, is not relevant to the analysis or the problem being solved by the present invention. Instead, the question is whether the cited combination would have taught or suggested to a person of ordinary skill in the art that there is a reasonable expectation of identifying micropapillary urothelial carcinoma patients with no HER2 gene amplification/overexpression, and then, upon detecting that subgroup of patients, still treat with a HER2-directed therapy.
Applicants argue that a general motivation to screen for HER2 mutations in various cancers does not constitute a teaching or suggestion of the existence of a prerequisite genomic/histologic profile (including micropapillary histology and lack of HER2 gene amplification/overexpression) for administration of a HER2-directed therapy in patients with micropapillary carcinoma of the urinary tract, bladder, or urothelial cells. While the Examiner has alleged that it would have been obvious "to sequence HER2 activating mutations" (Office Action, page 13), it was unclear at the time the instant application was filed that such mutations would even exist in these types of cancers along with the other genomic and histologic features recited in claim 31. This is particularly true since, as noted in the specification, only 1.3% of all urinary tract cancers in the comprehensive Catalogue of Somatic Mutations in Cancer (COSMIC) database at the time the instant application was filed were known to harbor mutations in HER2 (see, e.g., page 66, lines 26-28 of the as-filed specification). Furthermore, the Cancer Genome Atlas Program (TCGA) database did not describe any HER2 mutations in bladder urothelial carcinomas (see, e.g., page 68, lines 16-18 of the as-filed specification).
Applicants argue that the combined references fail to provide a reasonable expectation of successfully identifying the recited genomic profile in a real-world patient cohort, let alone successfully treating such patients with a HER2-directed therapy despite a lack of HER2 gene amplification/overexpression in micropapillary carcinoma of the urinary tract, bladder, or urothelial cells.
5. The arguments have been carefully considered but are not persuasive. The cited combined prior art teaches the motivation, commercial means, and reasonable expectation of success to screen cancers, including micropapillary carcinoma of the urinary tract, bladder, and urothelial cells, for HER2 activating mutations including known S310 mutations, and to simultaneously detect HER2 negative status or lack of HER2 gene amplification in the presence of HER2 activating mutation at S310. The cited combined prior art teaches the motivation, commercial means, and reasonable expectation of success to treat any cancers identified as having the HER2 activating mutation in the absence of HER2 gene amplification/overexpression by administering a known, successful HER2-inhibiting therapy including neratinib, afatinib, and trastuzumab, demonstrating success of killing cancer cells harboring the HER2 activating mutations with the HER2-inhibiting therapies.
The obviousness rationales in the rejection of record address all of Applicant’s arguments regarding the motivation and reasonable expectation of success that the combined references provide to identify a patient having micropapillary carcinoma of the urinary tract, bladder, or urothelial cells, having a HER2 activating mutation at S310 in the absence of HER2 amplification/overexpression, and administering known HER2-directed therapies that have demonstrated success against cancer cells comprising the S310F mutation. Contrary to arguments, the rejection was clearly NOT based on impermissible hindsight reasoning gleaned from Applicant’s specification, because the cited prior art teaches all of the motivation, means, and reasonable expectation of success to arrive at the claimed invention, for the reasons stated in the rejection.
Although Applicants argue that HER2 mutations were uncommon in the claimed micropapillary carcinomas at the time of filing, the cited prior art provides motivation to extend their screening methods to a variety of cancers in order to identify the HER2-driving mechanism. Herter-Sprie et al teach sequencing for HER2 activating mutations allows for the identification of a broader range of patients outside those previously recognized by HER2 amplification, providing motivation to extend their screening methods to other cancers. The cited prior art recognizes that bladder cancer expresses HER2 activating mutations including S310F or D769H that are demonstrated to be effectively inhibited by HER2-targeting drugs (Herter-Sprie et al, Basu et al, Greulich et al), providing a reasonable expectation of success for such screening methods and treatment to be applied to bladder cancers, including micropapillary variants known to also be HER2-driven (Lae et al, Huang et al, and Schneider et al).
