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
Amendments and Claim Status
The following amendment filed on 11/12/2025 is acknowledged and entered.
Claims 1, 16, and 18 are amended;
Claims 23-26 are added;
Claims 14, 21, and 22 remain withdrawn according to 37 CFR § 1.142(b), as being drawn to a non-elected invention and species;
Claim 25 is withdrawn pursuant to 37 CFR § 1.142(b), as it does not read on the elected species;
Claims 1-26 are pending.
Information Disclosure Statement
An Information Disclosure Statement has not been submitted.
Response to arguments
Applicant’s arguments filed 11/12/2025 with respect to the objection to the specification, and claim rejections under 35 U.S.C. §§ 112(a), 112 (b), and 103 have been fully considered.
With respect to the objection the abstract of the specification, the amendment to the abstract is insufficient to overcome the objection. With respect to the amendment, Applicant recites wherein, “for treating diseases associated ErbBs.” This is improper grammar, and should be amended to: “for treating diseases associated with ErbBs.” Secondly, the recitation of “the compound” and “pharmaceutical composition” should be plural so that it can logically flow from the previous sentence, i.e. “the compounds” and “pharmaceutical compositions.” Furthermore, the recitation of “the use of the compound in the pharmaceutical composition for treating” does not recite the steps of the process, i.e. administering the compounds or pharmaceutical compositions to a subject in need thereof, as required by MPEP § 608.01(b). Lastly, a suggested amendment to the language “the use of the compound.. for treating” would be “a method of treatment” instead of the language presently used by Applicant. As such, the objection to the abstract is maintained.
With respect to the rejection of claims 1-13 and 15-20 are rejected under 35 U.S.C. § 112 (a), the claim amendments 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.
Applicant further argues that experimental data for a single HER2-driven cancer is sufficient because HER2 involvement is common across the claimed disease states.
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.
Applicant further argues that undue experimentation would not be required because a person of ordinary skill in the art could reasonably apply known HER2 biology to the claimed method across cancers.
Applicant’s argument is not persuasive because the specification lacks teachings regarding appropriate patient populations, dosing regimens, biomarkers, treatment endpoints, or therapeutic efficacy for each claimed cancer. 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.
Finally, Applicant argues that the breadth of claims is justified by the supporting literature.
Applicant’s argument is unconvincing, because the breadth of prior art literature does not substitute for a requirement for enablement in the specification. According to searches of the prior art, the literature does not disclose the claimed compounds, nor do they teach methods of treating the full scope of claimed cancers using those compounds. As such, the specification is not commensurate in scope with the claims, which encompass the treatment of numerous cancers without corresponding enabling disclosure.
Accordingly, the rejection under 35 U.S.C. § 112(a) is hereby maintained.
With respect to the rejection of claims 1-13 and 15-20 under 35 U.S.C. § 112(b) as being indefinite for the use of a relative term, the amendment of claim 1 to list the specific diseases which are associated with HER2 is sufficient to overcome the rejection. As such, the rejection has been withdrawn.
With respect to the rejection of claims 1-13 and 15-20 under 35 U.S.C. § 112(b) as being incomplete for omitting essential elements, the amendment to claim 1 in listing the substituents of R5 is sufficient to overcome the rejection. As such, the rejection has been withdrawn.
With respect to the rejection of claims 16 and 18 under 35 U.S.C. § 112(b) for using the phrase “such as”, the amendment of claims 16 and 18 striking the language “such as” as well as the listings is sufficient to overcome the rejection. As such, the rejection has been withdrawn.
With respect to the rejection of claims 1-13, 15, 16, 18, 19, and 20 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 insufficient to overcome the rejection. The arguments made by applicant are herein addressed as follows.
Applicant argues that Lyssikatos fails to teach or suggest that the R3 substituent should be connected at the 5’ position of the quinazoline ring, rather than the 6’ position, and therefore does not render the amended claims obvious. Applicant argues that Lyssikatos provides no specific motivation to place the heterocycle substituent at the claimed 5’ position.
Applicant’s argument is found unpersuasive because Lyssikatos broadly teaches quinazoline with substituents at positions corresponding to those claimed (5’ position), and expressly encompasses positional variance within its disclosure. In the original rejection, this very point was addressed and compounds 111 and 112 on page 126 were specifically referenced for this point. For clarity of the record, said compounds have been included herein explicitly in order to demonstrate that the 5’ position substitution is disclosed within the referenced teachings (see Figure 1). Lyssikatos provides motivation through the disclosure of multiple quinazoline derivatives substituted at the same position (5’) as that of the instant claims (see Figure 1). Moreover, according to MPEP § 2123,
Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994).. "The prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
As such, the disclosure of compounds exhibiting substitution at the 5’ position clearly demonstrate that the substitution at this position is taught by the prior art, and has been executed by specific embodiments 110-112.
