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 .
Priority
The instant application, filed 08/11/2022, is a continuation-in-part (CIP) of U.S. Application No. 17/029,074, filed 9/23/2020, which is a Continuation of U.S. Application No. 16/910,267, filed 06/24/2020, which is a Continuation of PCT/CN2019/085949, filed 05/08/2019. Acknowledgment is made of Applicant's claim for foreign priority based on an application filed in China on 05/08/2018. Receipt is acknowledged of certified copies of papers required by 37 CFR § 1.55
Continued Examination Under 37 CFR § 1.114
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and the fee set forth in 37 CFR § 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR § 1.114.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 04/30/2026 has been entered.
Claim Status
Claims 1-26 are pending.
Response to Arguments
With respect to the objection the abstract of the specification, the amendment to the abstract is sufficient to overcome the objection. As such, the objection to the abstract is withdrawn.
With respect to the rejection of claims 1-13 and 15-20 are rejected under 35 U.S.C. § 112 (a), the arguments made by Applicant are insufficient to overcome the rejection. The arguments made by applicant are herein addressed as follows.
Applicant argues that the specification enables treatment of multiple cancers because the state of the art establishes a nexus between HER2 inhibition in the treatment of these diseases, as supported by the references listed in table A.
Applicant’s argument is unconvincing because the cited references suggest that HER2 may be expressed, overexpressed, or prognostic in variation cancers. However, they do not teach or suggest administration of the presently claimed compounds of Formula (I) are effective to treat each of the recited cancers. Enablement requires more than identification of a biological target. It requires teaching a person of ordinary skill in the art how to use the claimed compounds to achieve the claimed therapeutic effect without undue experimentation, which the specification fails to provide for cancers beyond HER2+ breast cancer. Furthermore, the previously referenced teachings of McKean and Yan are centered on the very specific point of the rejection: that HER2 drives cancer through distinct mechanisms that vary by cancer type. As such, HER2 is not a uniform biological target which a single therapy can treat across different disease contexts. Applicant has not addressed the teachings of neither McKean nor Yan in their arguments, which specifically demonstrate that treatment in a single disease context does not guarantee success in another disease context which implicates HER2.
Applicant further argues that the absence of specific dosing regimens or biomarkers for each cancer experimentation does not constitute undue experimentation across the various cancer types claimed.. Applicant argues that the specification provides a robust “proof of concept” that a compound of Formula (I) is capable of treating HER2-driven diseases.
Applicant’s argument is unconvincing because the assertion improperly assumes therapeutic predictability across distinct cancer types. The specification provides an enabling support for only HER2+ breast cancer. It does not disclose data, working examples, or guidance demonstrating that inhibition of HER2 using the claimed compounds would treat gastric, colorectal, pancreatic, ovarian, lung, or any other cancers. According to MPEP § 2164.03,
The scope of the required enablement varies inversely with the degree of predictability involved. A single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements. In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971). However, in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required.
Given the recognized heterogeneity of HER2 signaling, expression levels, mutation status, and tumor biology across cancer types, the claim scope is not enabled by a single disease-specific example. The specification lacks teachings regarding appropriate patient populations, dosing regimens, biomarkers, treatment endpoints, or therapeutic efficacy for the instantly claimed cancers. According to MPEP § 2164.06,
The quantity of experimentation needed to be performed by one skilled in the art is only one factor involved in determining whether "undue experimentation" is required to make and use the invention. "[A]n extended period of experimentation may not be undue if the skilled artisan is given sufficient direction or guidance." In re Colianni, 561 F.2d 220, 224, 195 USPQ 150, 153 (CCPA 1977). "‘The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed.’" In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) (citing In re Angstadt, 537 F.2d 498, 502-04, 190 USPQ 214, 217-19 (CCPA 1976)). Time and expense are merely factors in this consideration and are not the controlling factors. United States v. Telectronics Inc., 857 F.2d 778, 785, 8 USPQ2d 1217, 1223 (Fed. Cir. 1988), cert. denied, 490 U.S. 1046 (1989).
Absent guidance on essential teachings such as patient populations, dosing, biomarkers, treatment endpoints, and therapeutic efficacy, a skilled artisan would be required to engage in extensive trial and error experimentation to determine whether the claimed compounds are effective in each cancer type—constituting undue experimentation. The current state of the art as outlined by Yan specifically demonstrates that HER2 treatments are not widely applicable across multiple cancer types which implicate HER2, rendering applicant’s argument moot.