Applicants have not persuasively argued that the screening methods for detecting the claimed HER2 mutation and lack of gene amplification, that were successfully demonstrated by the cited prior art on a variety of tumor types, would not also predictably and successfully function to detect the same HER2 mutation and lack of amplification on micropapillary carcinomas of the urinary tract, bladder, or urothelial cells. An argument that HER2 mutations in micropapillary carcinomas of the urinary tract, bladder, or urothelial cell were uncommon at the time of filing does not mean that the HER2 mutations were undetectable or difficult to detect in micropapillary carcinomas of the urinary tract, bladder, or urothelial cell. Applicants have not persuasively argued that the commercial means to sequence HER2 and detect lack of gene amplification taught by the cited references would not also successfully detect the presence of S310 mutation in micropapillary carcinomas of the urinary tract, bladder, or urothelial cell.
Applicants have not persuasively argued that the cited combined references do not provide motivation and reasonable expectation of success to simultaneously detect lack of HER2 gene amplification or overexpression in the presence of HER2 S310F mutation. As stated in the rejection of record, the cited prior art successfully demonstrates simultaneously detecting HER2 activating mutations/S310F mutation and lack of HER2 gene amplification/HER2 negativity. The cited references explain why this occurs, because the S310F/Y mutation is a HER2-activating mutation and an oncogenic driver in the absence of HER2 gene amplification, therefore the presence of S310 HER2-activating mutation in the absence of HER2 gene amplification is known and expected. The cited prior art teaches this phenomenon is not unique to any particular cancer, and the HER2-activating mutation expectedly functions the same across different cancers, including in response to the identified HER2 inhibitor therapeutics. Contrary to arguments, the cited prior art provides motivation and a reasonable expectation of success to simultaneously identify: (i) a carcinoma of the urinary tract, bladder, or urothelial cells with micropapillary histology, (ii) one of the recited HER2 mutations, and (iii) a lack of HER2 gene amplification or overexpression.
Arguments that Bose and Geulich teach variable anti-cancer responses of patients to HER2 targeting agents in general or teach combination ERBB2 and MEK inhibition to inhibit cancer cells harboring 3S10F, does not teach away from or negate the teaching and demonstration of the cited prior art that HER2 targeting agents, including neratinib, afatinib, and trastuzumab, successfully inhibit HER2 signaling of cancer cells expressing HER2-activating mutations. As stated in the rejection, a variety of cancer cell types harbor HER2 activating mutations including S310 F, the mutations function the same across cancer cell types, and HER2 inhibitors including neratinib, afatinib, and trastuzumab successfully kill and inhibit survival of cancer cells harboring the HER2 activating mutation:
Herter-Sprie et al specifically teach S310F and S310Y mutations that are found in lung cancer, breast cancer, ovarian cancer, and a bladder cancer cell line that results in elevated C-terminal tail phosphorylation without receptor dimerization. (p. 2, col. 2 to p. 3, col. 2), wherein the bladder cancer cell line 5637 is derived from a patient with bladder carcinoma. Herter-Sprie et al teach targeting ERBB2 for human patients identified with activating ERBB2 mutations using known ECD-binding antibodies trastuzumab and pertuzumab, as well as known tyrosine kinase inhibitors such as lapatinib and neratinib. A tumor cell line expressing the S310 mutation was effectively inhibited upon trastuzumab treatment (p. 4, col. 1-2; Conclusion p. 6).
Bose et al also identified breast cancer as having the HER2 activating mutations S310F or D769H, and identified the breast cancer having S310F as being HER2 gene amplification negative, associated with under-expression of HER2 protein (abstract; p. 225, col. 1-2; Figure 1A+B; Figure 2E+B; p. 228, col. 1-2). Bose lists six references detecting somatic HER2 mutations in breast cancers, including S310F mutation in HER2 negative cancers (Supplementary Table 1). Bose teaches the S310F HER2 mutation is likely a driver event in a patient’s cancer (p. 233, col. 1, Discussion). Bose et al demonstrated the HER2-activating mechanism of mutation D769H and demonstrated that cancer cells expressing the mutation were responsive to treatment with tyrosine kinase inhibitors targeting HER2 including neratinib and lapatinib (Figures 2, 4, and 5; p. 233, col. 1; Table 1).