Figure 1. Compounds demonstrating 5’ and 6’ substitution of quinazoline ring in Lyssikatos
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Fig 1. Compounds 109-112 which demonstrate 5’ and 6’ substitution of quinazoline ring, on page 126 of Lyssikatos
Applicant further argues that Lyssikatos does not expressly disclose the claimed method with the compounds as recited.
Applicant’s argument is found unpersuasive because Lyssikatos discloses a method of treating a hyperproliferative disease in a mammal, comprising the administration of the prior art compound (see claim 26 of the prior art). Specifically, Lyssikatos teaches wherein the hyperproliferative disease is breast cancer (paragraphs [00336]). Furthermore, Lyssikatos teaches the genus that encompasses the elected species of compound. Differences in substituents between the prior art compound and elected species are expressly taught, suggested, and rendered obvious by Lyssikatos, which discloses interchangeable substituents and synthetic routes leading to structurally similar compounds used for a common purpose, i.e., treating cancer.
With regard to the newly added claims, 23, 24, and 26, the teachings of Lyssikatos are further applied to the compounds listed, the claims are rejected as such.
Accordingly, the rejection is hereby maintained.
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 insufficient to overcome the rejection for the reasons set forth above.
Accordingly, the rejection is hereby maintained.
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 are withdrawn from further consideration pursuant to 37 CFR § 1.142(b), as being drawn to a non-elected invention and species. Claims 1-13,15-20, 23, 24, and 26 are being examined as they read on the elected species.
Abstract of the Disclosure
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
In chemical patent abstracts for processes, the type of reaction, reagents and process conditions should be stated, generally illustrated by a single example unless variations are necessary.
With respect to the amendment, Applicant recites wherein, “for treating diseases associated ErbBs.” Firstly, this amendment does not make grammatical sense, it should be amended to: “for treating diseases associated with ErbBs.” Secondly, the recitation of “the compound” and “pharmaceutical composition” should be plural so that it can logically flow from the previous sentence, i.e. “the compounds” and “pharmaceutical compositions.” Furthermore, the recitation of “the use of the compound in the pharmaceutical composition for treating” does not recite the steps of the process, i.e. administering the compounds or pharmaceutical compositions to a subject in need thereof, as required by MPEP § 608.01(b). Lastly, a suggested amendment to the language “the use of the compound.. for treating” would be “a method of treatment” instead of the language presently used by Applicant.
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
Claim Objections
Claims 1-13 and 15-20 are objected to for the following informalities:
Throughout all of the amended claims submitted on 11/12/2025, the text and structural formulas as presented are of insufficient resolution and clarity to permit proper examination. Specifically, portions of the claim language and accompanying chemical structures are blurred, pixelated, and or otherwise illegible, hindering the accurate interpretation of the claimed subject matter. Because of this, the OCR tool is unable to read and properly interpret the text of the claims. This objection has been necessitated by the amendment to the claims, filed 11/12/2025.
Claim Rejections - 35 U.S.C. § 112
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 1-13, 15-20, and 23 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.
Claim Rejections - 35 U.S.C. § 103
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 1-13, 15, 16, 18-20, 23, 24, and 26 are rejected under 35 U.S.C. § 103 as being unpatentable over Lyssikatos et al. (WO 2007059257 A2, published May 24, 2007), hereinafter Lyssikatos.
The instant claims are drawn to a method of treating a disease associated with HER2 in a subject, such as breast cancer, comprising the administration of compound of Formula (I), elected to be a compound found in Figure 2a, below.
Lyssikatos teaches novel inhibitors of type I receptor tyrosine kinases and related kinases, pharmaceutical compositions containing the inhibitors, and methods for preparing these inhibitors [0002] and [0007]. Lyssikatos teaches that these inhibitors are useful for the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals and especially in humans [0002]. Lyssikatos teaches that the type I receptor tyrosine kinase family consists of four closely related receptors: EGFR (ErbB1 or HER2), ErbB2 (HER2), ErbB3 (HER), and ErbB4 (HER4) [0003].
Lyssikatos specifically teaches that the compounds are inhibitors of ErbB and that the compounds are useful for inhibiting type I receptor tyrosine kinases, such as EGFR (HER1), ErbB2 (HER2), ErbB3 (HER3), ErbB4 (HER4), VEGFR2, Flt3 and FGFR [0042]-[0043]. Lyssikatos teaches methods of treating cancer, comprising administering to a mammal in need thereof a therapeutic amount of a composition comprising a compound of formula I [00334]. Lyssikatos specifically teaches the cancer to be treated is breast cancer [00336]. Lyssikatos specifically teaches that the compounds are expected to be useful in the treatment of cancer by providing an anti-proliferative effect, particularly in the treatment of Class I receptor tyrosine kinase sensitive cancers such as cancers of the breast, lung, colon, rectum, stomach, prostate, bladder, pancreas and ovary [00330].
