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 .
Continued Examination Under 37 CFR 1.114
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 20, 2026 has been entered. Claim 31-43, 45, 50-54, 57, 60-68, 71, 73-75 are now pending. Claims 31, 54, 60 are amended. Claims 33-36, 60, 74 remain withdrawn. Claims 31, 32, 37-43, 45, 50-54, 57, 61-68, 71, 73, 75 are 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
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. Claim 53 is 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 53 depends from claim 50. Claim 50 recites that the subject is undergoing (present tense) or has undergone (past tense) a treatment with a non-HER2 therapeutic agent or therapeutic modality, indicating that subjects are of two populations: (1) still undergoing treatment with a non-HER2 therapeutic agent or therapeutic modality; or (2) previously received treatment with a non-HER2 therapeutic agent or therapeutic modality, indicating the treatment was stopped before conducting the claimed method. Claim 53 recites that the non-HER2 therapeutic agent or therapeutic modality is discontinued responsive to detecting the HER2 mutation in the sample. It is unclear how the non-HER2 therapeutic agent or therapeutic modality is discontinued after detecting HER2 mutation in the sample when it was already discontinued before testing for population (2). Clarification is required.
3. Claim 54 is 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 54 depends from claim 50, and claim 50 depends from claim 31. Claim 54 recites the method of claim 50 further comprising administering the identified treatment to the subject after cessation of the non-HER2 therapeutic agent or therapeutic modality. As stated above, claim 50 includes a population of subjects still undergoing non-HER2 therapeutic agent or therapeutic modality, therefore treatment was never stopped. There is no method step requiring cessation of the non-HER2 therapeutic agent or therapeutic modality in any prior claims. There is insufficient antecedent basis for this limitation in the claim.
Maintained Rejection
4. Claims 31, 32, 37-43, 45, 50-54, 57, 61-68, 71, 73, and 75 remain 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 step c) identifying a treatment for the micropapillary carcinoma in the subject “based on the micropapillary histology, the presence of the HER2 mutation, and the lack of gene amplification or overexpression of a HER2 gene or gene product,” but does not indicate what basis is used to identify a treatment and does not indicate a treatment was identified for which subjects based on micropapillary histology, the presence of the HER2 mutation, and the lack of gene amplification or overexpression of a HER2 gene or gene product. Identifying a treatment based how on micropapillary histology, the presence of the HER2 mutation, and the lack of gene amplification or overexpression of a HER2 gene or gene product? The scope of the treatment identified for which subjects, is unclear. Given the above reasons, the metes and bounds of the claims cannot be determined.
Examiner Suggestion: Delete steps c) and d) and amend step e) to recite administering treatment to the subject, wherein treatment is selected from the group consisting of a kinase inhibitor,….and a HER2 cellular immunotherapy”.
Response to Arguments
5. Applicants argue that the claims as amended are clear. Applicants argue that the basis upon which treatment is identified is the micropapillary histology, presence of specified HER2 mutation, and lack of HER2 amplification/overexpression.
6. The arguments have been considered but are not persuasive. The claims recite that the treatment is identified “based on” micropapillary histology, presence of specified HER2 mutation, and lack of HER2 amplification/overexpression, but still does not indicate how it is based on micropapillary histology, presence of specified HER2 mutation, and lack of HER2 amplification/overexpression. Is a treatment identified or not? The scope of the treatment identified for which subjects, is unclear.
Maintained Rejections
(addressing amendments – adding Banerji reference)
Claim Rejections - 35 USC § 103
(Amendments addressed in rejection - additional Bannerji reference added)
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.
7. 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 HER2 activating mutations, including S310F, and detect lack of HER2 gene amplification/overexpression in a 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, 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 with a HER2-activating mutation, such as S310F, 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
8. Applicants state that claim 31 as amended requires detecting the presence of micropapillary histology, the claimed HER2 mutation, and lack of HER2 amplification/overexpression. Applicants state that the claimed method requires treatment identified and administered. Applicants argue that the cited combined reference of the rejection fail to teach or suggest detecting both the presence of the HER2 mutation and lack of HER2 gene amplification/overexpression in a sample from a subject identified as having carcinoma of the urinary tract, bladder, or urothelial cells with micropapillary histology. Applicants argue that the combination of references fails to provide explicit guidance for the genomic/proteomic profile described by the claims and identifying a treatment for micropapillary carcinoma based on all three of the claimed characteristics. Applicants argue that providing motivation to screen for one of the recited HER2 mutations and lack of HER2 gene amplification/overexpression in a variety of cancers does not provide any reasonable expectation of success to identify both of these characteristics in a single micropapillary carcinoma of the urinary tract, bladder, or urothelial cells. Applicants argue there is no expectation to find these characteristics in the claimed micropapillary cancer because at the time the instant specification was filed, only 1.3% of all urinary tract cancers in the comprehensive Catalogue of Somatic Mutations in Cancer (COSMIC) database were known to harbor mutations in HER2 (see as-filed specification p. 66). Applicants argue that even if screening method suitable for identifying HER2 mutation and/or lack of HER2 gene amplification/overexpression were known in the art at the time of filing, and one would be motivated to extend their screening methods to other cancers (as stated in the rejection of record), there was no reasonable expectation of successfully identifying a carcinoma of the urinary tract, bladder, or urothelial cells with micropapillary histology, one of the recited HER2 mutations, and a lack of HER2 gene amplification or overexpression.
10. 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.
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).
The cited prior art recognizes that HER2-driven cancers include micropapillary variants of urothelial carcinoma and that they are in need to HER2-targeted therapy, providing motivation and reasonable expectation of success to extend screening methods to these cancers to characterize the HER2 driving mechanism and treatment susceptibility.
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 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.
Examiner maintains the cited prior art provides motivation and reasonable expectation of success to extend their screening methods to other cancers, especially known HER2-driven cancers including micropapillary variants of urothelial carcinoma, and to identify and administer anti-HER2 antibody (trastuzumab) or kinase inhibitors for cancers harboring the HER2 activating mutations known to be susceptible to these HER2-inhibiting treatments.
9. 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
10. Applicants argue that the secondary reference, Huston, fails to remedy the deficiencies argued for the cited combined references above.
11. 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.
12. Conclusion: No claim is allowed. The rejection of claims under 35 USC 101 is withdrawn in view of amendments to claim 31 requiring administering particular therapies inhibiting HER2 listed in claim 31, thereby practically applying the judicial exception with administering a particular therapy.
13. 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