Greulich et al teach and demonstrate that HER2 extracellular domain mutation S310F, as determined by sequencing, is oncogenic and is a HER2 activating mutation present in lung cancer, breast cancer, as well as a bladder cancer cell line (p. 14477, col. 1-2; Figure 1; p. 14478, col. 1-2; Table 1; p. 14479, col. 2). Greulich et al teach that the S310F mutation does not inhibit trastuzumab binding, and trastuzumab effectively inhibits survival of cancer cells expressing S310F mutation (p. 14479, col. 2). Greulich et al teach bladder cancer cells harboring the S310F mutation were effectively killed by agents that inhibit HER2 and MEK (p. 14479, col. 2; Figure 4). Greulich et al specifically suggest clinical utility of treating bladder cancer that comprises HER2 extracellular domain mutations by administration with anti-HER2 agents, alone or in combination with other agents (p. 14480, col. 2). Greulich et al teach trastuzumab and lapatinib are known inhibitors of HER2 used to treat cancer (p. 14476, col. 1) and demonstrate inhibition of cancer cells expressing S310F with HER2 inhibitors neratinib, afatinib, and trastuzumab (p. 14479, col. 1-2; Figure 4).
Examiner maintains the cited prior art provides motivation and reasonable expectation of success to treat any cancer identified as having a HER2 activating mutation, including at S310, and in the absence of HER2 amplification, by administering known HER2 targeting agents neratinib, afatinib, and trastuzumab that were demonstrated to be effective against cancer cells harboring HER2 activating mutations. The cited prior art teaches the HER2 activating mutations result in constitutively activated HER2 oncogenic signaling in the absence of HER2 amplification in cancer cells regardless of cancer type. HER2 activation by mutations (i.e., S310F) is a universal function across cancers cells and is not unique to any specific cancer type. The cited prior art demonstrated successfully inhibiting or killing cancer cells expressing HER2 activating mutations by administration of known HER2 targeting agents neratinib, afatinib, and trastuzumab and suggests treating cancers having the HER2 activating mutation with these agents. Nowhere, does the cited prior art teach these mutations, mechanism of action, and success of inhibiting cancers harboring the mutations with HER2-targeting agents, is unique to any particular cancer type or that they function differently in different cancer types. Instead, the cited prior art demonstrates these HER2 activating mutations occur across a variety of different cancer cell types and suggests expanding testing for the HER2 mutations across cancers to identify patients that would benefit from such treatment. Given the known expression of HER2 activating mutations (i.e., at S310) across different cancer types, the commercially available assays to rapidly identify such cancers, the known mechanism of action of these mutations to maintain oncogenic HER2 signaling in the absence of HER2 amplification/overexpression, the known need to identify cancers harboring these mutations in order to appropriately treat them, the suggestion to expand the identification of cancers harboring the mutations, and the known successful treatments of HER2-targeting inhibitors against cancer cells harboring the mutations, it is well within the level of the ordinary skilled artisan to: (1) expand their identification of cancers harboring the HER2 activating mutations to micropapillary carcinomas of the urinary tract, bladder, and urothelial cells, given these cancers’ known dependence on HER2 signaling, and given bladder cancer cells have been identified as harboring S310F mutation, and (2) treat these cancers by administration of the same HER2-targeting inhibitors demonstrated to successfully inhibit cancer cells harboring the same HER2 activating mutations.
6. Claim(s) 75 remains rejected under 35 U.S.C. 103 as being unpatentable over Herter-Sprie et al (Frontiers in Oncology, 2013, 3:1-10; published online February 12, 2013); US Patent Application Publication 2015/0307947, Basu et al, claiming priority to January 2013; Bose et al (Cancer Discovery, 2013, 3:224-237, published online Dec. 7, 2012, IDS) and Supplementary Table 1; Banerji et al (Nature, June 2012, 486:405-409); Weigelt et al (Cancer Discovery, February 2013, 3:145-147); Greulich et al (PNAS, September 2012, 109:14476-14481, IDS); Laé et al (Annals of Oncology, 2010, 21:815-819, IDS), Huang et al (March 5, 2013, US and Canadian Academy of Pathology (USCAP) Meeting, Poster Session, [908], IDS) and Schneider et al (Journal of Urology, vol. 189, No. 4S, Supplement, May 5, 2013, p. e160, abstract 395), as applied to claims 31, 32, 37-43, 45, 50-54, 57, 61-68, 71, and 73 above, and further in view of US Patent 5,877,305, Huston et al.