Lyssikatos further teaches that the compounds of Formula I may be used advantageously in combination with other known therapeutic agents such as the anti-erbB2 antibody trastumuzab, which is one of several inhibitors of the EGFR and the ErbB2 signaling pathway that have demonstrated clinical efficacy in cancer treatment, known as HERCEPTIN®, a humanized version of anti-ErbB2 monoclonal antibody, which was approved for use in breast cancer in the United States in 1998 ([0006], [0014], [00346]-[00347], [00352]).
Lyssikatos teaches a method of treating a proliferative disease in a mammal (claim 26), comprising the administration of a compound of Formula (I), shown in Figure 2.
Regarding claims 1-8, the elected species (Figure 2a) is directly encompassed by the compound of Formula (I) taught by Lyssikatos (Figure 2b, claim 1 of Lyssikatos) to inhibit HER2 (paragraph [0043]) according to Figure 2, wherein,
B is a fused 6-membered aryl ring
A is O
E is as shown in Figure 2c, wherein D1 and D3 are N and D2 is CR19, wherein R19 is H
R1 is H
R2 is CH3 and n is 1
R3 is OR15 and m is 2, wherein R15 is CH3 and heterocycyl substituted with Fluoro and alkyl
Figure 2. Elected species compared to Lyssikatos teachings
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Figure 2. a) Elected species; b) Lyssikatos Formula (I); c) Lyssikatos E substituent
The elected species is further-rejected using compound 105, explicitly synthesized by Lyssikatos, also known as CAS Registry Number: RN 937264-44-3 [Database Registry Chemical Abstracts Service, Columbus, Ohio, Accession No. RN 937264-44-3, Entered STN: 14 Jun 2007], as shown in Figure 3.
Figure 3. Elected species compared to prior art compound
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Figure 3. a) Elected species; b) Lyssikatos CAS Registry Number RN 937264-44-3
In comparison, the prior art compound is similar, but does not directly anticipate the elected species. However, all of the differences in substituents between the prior art compound and elected species are taught and encompassed by claim 1 of Lyssikatos, as described above. Furthermore, with respect to the substitution position of the heterocycle substituent 5’ position, Lyssikatos synthesizes several compounds using substitution at the very same position of the heterocycle in the instantly claimed elected species (see compounds 111 and 112, page 126). Therefore, the person of ordinary skill in the art following the teachings of Lyssikatos would have contemplated making the elected species, as all of the substitutions are encompassed by the teachings of the prior art.
Further regarding claims 1 and 2, and in the interest of compact prosecution, the search of the Markush-type claim has been extended to a single species beyond the above-rejected elected species. The instant claims are thus, further-rejected. Lyssikatos teaches compound 167 (page 133), also known as CAS Registry Number: RN 937265-04-8. [Database Registry Chemical Abstracts Service, Columbus, Ohio, Accession No. RN 937265-04-8, Entered STN: 14 Jun 2007]. The prior art compound renders obvious the instant claims wherein,
Figure 4. Prior art compound (non-elected species) compared to the instantly claimed
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Figure 4. a) Lyssikatos CAS Registry Number RN 937265-04-8; b) instantly claimed Formula (I)
G is N
R1 is H
R2 is CH3
A and W are O
E is as in Figure 4c, wherein X1, X3, and X4, are N and X2 is CR
Y is a C1 alkylene
R3 is a 3-membered saturated unsubstituted carbocyclyl
i and j are 0
Further regarding claim 1, wherein the substitution of R3 of the instantly claimed Formula (I) is at an adjacent position, this is considered a positional isomer of the prior art compound. Regarding positional isomers, the courts have stated:
[c]ompounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious) (see MPEP § 2144.09).
Therefore a person of ordinary skill in the art would have found it obvious to change the location of R3 substituent to arrive at the instantly claimed compound in a method of treating diseases related to HER2, as the resulting change in position would have resulted in a homologous structure, considered by the courts to be prima facie obvious.
Regarding claim 9, Lyssikatos teaches the use of crystallization from a solvent to provide the compounds (paragraph [00321]).
Regarding claim 10, Lyssikatos teaches the compound of Formula (I) in combination with a pharmaceutically acceptable carrier (claim 23).
Regarding claim 11, Lyssikatos teaches the combination of the compound of Formula (I) with other known therapeutic agents (paragraph [0014]).
Regarding claim 12, Lyssikatos teaches the combination of the compound of Formula (I) with anti-tumor agents (paragraph [00349]).