Accordingly, the rejection under 35 U.S.C. § 112(a) is hereby maintained.
With respect to the rejection of claims 1-13, 15, 16, 18-20, 23, 24, and 26 under 35 U.S.C. § 103 as being unpatentable over Lyssikatos et al. (WO 2007059257 A2, published May 24, 2007), hereinafter Lyssikatos, the claim amendments and arguments made by Applicant are sufficient to overcome the rejection. Specifically, reconsideration of the arguments of obviousness in light of the substitution pattern of the compounds of the prior art has been made. The compounds of the instant disclosure are not deemed to be obvious over the prior art compounds, specifically because of the substitution at the 5’ position, which in the disclosure by Lyssikatos is generally a hydrocarbon chain, and not a heterocycle, as instantly claimed.
Upon further examination and consideration, the elected compound, as well as the genus encompassing the elected compound is deemed to make a contribution over the prior art.
Accordingly, the rejection is hereby withdrawn.
With respect to the rejection of claim 17 under 35 U.S.C. § 103 as being unpatentable over Lyssikatos in view of Scott and Kesari (Am J Cancer Res. Volume 3, Issue 2, pg.117-126, published April 3, 2013), the claim amendments and arguments made by Applicant are sufficient to overcome the rejection for the reasons set forth above.
Accordingly, the rejection is hereby withdrawn.
Thus, all arguments presented by Applicants have been addressed and are found unpersuasive for the reasons presented herein and in the previous non-final rejection.
Status of Claims
Claims 1-26 are pending in the instant application. Claims 14, 21, 22, and 25 were previously withdrawn from further consideration pursuant to 37 CFR § 1.142(b), as being drawn to a non-elected invention and species. In view of the allowability of the elected compounds, claims 14 and 25 are hereby rejoined and fully examined for patentability under 37 CFR § 1.104. Claims 21 and 22 remain withdrawn from consideration pursuant to 37 CFR § 1.142(b), as being drawn to a non-elected invention. As such, claims 1-20, and 23-26 are being examined on the merits as they read on the elected invention.
Claim Rejections - 35 U.S.C. § 112 (a)
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-20, and 23-26 are rejected under 35 U.S.C. § 112 (a), or 35 U.S.C. § 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating HER2+ breast cancer in a subject comprising the administration of a compound of Formula (I), it does not reasonably provide enablement for a method of treatment of any other cancer including gastric, colorectal, pancreatic, prostate, bladder, ovarian, and lung cancer (including non-small cell lung cancer), or a disease associated with HER2 comprising the administration of a compound of Formula (I).
The instant specification fails to provide information that would allow the skilled artisan to fully practice the instant invention without undue experimentation. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: Claims 1-13, 15-20, and 23 of the instant application are drawn to a method of treating a disease associated with HER2 comprising the administration of a compound of Formula (I). The claims are further drawn to the treatment of a disease associated with HER2 such as breast, gastric, colorectal, pancreatic, prostate, bladder, ovarian, and lung cancers (including non-small cell lung cancer).
Breadth of the claims: The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims. The rejected claims are extremely broad. Applicant claims that the claimed compounds can be used to commonly treat breast, gastric, colorectal, pancreatic, prostate, bladder, ovarian, and lung cancers (including non-small cell lung cancer), or a disease associated with HER2. Thus the cited claims are deemed very broad since these claims read on treating a wide range of cancers and diseases.
State of the Prior Art: There are no art recognized methods that could be used to establish that the range of claimed cancers can be commonly addressed using the claimed therapeutic method. Additionally, the disclosure does not discuss, or demonstrate through working examples, a method using the claimed agents. Additionally, there are no art-recognized methods that could be used to identify subjects with the broad spectrum of claimed diseases and cancers and were commonly treated using the claimed methods.