Sprie et al, Basu et al, Bose et al, Banerji, Weigelt et al, Greulich et al, Laé et al, Huang et al and Schneider et al (the combined references) teach as set forth above.
The combined references do not teach the published sequence of HER2, instant SEQ ID NO:1.
US Patent 5,877,305, Huston et al, publish the known sequence of human HER2 tumor antigen SEQ ID NO:2 that is 100% identical to instant SEQ ID NO:1 (see sequence alignment below), and teach producing therapeutic antibodies against HER2 for cancer treatment (Summary of Invention).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the HER2 sequenced by the cited combined references to comprise instant SEQ ID NO:1. One would have been motivated to and have a reasonable expectation of success to because US Patent 5,877,305, Huston et al published the known sequence of human HER2 expressed in cancers, and the combined references teach or demonstrate detecting known cancer-associated mutations in the HER2 sequence at serine position 310.
RESULT 1
US-08-356-786-2
(NOTE: this sequence has 173 duplicates in the database searched.
See complete list at the end of this report)
Sequence 2, US/08356786
Patent No. 5877305
GENERAL INFORMATION
APPLICANT: Huston, James S.
APPLICANT: Oppermann, Hermann
APPLICANT: Houston, L. L.
APPLICANT: Ring, David B.
TITLE OF INVENTION: Biosynthetic Binding Protein for Cancer
TITLE OF INVENTION: Marker
CURRENT APPLICATION NUMBER: US/08/356,786
PRIOR APPLICATION NUMBER: 07/831,967
PRIOR FILING DATE: 06-FEB-1992
NUMBER OF SEQ ID NOS: 16
SEQ ID NO 2
LENGTH: 1255
TYPE: PRT
Query Match 100.0%; Score 6815; Length 1255;
Best Local Similarity 100.0%;
Matches 1255; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MELAALCRWGLLLALLPPGAASTQVCTGTDMKLRLPASPETHLDMLRHLYQGCQVVQGNL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MELAALCRWGLLLALLPPGAASTQVCTGTDMKLRLPASPETHLDMLRHLYQGCQVVQGNL 60
Qy 61 ELTYLPTNASLSFLQDIQEVQGYVLIAHNQVRQVPLQRLRIVRGTQLFEDNYALAVLDNG120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ELTYLPTNASLSFLQDIQEVQGYVLIAHNQVRQVPLQRLRIVRGTQLFEDNYALAVLDNG120
Qy 121 DPLNNTTPVTGASPGGLRELQLRSLTEILKGGVLIQRNPQLCYQDTILWKDIFHKNNQLA180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 DPLNNTTPVTGASPGGLRELQLRSLTEILKGGVLIQRNPQLCYQDTILWKDIFHKNNQLA180
Qy 181 LTLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGCARCKGPLPTDCCHEQC240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LTLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGCARCKGPLPTDCCHEQC240
Qy 241 AAGCTGPKHSDCLACLHFNHSGICELHCPALVTYNTDTFESMPNPEGRYTFGASCVTACP300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 AAGCTGPKHSDCLACLHFNHSGICELHCPALVTYNTDTFESMPNPEGRYTFGASCVTACP300
Qy 301 YNYLSTDVGSCTLVCPLHNQEVTAEDGTQRCEKCSKPCARVCYGLGMEHLREVRAVTSAN360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 YNYLSTDVGSCTLVCPLHNQEVTAEDGTQRCEKCSKPCARVCYGLGMEHLREVRAVTSAN360
Qy 361 IQEFAGCKKIFGSLAFLPESFDGDPASNTAPLQPEQLQVFETLEEITGYLYISAWPDSLP420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 IQEFAGCKKIFGSLAFLPESFDGDPASNTAPLQPEQLQVFETLEEITGYLYISAWPDSLP420
Qy 421 DLSVFQNLQVIRGRILHNGAYSLTLQGLGISWLGLRSLRELGSGLALIHHNTHLCFVHTV480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 DLSVFQNLQVIRGRILHNGAYSLTLQGLGISWLGLRSLRELGSGLALIHHNTHLCFVHTV480