Regarding claims 13 and 15, Lyssikatos teaches the combination of the compound of Formula (I) with trastumuzab (paragraph [00352]). Aside from this direct teaching, it is also considered prima facie obvious to combine equivalents used for the same purpose. According to MPEP § 2144.06 (I), combining equivalents known for the same purpose is rendered obvious. The courts have said,
It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re KHER2hoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.).
Therefore a person of ordinary skill in the art would have found it prima facie obvious to combine the compound of Formula (I) with trastumuzab, as they are both known to treat cancer according to the teachings of the prior art.
Regarding claim 16, Lyssikatos teaches breast cancer as a target for the compound of Formula (I) (paragraph [0013]).
Regarding claim 18, Lyssikatos teaches the compound of Formula (I) to be used in a method of administering to a warm-blooded animal (paragraph [0011]), or treating a human subject (paragraph [0013]).
Regarding claim 19, Lyssikatos teaches the compound of Formula (I) used to treat “abnormal cell growth” that proliferate by expressing a mutated tyrosine kinase (paragraph [00334]). As HER2 is known to be a ErbB2 tyrosine kinase (paragraph [0043]), the disclosure suggests that a mutated HER2 may also be treated.
Regarding claim 20, the ability of the compound to cross the blood brain barrier is an inherent property of the compound. Regarding inherent properties, the courts have stated,
In re Reynolds, 443 F.2d 384, 170 USPQ 94 (CCPA 1971); In re Smythe, 480 F. 2d 1376, 178 USPQ 279 (CCPA 1973); Yeda Research and Dev. Co. v. Abbott GMBH & Co., 837 F.3d 1341, 120 USPQ2d 1299 (Fed. Cir. 2016) ("Under the doctrine of inherent disclosure, when a specification describes an invention that has certain undisclosed yet inherent properties, that specification serves as adequate written description to support a subsequent patent application that explicitly recites the invention’s inherent properties." See MPEP § 2163.07 (a).
Thus, all compounds within Formula (I) are presumed to share the same properties. Therefore, the compounds detailed by Lyssikatos will necessarily cross the blood-brain barrier, although not explicitly taught within the reference.
Regarding claims 23, 24, and 26, these are merely stereoisomers of the elected species, which result in compounds of similar structure and property. With respect to stereoisomerism, the courts have stated,
it is noted that in Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293 (Fed. Cir. 2007), the court also relied on the settled principle that in chemical cases, structural similarity can provide the necessary reason to modify prior art teachings. The Federal Circuit also addressed the kind of teaching that would be sufficient in the absence of an explicitly stated prior art-based motivation, explaining that an expectation of similar properties in light of the prior art can be sufficient, even without an explicit teaching that the compound will have a particular utility. The Federal Circuit cautioned that requiring such a clearly stated motivation in the prior art to isolate 5(S) ramipril ran counter to the Supreme Court' s decision in KSR. The court stated" [r]enquiring an explicit teaching to purify the 5(S) stereoisomer from a mixture in which it is the active ingredient is precisely the sort of rigid application of the TSM test that was criticized in KSR. Id. at 1301 (See MPEP § 2143).
As such, the stereoisomers are deemed to be obvious variants due to their structural similarity, an expectation of similar properties.
Claim 17 is rejected under 35 U.S.C. § 103 as being unpatentable over Lyssikatos, as applied to claims 1-13, 15, 16, 18- 20, 23, 24, and 26 above and further in view of Scott and Kesari (Am J Cancer Res. Volume 3, Issue 2, pg.117-126, published April 3, 2013).
Claim 17 of the instant application is further drawn to treating breast cancer with brain and leptomeningeal metastasis.
Lyssikatos is as set forth above.
Lyssikatos does not specifically teach treating the breast cancer with brain and leptomeningeal metastasis.
However, it is well-known in the art that HER2 breast cancer is capable of metastasizing to the brain, and capable of leptomeningeal metastasis (LM), according to the teachings of Scott and Kesari (page 119). Scott and Kesari teach wherein survival following a diagnosis of LM is unacceptably short (page 122), providing direct motivation to target LM with a method comprising the administration of a compound of Formula (I).
As the compounds taught by Lyssikatos, which render obvious the compounds administered in the instantly claimed method (according to the above rejection), are inhibitors of HER2 implicated in hyperproliferative cancers such as breast cancer, it would be obvious to treat the same cancer that has metastasized using the same compounds. Therefore, it would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the claimed invention to use the compounds of Formula (I) in a method to treat HER2 breast cancer with brain and leptomeningeal metastasis, as HER-2 has been associated with an increased incidence of central nervous system metastasis compared to other molecular subtypes (page 119), and there is an urgent need for such methods of treatment.
Thus claim 17 is rendered obvious in view of the cited prior art teachings.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623