Regarding common disease mechanisms and biomarkers, McKean et al. (Biomarkers in precision cancer immunotherapy: Promise and challenges. American Society of Clinical Oncology – Educational Book (2020), 40, p.e275-e291), hereinafter McKean, teaches that although ongoing studies and trials investigate the use of multiple biomarkers predictive of patient response or harm, none of these are comprehensive in predicting potential benefit (of treatment). This unmet need for validated biomarkers is largely secondary to a prohibitive complexity within tumor parenchyma and microenvironment, dynamic clonal and proteomic changes to therapy, heterogenous host immune defects, and varied standardization among sample preparation and reporting (abstract). McKean also teach that treatment failures occur even in ICI patient cohorts, despite respective prescreening with biomarkers such as PD-L1 tumor proportion scores (p.e275). Regarding gene expression profiles specifically, McKean teaches that an important concept within gene expression profiles is that the predictive utility of such algorithms may be dependent on individual therapy plans. Data suggest that signaling and transcriptomic patterns may correlate only with response to therapy of directly related targets (p.e280). Unrelated immune pathways may require separate and individualized gene expression assays for different therapies (p.e280). Therefore, the selection of a particular therapy for any specific type of cancer is unpredictable, and requires individualized assays that are fully described to achieve correlation.
Regarding HER2 diseases and cancers, the state of the prior art demonstrates that cancer is a highly heterogeneous group diseases the distinct molecular profiles, therapeutic targets, and clinical responses. Even for well-characterized oncogenic drivers, expression and therapeutic relevance may vary dramatically among cancer types. For example, Yan et al. (Canc Met Rev, Volume 34, pg. 157-164, published February 25, 2015), hereinafter Yan, evaluated HER2 status across a wide range of malignancies and found that HER2 overexpression was present in Celtic 4% bladder cancers, 10.5% of breast cancers, and 9.8% of gallbladder cancers, but was virtually absent in sarcomas, small cell lung cancers, glioblastomas, kidney cancers, and neuroendocrine tumors (pages 159-160, Table 1, Figure 1). Finally, Yan teaches wherein HER2 positivity was largely confined to malignancies of epithelial origin (page 161).
These teachings of variability underscore that therapeutic efficacy, observed in one cancer type, cannot reliably be extrapolated to unrelated malignancies—even when targeting the same molecular pathway. As such, one of ordinary skill in the art will recognize that the successful targeting of the given pathway in one tumor type provides little predictive value for other cancers without cancer-specific preclinical or clinical data. The art, therefore, teaches that broad cancer treatment assertions require substantial supporting evidence tailored to the biological characteristics of the cancer type, and thus does not support the instant claims.
Predictability/Unpredictability in the Art: It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the instant claimed invention is highly unpredictable since one skilled in the art would recognize that the recitation encompasses administering a compound of Formula (I) a range of cancers and HER2-related diseases, and thus encompass the treatment of a vast number of diseases. Thus, the skilled artisan would view that the treatment of the range of cancers and HER2 diseases encompassed by the claims, by administering a compound of Formula (I) is highly unpredictable.
Moreover, one of skill in the art would recognize that it is highly unpredictable in regard to therapeutic effects, side effects and toxicity generated by administering a singular class of compounds for treating all the disorders and diseases encompassed by the claims.
Guidance of the Specification/Working Examples: Applicant has provided working examples suggesting that compounds of claim 1 inhibit HER2 (Example 30, page 101). Applicant has further demonstrated that the compounds are capable of penetrating the blood-brain barrier in mammals in vivo (pages 104-105, Table 3). Finally, Applicant has demonstrated that the compounds are capable of treating breast cancer in a mammalian subject in vivo, using models of different tumor types of metastatic breast cancer models (page 106-107). The specification fails to provide sufficient evidence in support of the broad treatment of all the cancers and diseases related to HER2 as recited in the instant claims.
The Quantitation of Experimentation Required: In order to practice Applicants invention, it would be necessary for one to design and conduct an exhaustive amount of complex experiments to demonstrate that the large range of cancers and diseases can be treated by the administration of the compounds claimed. Therefore, in order to practice the claimed invention, the amount of experimentation required would be considered undue and burdensome.
In conclusion, Genentech, 108 F.3d at 1366, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”. A method for treating any disease associated with HER2 including all cancers other than breast cancer comprising administering a compound of Formula (I) is not enabled by the instant specification.
Correspondence
No claim is allowed.
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/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/VALERIE RODRIGUEZ-GARCIA/Primary Examiner, Art Unit 1621
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