Qy 481 PWDQLFRNPHQALLHTANRPEDECVGEGLACHQLCARGHCWGPGPTQCVNCSQFLRGQEC540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 PWDQLFRNPHQALLHTANRPEDECVGEGLACHQLCARGHCWGPGPTQCVNCSQFLRGQEC540
Qy 541 VEECRVLQGLPREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFCVARC600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 VEECRVLQGLPREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFCVARC600
Qy 601 PSGVKPDLSYMPIWKFPDEEGACQPCPINCTHSCVDLDDKGCPAEQRASPLTSIISAVVG660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 PSGVKPDLSYMPIWKFPDEEGACQPCPINCTHSCVDLDDKGCPAEQRASPLTSIISAVVG660
Qy 661 ILLVVVLGVVFGILIKRRQQKIRKYTMRRLLQETELVEPLTPSGAMPNQAQMRILKETEL720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 ILLVVVLGVVFGILIKRRQQKIRKYTMRRLLQETELVEPLTPSGAMPNQAQMRILKETEL720
Qy 721 RKVKVLGSGAFGTVYKGIWIPDGENVKIPVAIKVLRENTSPKANKEILDEAYVMAGVGSP780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 RKVKVLGSGAFGTVYKGIWIPDGENVKIPVAIKVLRENTSPKANKEILDEAYVMAGVGSP780
Qy 781 YVSRLLGICLTSTVQLVTQLMPYGCLLDHVRENRGRLGSQDLLNWCMQIAKGMSYLEDVR840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 YVSRLLGICLTSTVQLVTQLMPYGCLLDHVRENRGRLGSQDLLNWCMQIAKGMSYLEDVR840
Qy 841 LVHRDLAARNVLVKSPNHVKITDFGLARLLDIDETEYHADGGKVPIKWMALESILRRRFT900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 LVHRDLAARNVLVKSPNHVKITDFGLARLLDIDETEYHADGGKVPIKWMALESILRRRFT900
Qy 901 HQSDVWSYGVTVWELMTFGAKPYDGIPAREIPDLLEKGERLPQPPICTIDVYMIMVKCWM960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 HQSDVWSYGVTVWELMTFGAKPYDGIPAREIPDLLEKGERLPQPPICTIDVYMIMVKCWM960
Qy 961 IDSECRPRFRELVSEFSRMARDPQRFVVIQNEDLGPASPLDSTFYRSLLEDDDMGDLVDA 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 961 IDSECRPRFRELVSEFSRMARDPQRFVVIQNEDLGPASPLDSTFYRSLLEDDDMGDLVDA 1020
Qy 1021 EEYLVPQQGFFCPDPAPGAGGMVHHRHRSSSTRSGGGDLTLGLEPSEEEAPRSPLAPSEG 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1021 EEYLVPQQGFFCPDPAPGAGGMVHHRHRSSSTRSGGGDLTLGLEPSEEEAPRSPLAPSEG 1080
Qy 1081 AGSDVFDGDLGMGAAKGLQSLPTHDPSPLQRYSEDPTVPLPSETDGYVAPLTCSPQPEYV 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1081 AGSDVFDGDLGMGAAKGLQSLPTHDPSPLQRYSEDPTVPLPSETDGYVAPLTCSPQPEYV 1140
Qy 1141 NQPDVRPQPPSPREGPLPAARPAGATLERPKTLSPGKNGVVKDVFAFGGAVENPEYLTPQ 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1141 NQPDVRPQPPSPREGPLPAARPAGATLERPKTLSPGKNGVVKDVFAFGGAVENPEYLTPQ 1200
Qy 1201 GGAAPQPHPPPAFSPAFDNLYYWDQDPPERGAPPSTFKGTPTAENPEYLGLDVPV 1255
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1201 GGAAPQPHPPPAFSPAFDNLYYWDQDPPERGAPPSTFKGTPTAENPEYLGLDVPV 1255
Response to Arguments
7. Applicants argue that the secondary reference, Huston, fails to remedy the deficiencies argued for the cited combined references above.
8. The arguments have been considered but are not persuasive. The cited combined references do not have the deficiencies argued by Applicants for the reasons stated above.
9. All other rejections recited in the Office Action mailed March 5, 2026 are hereby withdrawn in view of amendments.
10. Conclusion: No claim is allowed.
Conclusion
11. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Laura B Goddard/Primary Examiner, Art Unit 1642
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